The Role of Radiation in the Treatment of Hepatocellular Carcinoma

Abstract

In the past two decades, Radiation Therapy (RT) has become a cornerstone in the treatment of hepatocellular carcinoma (HCC), thanks to significant advancements in radiation delivery techniques. Previously, conventional RT played a limited role in treating HCC due to the high risk of toxicity to normal liver tissue. However, with the introduction of advanced techniques like stereotactic body radiation (SBRT), radiation has become more precise and targeted. SBRT, in particular, has emerged as a valuable locoregional therapy for HCC patients who are not candidates for surgery or other local treatments. This chapter aims to explore the evolving role of RT in multidisciplinary HCC care and highlight the technique, indications, and supporting literature for SBRT and proton therapy in early and intermediate HCC treatment. Additionally, we will delve into the palliative uses of RT for pain relief and tumor burden reduction in HCC patients. Finally, we will review recent advances in RT, such as adaptive radiotherapy and biological-guided radiotherapy, discussing their potential impact on HCC treatment.

1. Introduction

Crouched over a wooden table scattered with handwritten parchments, glass tubes, and metal coils in a dimly lit lab at the University of Würzburg, a German Scientist named Wilhelm Conrad Röntgen would accidentally discover the beams we would come to know now as X-rays. He would shut himself away in that lab for months, consumed by the mystery of these invisible rays, conducting a series of experiments to understand their nature and properties. His experiments would even include exposing his own wife’s hand to the beams in front of a film, which revealed the bones and structures within, marking a pivotal moment in the history of modern medicine (Figure 1).

Figure 1.

The first X-ray ever taken of the hand of Anna Bertha Ludwig, the wife of Röntgen. She would famously exclaim upon looking at the X-ray: “I have seen my death!”.

Röntgen’s groundbreaking discovery was met with immediate interest and excitement from the scientific community. Just 3 days after his report on these experiments was published in January of 1896, a woman with an ulcerating breast cancer would become the first recorded patient treated with radiation. This marked the beginning of a new era in cancer treatment, as physicians began to explore the therapeutic potential of X-rays in targeting and destroying cancerous cells.

Since then, X-rays have been applied to the treatment of benign and malignant tumors arising from every organ in the body. In the field of radiation oncology, X-ray-based therapies have evolved significantly, with the development of techniques such as intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and proton therapy, among others. Today, radiation therapy is one of the three key pillars of modern cancer treatment, alongside systemic drug therapies and surgery. Radiation oncology has become a subspecialty field of medicine, with highly trained clinicians prescribing, planning, and delivering highly conformal treatment to a plethora of cancers. For many tumors, radiation therapy (RT) has become a key part of the standard of care, such as in the adjuvant setting in breast cancer or in combination with hormonal therapy in high-risk prostate cancer. In the case of hepatocellular carcinoma (HCC), RT has emerged as an important treatment modality among nonoperative candidates, particularly with the advent of SBRT.

This chapter reviews the specific role that radiation therapy plays in the care of patients with HCC. It focuses on the current approach to HCC radiation therapy, namely, SBRT or proton therapy, and discusses recent advances that may shape the future of HCC treatment in the coming decades.

2. The role of radiation in the multidisciplinary treatment of cancer

As evident in this textbook, cancer treatment is typically multifaceted, necessitating input and collaboration from various physician specialists. RT is a pivotal component forming the third pillar in the essential triangle of cancer care, also including chemotherapy and surgery. RT employs high-energy photons directed at solid tumors to bolster locoregional control, inhibit the spread of primary tumors, prevent metastases, extend survival, and alleviate tumor-associated pain and discomfort. In this section, we will delve into the principles of radiobiology that underlie the use of RT and elaborate on some of its applications in clinical cancer care.

2.1 Rationale for treating solid tumors with ionizing radiation

To understand the role of RT in cancer care, it is important to first understand the mechanisms by which RT exerts its anticancer effects. Radiation itself can represent any form of high energy moving subatomic particles, whether this be high-energy photons, electrons, or protons. These can be given off by radioactive decay of elements such as radium or uranium, or, as is seen more often clinically, high-energy particles can be produced through the use of linear accelerators (LinAcs). LinAcs are capable of producing ionizing radiation by shooting high-energy electrons at high speeds onto an elemental target, such as tungsten, causing the production of high-energy photons via Bremstrahlung radiation, which are then directed at the tumor.

There are various forms of radiation present in our modern world, such as the waves utilized to enable the connectivity of our cellphones. However, such radiation is generally not harmful to human cells because it lacks sufficient energy to ionize atoms. High-energy radiation utilized in clinical oncology, on the other hand, possesses the capability to ionize atoms by removing valence orbital electrons, leaving behind charged radicals that are highly reactive with nearby atoms [1]. This ionizing energy can exert both direct and indirect effects on the DNA of exposed cells. Direct effects occur when atoms in the DNA of cells are directly ionized, whereas indirect effects stem from the generation of free hydroxide radicals that subsequently damage the nucleic acids of the cell [2]. Figure 2 illustrates the difference between direct and indirect DNA damage. Although both types of damage contribute to the clinical effects of radiation, indirect DNA damage typically prevails as the primary mechanism inducing cellular damage following radiation exposure [1].

Figure 2.

Indirect versus direct DNA insults. Here is shown the direct effect of high-energy photons on the DNA backbone and the production of hydroxide free radicals that can then go on to react with the nucleic acids. Adapted from Desouky et al. [1].

When interacting with DNA, hydroxide radicals have the potential to cause double-stranded DNA breaks, a severe form of damage that can induce cell death if present during the division process through a process called mitotic catastrophe [3]. Given the severe implication of double-strand DNA breaks, normal cells have numerous and redundant mechanisms to repair such damage including nonhomologous end joining or homologous recombination [3]. Malignant cells, in contrast, have typically undergone numerous mutations to circumvent cell cycle checkpoint controls, often leading to the loss of DNA repair mechanisms. While this benefits highly replicating tumors seeking to acquire more mutations for invasive and metastatic potential, it also means that the burden of DNA damage is significantly higher when exposed to DNA insults including radiation [3]. Therefore, chemotherapy and radiation therapy target DNA because they preferentially impact tumor cells. Conversely, normal cells in the body typically retain intact DNA repair mechanisms, enabling them to effectively repair DNA damage secondary to radiation exposure.

2.2 Fractionation

Radiation doses delivered in external beam radiation therapy (EBRT) are measured in units called Gray (Gy), representing the absorption of 1 Joule per kilogram of tissue. In RT, doses may range from as small as 8 Gy for palliative purposes to as large as 81 Gy for definitive therapy in cases of prostate cancers. Administering higher doses of radiation in a single exposure poses significant risk to the normal tissues surrounding the tumor, potentially causing extensive damage to these cells in addition to targeted tumor cell death. To mitigate such risks, fractionation, or the division of the total radiation dose into smaller, individual doses, is commonly employed. Each fraction represents a single exposure, with the dose per fraction determined by dividing the total dose to be delivered by the number of fractions.

Fractionation offers several key advantages. By allowing intervals between treatments, normal tissues can repair themselves, which reduces the side effects associated with a radiation dose. Recall that normal cells possess mechanisms to repair DNA and cellular damage caused by radiation exposure, whereas many of these repair mechanisms are defective or absent in tumor cells [4]. Fractionation capitalizes on this biological disparity to deliver potent doses to tumors while minimizing severe side effects in normal tissue.

In planning radiation schedules, the biological effective dose (BED) is utilized to quantify the biological impact of a specific radiation treatment [5]. This metric considers not only the physical dose but also the fractionation schedule and the type of radiation employed, providing a comprehensive assessment of the treatment’s biological efficacy. This concept helps provide a quantitative explanation for why the delivery of 30 Gy in 5 fractions can have a larger impact than the same dose divided over 10 or 15 fractions. A patient’s radiation team utilizes various techniques to ensure the BED will be maximally efficacious as well as inflict minimal side effects for the patient.

2.3 Application to multidisciplinary cancer care

Patients diagnosed with most types of cancer should be promptly referred to Radiation Oncology upon diagnosis, as consideration for RT should be an integral component of the multidisciplinary care approach. Upon referral, patients will undergo evaluation by a specialized physician experienced in the use of RT for cancer treatment. RT offers a variety of uses and endpoints for patients, including curative intent, locoregional control, or palliation. RT has proved extremely efficacious in all of these endpoints and directly contributes to cure in 40% of cases who achieve this outcome [6].

RT with curative intent may serve as the primary local treatment, aiming to eliminate cancer cells without resorting to surgical intervention, or it may be combined with surgery. When RT is employed to avoid surgery altogether, it is termed definitive. Definitive RT is applicable to various cancers such as prostate cancer, head and neck cancers, lung cancer, or HCC. In conjunction with surgery, RT can be either performed adjuvantly (i.e., administered after surgery) or neoadjuvantly (i.e., given before surgery to facilitate easier tumor resection). For instance, breast cancer frequently requires adjuvant radiation with postoperative surgical bed or chest wall RT considered standard of care for optimal outcomes. Similarly, tumors of the gastrointestinal tract, such as colon or esophageal tumors, may benefit from neoadjuvant therapy, where RT aids in shrinking tumors to improve outcomes of curative resection.

RT is often combined with chemotherapy or immunotherapy to enhance the likelihood of cure. The combination of modalities can lead to mutual sensitization. For example, RT’s killing of cancer cells can induce the release of tumor-associated antigens, which, when combined with tumor-directed immunotherapy, can augment the body’s ability to mount an immune response [7]. The synergy that can be achieved by these modalities is often utilized in the treatment of lung cancer for example, which has led to great strides in survival in lung malignancies [8]. Similarly, chemotherapies arrest a cancer cell’s capability to produce new nucleic acids or repair DNA damage, leading to sensitization of the tumor cells to DNA damage from RT.

A critical aspect often overlooked by care teams is the role of RT in the care of patients with primarily palliative intent. RT therapy is highly effective in alleviating pain secondary to metastatic disease, notably in bone metastases. RT can reduce tumor-associated pain in 60–80% of treated patients, with a third reporting complete resolution of pain [9]. Other palliative applications may include reducing focal symptoms from mass effect of intracranial tumors, reducing ulceration or from tumors invading the skin or GI tract, and even reducing airway compression or hemoptysis in lung malignancy [10].

Integrating RT into the treatment plan at the outset enhances cancer treatment strategies and overall outcomes for patients. This holds true in the case of HCC, as will be further discussed in subsequent sections of this chapter.

3. Stereotactic body radiation therapy in the treatment of hepatocellular carcinoma

While tumor resection and transplantation have been the mainstays of curative therapy for HCC for decades, only a minority of patients (approximately 30%) are eligible for these treatments due to factors such as cancer stage, tumor size, or baseline liver function [11]. Other local therapies, such as radiofrequency ablation and trans-arterial chemoembolization (TACE), can also be utilized in select patients, offering significant survival benefits [12]. RT was not historically as widely used as other modalities until the early 2000s in the treatment of HCC. Before the advent of modern conformal RT technologies, whole and partial EBRT for liver cancer was associated with high rates of radiation-induced liver disease (RILD) [13]. The risk of classical presentations of RILD appeared to be minimal when radiation doses were kept below certain thresholds, but such constraints made achieving tumoricidal doses challenging [13].

However, in the 1990s, the development of multi-leaf collimators combined with CT-based treatment planning enabled RT to become much more targeted, sparing surrounding tissues from a majority of the delivered dose [13]. With the development of three-dimensional conformal RT (3D RT), more targeted radiation planning could offer higher doses to the tumor while simultaneously sparing surrounding tissues from RILD-inducing exposure. Tumor immobilization techniques also advanced the field as now there was a method of controlling for the organ motion associated with breathing [13]. The University of Michigan group showed that with 3D RT conventional fractionation, they were able to reach doses from 60 to 90 Gy while respecting acceptable dose constraints to normal tissues in patients with unresectable intrahepatic tumors [14, 15].

With even further advancement, SBRT emerged, allowing for large tumoricidal doses to be delivered in fewer fractions and with lower incidences of toxicities [13]. The development of SBRT marked a significant step forward in the technique of RT delivery. This step only became possible in the past 10–20 years alongside improvements in target visualization of the time of treatment (i.e., image-guided RT), ability to shape and conform RT doses tightly around target volumes, and computing capabilities that allowed such treatments to be planned efficiently. SBRT has since become a significant component of the standard treatment for numerous cancers including HCC. This section will discuss the technique of SBRT, the supportive literature, indications for clinical use, and the expected toxicities in patients undergoing liver SBRT.

3.1 Understanding stereotactic body radiation therapy

SBRT is a widely utilized method for delivering EBRT, usually utilizing photon-based external beam radiation. SBRT employs highly conformal treatment plans to administer significantly larger radiation doses per fraction (~6–10 Gy) as compared to conventional RT (1.8–2.2 Gy per fraction) [13]. This method can deliver higher doses compared to conventional EBRT and often can do so in 3–5 fractions instead of the typical 10–20 fractions. Utilizing advanced imaging techniques like CT scans, SBRT precisely targets the tumor, directing radiation beams from multiple angles along multiple planes to maximize tumor dose while minimizing exposure to healthy tissues [13].

SBRT finds particular utility in treating small to medium-sized tumors such as prostate adenocarcinoma, lung malignancies, and spinal tumors. It can be employed for definitive treatment of primary tumors or in managing limited metastatic disease, including spinal or lymph node disease. Early studies exploring SBRT included sites like the liver, lungs, and retroperitoneal space were first published in the late 1990s [16, 17]. The technology behind SBRT shares similarities with Stereotactic Radiosurgery (SRS), which is used for the treatment of intracranial disease. Today, both SBRT and SRS are daily tools in Radiation Oncology, treating a variety of common malignancies.

When planning SBRT, radiation oncologists work in a series of treatment volumes that represent tissues that are either to be targeted by the beams or to be avoided. Gross tumor volume (GTV) represents the actual tumor’s volume as seen on imaging [18]. Typically, a margin around the GTV, called the planning target volume (PTV), is also delineated to ensure full dose coverage of the tumor while accounting for any errors in daily setup or tumor motion [18]. The goal of EBRT planning is to ensure the entire GTV and PTV receive at least 95% of the prescribed radiation dose while minimizing the dose to the tissues outside of these volumes. This can be accomplished by changing the angle of beams and the energy that each beam emits. Figure 3 illustrates these planning components and their delineation in planning software. While the literature includes many treatment prescriptions and fractionation schemes, typically, SBRT plans include doses of 30–50 Gy in 3–5 fractions [19].

Figure 3.

(A, B, and C) here is shown an example of the outcome of planning SBRT for a 2 cm tumor identified on pathology as HCC. The prescribed dose was 50 Gy in 5 fractions. GTV and PTV volumes are delineated and labeled here. Surrounding the volumes are shades correlating to dose that they will be receiving. Tissues in red are receiving 100% of the dose; regions in green are receiving 50% (25Gy) of the dose, and those in blue are receiving 20% (10Gy) of the dose. (D) Shows a liver on cross section on autopsy after liver SBRT showing the necrosis and fibrosis of tissue included in the GTV and PTV. Adapted from Haddad et al. [18].

Often, fiducial markers can be placed in the tumor by a radiologist in order to help with targeting the GTV. Fiducial markers are small (3 mm) metal markers that are placed in or around the tumor by needles through image guidance. These are radiopaque and appear clearly on imaging and can be used to assist in target volume delineation and in ensuring accuracy during treatment delivery. More specifically, fiducials may be used either during initial set up of patient’s during SBRT delivery, matching the position and orientation to that of initial CT simulation, or continuously through treatment for “real time” tumor tracking and accuracy during beam delivery.

Other volumes also include delineating the organs at risk (OARs). These are volumes that we hope to protect from radiation dose. For the liver, these may include healthy liver volume, the spinal cord, the kidneys, the stomach, and the ribs, among others. After these volumes are delineated by the physician and beam position and energies are planned, computer software can calculate the doses delivered to each volume, including the OARs. Based on these calculations, the physician decides whether these doses are safe and efficacious enough to move forward with treatment or if the plan should be re-optimized to produce a better therapeutic ratio. Radiation oncologists use published tissue constraints for OARs that are often referred to for such clinical decisions. These list the doses that are maximally allowed for a healthy OAR to receive before the risk of toxicity becomes significant.

3.2 Indications and guidelines

Key to understanding the role of RT in HCC is identifying which patients are suitable for liver SBRT. Resection and transplantation remain the first-line therapies for early-stage HCC with normal liver function and in patients who are good candidates for surgery [20]. Surgery could involve resection of only affected lobes or liver transplant after total hepatectomy. Tumors smaller than 2 cm and patients without signs of portal hypertension are the most ideal candidates for resection followed by transplantation [20]. However, there is no upper limit of tumor size for surgical resection alone without transplantation, and it has been shown to confer a survival benefit. Thus, referral to a surgical oncologist should be considered for any patient presenting with HCC [21]. If the patient is not a candidate for surgery, other locoregional therapies should be considered, as HCC tends to remain confined to the liver. These can include ablation, arterially directed embolization, or radiotherapy.

Radiofrequency ablation (RFA) is a well-supported method of locoregional therapy but is most effective in tumors ≤3 cm and is often avoided if the tumor is near a major blood vessel [22]. Arterially directed embolization is also a well-supported localized treatment for HCC, working by blocking arterial blood flow to the tumor and inducing ischemia. Because HCC tumors primarily derive blood flow from the hepatic artery, whereas healthy liver parenchyma derive most of its perfusion from the portal circulation, this is an efficient and targeted way to starve tumor cells while sparing normal tissue [21]. TACE has no constraints in terms of tumor size but is generally avoided if the patient presents with portal venous thrombosis, as embolization of both components of the liver’s dual blood supply would cause ischemia to normal tissues as well [21].

SBRT is a viable option for uni- or multifocal intermediate-stage hepatocellular carcinomas with or without vascular involvement [20]. Unlike RFA, SBRT does not have tumor size constraints and thus can be used in patients with larger tumors as long as dose constraints for the normal liver can be met and there is sufficient healthy liver for normal function [20]. A relative contraindication to SBRT would include Child-Pugh Class (CPC) -C liver function, as studies have shown CPC-C patients are at highest risk for RILD due to radiosensitivity of the tissue [20].

In advanced disease with extrahepatic spread and end-stage liver function, the role of RT is limited to the palliative setting. For extrahepatic spread, treatment with systemic therapies such as sorafenib or more recently combined targeted and immunotherapy (e.g. bevacizumab/atezolizumab) is the standard of care [20, 23]. Multidisciplinary input and shared decision-making with the patient should be emphasized in advanced disease, as some patients with poor functional status may prefer supportive care over anti-tumor therapy.

3.3 A review of SBRT as definitive therapy in hepatocellular carcinoma

A series of prospective studies published in the last 20 years have supported the use of SBRT in the definitive treatment of early or intermediate stage HCC. SBRT has been found to achieve excellent locoregional control (LC), demonstrate comparable overall survival rates compared to other local treatment methods, and exhibit minimal toxicity. This section provides a review of these seminal studies and discusses their implications for the current treatment of HCC in the radiation oncology suite.

Kwon et al. published one of the earliest phase II clinical trials on the use of SBRT for HCC [24]. They reported on 42 patients with HCC who were ineligible for surgery or RFA. Patients had to have CPC-A or -B disease and no prior history of RT. Each patient was treated with 30–39 Gy in 3 fractions. One- and three-year survival rates were 92.9 and 58.6%, respectively. They reported one patient died of hepatic failure, which may have been related to their RT, but no other significant toxicities were reported [24].

Kang et al. focused on 47 patients with inoperable HCC, including those with CPC-A or -B disease who had failed previous TACE treatment [25]. The inclusion criteria also limited tumor size to less than 10 cm and included patients with portal vein tumor thrombosis. SBRT was delivered in doses ranging from 42 to 60 Gy in 3 fractions. The authors reported a 2-year local control rate of 94.6% and an overall survival of 68.7%. Rates of grade 3 gastrointestinal toxicities were limited to 6.4%, with grade 4 toxicities at 4.3%. This trial established that salvage SBRT in patients with failed TACE treatment was well tolerated and provided excellent local control and overall survival [25].

Bujold et al. reported outcomes of a sequential Phase I and II clinical trials for SBRT in 102 patients with locally advanced HCC and CPC-A disease [26]. There was tumor vascular thrombosis in 55% of these patients, making them ineligible for TACE. Half of these patients had undergone previous local treatment including surgical resection, RAF, or TACE, and half were receiving SBRT as their primary definitive treatment. They delivered SBRT in doses of 24–54 Gy in 6 fractions. The authors reported no cases of RILD but did report progression to liver failure in 5 patients and a duodenal bleed in 1 patient, which may have been secondary to duodenal RT exposure. LC at 1 year was 87%, and one-year survival rate was 55% with median survival of 17 months. Compared to systemic therapy, which is the only other treatment option available for patients with tumor vascular thrombosis, SBRT was highly favorable as median survival for those on sorafenib is 7.9 months [23]. This study established that SBRT is a favorable option for patients with underlying tumor vascular thrombosis without otherwise advanced disease.

Lasley et al. then published a similar phase I and II clinical trial of 59 patients with nonresectable HCC with CP-A or -B disease [27]. Most of these patients (85%) had no prior local therapy. 20% of these patients had portal tumor vascular thrombosis, and the maximum tumor size for enrollment was 6 cm. This study delivered SBRT doses ranging from 36 to 55 Gy in 3 or 5 fractions and on average gave higher doses to CPC-B patients. Local control rates at 6 months for CPC-A patients was 92% and for CPC-B patients was 93% [27]. Median overall survival for CPC-A patients was 44.8 months and for CPC-B patients was 17.0 months. Notably, 12 patients experienced radiation-related grade III or IV liver toxicities, and 14% of CPC-B patients experienced RILD.

Studies comparing definitive RFA and SBRT have not made clear which option is preferable. Wahl et al. published a study of 224 patients with inoperable HCC who underwent RFA or SBRT retrospectively [28]. SBRT doses ranged from 27 Gy to 60 G in 5 fractions. Local control with RFA at 1 year was 83.6% and was 97.4% for those in the SBRT group. At 2 years, local control rates were 80.2 and 83.8% for RFA and SBRT, respectively [28]. Overall survival at one and 2 years were comparable for both groups. However, another study of 3980 patients from the National Cancer Database found 5-year overall survival to be higher in the RFA group as compared to the SBRT group (30 vs. 19%) [29]. Given the retrospective nature of these comparisons, both are susceptible to bias and should be interpreted with caution.

Finally, the recent TRENDY trial has compared TACE and SBRT in a small sample of 30 patients [30]. The trial closed early due to slow accrual but did publish their findings with the caveat of a small n-value. The authors found local control rates were improved in the SBRT group and saw no differences in overall survival or quality of life. They recommended international multicenter cooperation in future work to compare these two treatment options [30].

The combination of locoregional therapies has also been an area of investigation. When used together, the synergy of two treatment modalities should result in more effective tumor killing. Meng et al. reported on 1476 patients across 17 studies combining TACE and SBRT, showing improved survival rates compared to TACE alone [31]. More recently, early data has found that sequential systemic therapy following SBRT was more beneficial than systemic therapy alone [32]. The recently reported results of RTOG 1112, a phase III randomized controlled trial of sorafenib alone versus sorafenib and SBRT, has found an overall survival benefit from the addition of SBRT. Among patients receiving SBRT followed by sorafenib, the median overall survival was 15.8 months, compared to 12.3 months with sorafenib alone [32]. While this benefit was low, it was among a heavily pretreated population with a large percentage of patients showing macrovascular tumor thrombosis. Additionally, they found no significant difference in treatment-related gastrointestinal side effects between the groups, and in fact, quality of life scores were 10% higher in the sequential treatment group at 6 months with the addition of SBRT. These studies suggest the potential for future work to expand the use of SBRT in combination with other systemic or local therapies.

The current NCCN guidelines recommend SBRT be utilized when RFA and TACE are contraindicated or have failed [20]. Many questions remain to be answered in terms of which order locoregional therapies should be considered, or for which patients each therapy is optimal for. One currently open trial at Stanford University hopes to compare in patients who have recurrent or persistent disease after initial TACE whether further subsequent attempts at TACE or SBRT is more efficacious. A similar trial published from Italy demonstrated improved LC and PFS among patients treated with SBRT after failed TACE; however, this trial suffered from low accrual and high crossover from the TACE to SBRT arm, which may have diluted the impact of treatment arms on more concrete endpoints including overall survival [33].

Clearly, however, for many patients who have larger tumors with vascular involvement or unfavorable tumor location for ablation, SBRT is an efficacious and well-tolerated treatment option that can prolong life and provide excellent local control.

3.4 Dose: volume effects and toxicities

While SBRT is an effective local therapy with outstanding local control rates, as with any cancer therapy, one must consider the potential side effects and toxicities compared to the tumoricidal effect. Doses in SBRT are primarily limited by the surrounding healthy liver and nearby luminal gastrointestinal organs, such as the duodenum and stomach. The presence of HCC alone as compared to liver metastases increases the radiosensitivity of the surrounding normal liver, so this is a critical consideration [34].

Significant efforts have focused on understanding the impact of radiation exposure on liver function. RILD is categorized into two main diagnostic groups: “classical” and “nonclassical” disease. Classical RILD is characterized by hepatomegaly (without jaundice), elevated liver enzymes (especially alkaline phosphatase), and ascites within 3 months of RT [35]. Nonclassical disease represents any liver disease seen within the 3 months following RT other than classical RILD. Either condition can also present with other signs of liver dysfunction including coagulopathy, low serum albumin, elevations in serum bilirubin, and even in severe cases hepatic encephalopathy [35]. Gastrointestinal (GI) complications could include nausea, fatigue, gastritis, duodenal or gastric ulcers, colitis, and diarrhea [36].

The risk for developing RILD is much higher in preexisting disease (CPC- B or -C patients) as low baseline liver reserve leaves little room for loss of functional liver [35]. Wei et al. reported that hepatic function loss after SBRT for HCC was related to the dose delivered and is in part mediated by liver inflammation [37]. Their study concluded that regional differences in liver function can be mapped, and adjustments in dose arrangement in SBRT planning can mitigate damage to liver regions that are already partially compromised.

Radiation dose limits have been established that consider the dose-volume effects of SBRT and the risk of developing worsening liver function after specific doses of radiation [36]. After analysis of a number of studies, Miften et al. reported constraints to the mean liver dose (MLD), where dose to the entire volume of the patient’s liver minus the GTV is calculated [36]. Here, they recommend for primary HCC, the MLD be less than 13 Gy in 3 fractions or less than 18 Gy in 6 fractions as this was associated with a less than 20% probability of developing grade III liver enzyme toxicities [36]. Other constraints for liver SBRT are based on the volume of liver that receives below a particular dose (i.e., a reserved cold volume). Son et al. suggested ensuring >800 cm³ of normal liver should receive <18 Gy in 3–5 fractions [38]. For luminal GI organs such as the stomach or bowel, dose constraints primarily relate to maximal point dose rather than mean or volumetric dose constrain. Based on the constraints of the RTOG 1112 trial, for such organs doses during SBRT should limit the volume of stomach, small bowel, and duodenum exposed to greater than 30 Gy to 0.5 cc of the organ volume [39].

4. Proton beam therapy for hepatocellular carcinoma

Proton-based RT is a well-established method for treating various malignancies. Proton therapy has been extensively studied and found to be just as or in some instances more efficacious than photon therapy. Protons are particularly useful in the pediatric population in the treatment of tumors of the brainstem, paranasal sinuses, spinal cord, or skull base [40]. Studies have also shown proton therapy to efficacious in treating tumors of the prostate, lung, and breast, but often, protons are not significantly more efficacious options than traditional photon therapy for these disease sites unless under specific clinical circumstances.

The advantages of proton therapy stem from a unique property of protons that lowers dose delivered to the surrounding tissues. Depending on the energy of the beam, protons penetrate tissues to a specific depth, where they deposit all their energy into target tissues and exhibit minimal exit dose [40]. This point where the proton deposits its energy is known as the Bragg peak [40]. This characteristic allows for the sparing of tissues beyond the target depth, which is an advantage not achievable with photons. This decreased backscatter allows for less normal tissue irradiation and therefore allows for the delivery of higher doses to the tumor while avoiding toxicities. Figure 4 depicts the differences in RT dose distributions between conventional RT, proton therapy, and SBRT [41]. This difference may be especially advantageous in patients with underlying liver disease wherein sparing of functional liver is critical to reducing the risk for RILD.

Figure 4.

Here, dose distributions are compared between the key methods of EBRT delivery discussed thus far. Proton therapy (left) has the least dose exposure in healthy surrounding tissue due to the Bragg peak properties of proton therapy. SBRT (middle) is also compared to conventional RT (right), which shows SBRT still has dose exposure to surrounding normal tissues, but less so than conventional EBRT. Adapted from Cheng et al. [41].

Doses in particle therapy, specifically protons, are denoted in Gray Equivalents (GyE). This measure is used because the relative biological effectiveness of photons versus protons differs. Proton beams have a slightly higher relative biological effect compared to photons for the same physical energy deposition (the relative biological effectiveness of protons to photons is about 1.1), so to measure doses that would be biologically equivalent to photons, we use GyE [42].

However, proton therapy is significantly more expensive than photon-based RT, and as such, its availability is comparatively limited. As of 2024, there are 44 proton centers in the United States and 89 worldwide [43, 44]. Despite these limitations, several trials have investigated the impact of proton therapy in treating HCC.

4.1 Protons in definitive therapy for hepatocellular carcinoma

While photon trials have shown enormous promise in terms of local control and survival, proton trials have been just as encouraging, if not slightly better. Fukumitsu et al. reported on 51 patients with Child-Pugh Class A or B HCC who were treated with 66 GyE in 10 fractions [45]. The study demonstrated promising overall survival rates, with 49.2% at 3 years and 38.7% at 5 years. Additionally, they achieved excellent local control rates of 94.5% at 3 years and 87.8% at 5 years. Proton therapy was well tolerated, with only grade I or II toxicities reported.

Hong et al. reported a Phase II multi-institutional study of proton therapy in patients with multiple forms of liver tumors, half of whom had HCC [46]. This study included patients with CPC- A and -B disease, and 27% had multiple hepatic HCC tumors. The median dose delivered was 58 GyE in 15 fractions. The overall survival rate of HCC patients was 63.2% at 2 years, and the local control rate at the same time point was 94.8% [46]. They reported patients tolerated treatment well with few side effects.

Finally, a prospective multicenter study published by Mizumoto et al. followed 576 patients treated with protons across 12 centers in Japan [47]. They found the average overall survival time was 48.8 months and the median progression-free survival time was 14.7 months with 7.8% of patients developing local recurrence [47]. The complication rate at 27 months of follow-up was 4.7% the most common of which was liver failure in 7 patients.

While these studies paint a promising picture for proton therapy, as of yet, phase III randomized trials comparing proton beam therapy to photon therapy or other locoregional therapies have not been completed. However, for patients presenting to a center with proton capabilities, proton therapy is an efficacious option, particularly for those for whom RFA and TACE are not viable options.

5. Palliative radiotherapy

While much of this chapter has focused thus far on the ways in which RT is useful in the definitive treatment of HCC, it is important to discuss palliative RT, as 40% of referrals to the radiation oncology department are typically palliative in nature [48]. RT can have multiple roles in the care of patients whose prognosis does not include a possibility of cure. Often, RT offers a cost-effective, efficacious, and well-tolerated method of relieving pain or other consequences of local tumor growth. These could include pain, bleeding, weight loss, and the effects of local tumor mass effect. Common indications for palliative RT include painful metastatic disease to the bones, focal neurological symptoms secondary to tumor mass effect, and bleeding due to tumors in the lungs and stomach. In patients with end-stage HCC, palliative RT may be utilized to alleviate abdominal pain or discomfort, obstruction of the biliary tract, or in those who have painful bone metastases [49]. Here, we will discuss some of the data on these applications of palliative RT and discuss which patients are ideal for palliative RT.

5.1 Palliative RT in HCC related abdominal symptoms

Liver RT can be utilized in a palliative setting for patients with HCC experiencing abdominal or region-specific symptoms. Although not as extensively studied as other indications, it remains an important consideration for HCC patients. Trials investigating this indication have shown that even in advanced and incurable HCC, RT should be limited to patients with Child-Pugh Class A or B disease, as even lower palliative doses can lead to radiation-related toxicities in patients with Child-Pugh Class C disease [50]. Whole or partial liver RT has been well studied in patients with liver metastases secondary to colon cancer, as well as SBRT, which has been used to reduce tumor burden and alleviate pain. However, there is less research on these treatments for similar symptoms in the HCC population [50].

Several phase II trials have shown promising results in HCC patients receiving a single fraction of whole liver RT, with improvements in symptom management [51, 52]. A recent Phase III clinical trial by Dawson et al. has compared best supportive care alone to single fraction palliative RT (8 Gy) in 66 patients with HCC and liver metastases experiencing abdominal pain due to tumor burden [53]. The trial found that at 1 month follow-up, a significantly higher number of patients in the RT group reported “pain at its least” (63 vs. 28%) and reported pain relief on the Brief Pain Inventory (59 vs. 25%) [53]. Interestingly, the RT group also showed improved overall survival at 3 months compared to best supportive care (51 vs. 33%), indicating the potential benefit of single fraction palliative liver RT in advanced HCC patients with tumor-related abdominal pain and discomfort.

Palliative SBRT for painful HCC tumors has also shown promise quite recently. Sharma et al. reported in an observational retrospective study that 82.75% of 35 patients with advanced HCC, most of whom had portal IVC tumor thrombosis, experienced a reduction in pain, and 78% reported reductions in overall discomfort after SBRT [54]. Minimal toxicities and only slight worsening of liver function were observed. Future research comparing palliative SBRT to single fraction liver RT in HCC is warranted, but SBRT could be a valuable therapy for improving patient pain in advanced HCC in the future.

5.2 Palliative RT in bone metastases

Bone metastases are an extremely common indication for palliative RT. In patients with metastatic HCC, only 3–20% present with bone metastases, indicating that bone metastasis is rare compared to other tumors, such as breast, prostate, or lung tumors, which have very high rates of metastasis to the bone [55]. However, as HCC is relatively common, a large overall number of patients will still present with painful bone metastases secondary to cancer progression. As such, palliative RT for those with painful bone metastases is an important consideration in the multidisciplinary care of HCC patients.

Palliative therapy regimens for patients with painful bone metastases could include single fraction regimens of 8 Gy or multifractional regimens such as 30 Gy in 10 fractions. In either case, the response rates to pain from such palliative treatments are high. Hartsell et al. reported on a phase III trial of 898 patients with painful bone metastases randomized to either single fraction or multifractional palliative RT [56]. There was no statistical difference between these groups, but overall response to therapy was 66%. Of those who had a reduction in their pain level, about a third would report their pain totally resolved after either kind of RT [56].

Ultimately, in the treatment of bone mets, palliative RT is extremely well supported and has excellent response rates. Therefore, in advanced HCC patients presenting with painful bone mets, no matter their Child-Pugh Class, we recommend they be referred to the radiation oncology department for consideration for palliative radiation. This is a well-tolerated form of radiation that has few contraindications or toxicities. Thus, the radiation oncologist can serve a pivotal role in the palliative setting and improve the patients’ quality of life tremendously.

6. Future directions

Finally, we will explore some innovative technologies that have recently emerged and may potentially revolutionize the treatment landscape for HCC in the coming decade. Specifically, we will delve into Adaptive RT and Biology-Guided RT, both of which represent recent significant advancements in treatment targeting. Despite the promising potential of these technologies, further research is needed to fully understand their impact on HCC treatment. Future studies should focus on elucidating the optimal patient selection criteria, treatment protocols, and long-term outcomes associated with Adaptive RT and Biology-Guided RT in HCC. If proven effective, these technologies could significantly enhance the therapeutic arsenal against HCC and improve the quality of life for patients facing this challenging disease.

6.1 Adaptive radiotherapy

Adaptive Radiotherapy first emerged as a possible avenue for improved RT planning in the late 1990s by Yan et al. who reported on its utility in the treatment of prostate cancer [57]. Adaptive RT is a cutting-edge technique that allows for real-time, day-to-day adjustments to radiation doses based on changes in the tumor’s size, shape, and 3-D position. This approach ensures that the maximum dose is delivered to the tumor while minimizing damage to surrounding healthy tissue by accounting for daily anatomical differences.

CT or MRI images are taken while the patient is laying on the treatment table every day. This allows the radiation oncologist to redefine the location of the OARs and the tumor’s location as these variables may vary somewhat on a day-to-day basis. The treatment software is then able to calculate the doses that each volume is going to receive and compare the adaptive treatment plan to the pre-planned treatment plan and allows the physician to choose the plan that maximizes tumor dose and minimizes OAR exposure.

Several studies have begun to investigate the efficacy of Adaptive RT in HCC treatment, with promising early results suggesting improved tumor control rates and reduced side effects compared to traditional RT approaches. The University of Michigan group reported a phase II study including 56 patients with HCC treated with adaptive SBRT [58]. Local control rates at 1 year follow-up were excellent with a recurrence rate of 6.4%. Using overlap weighting, they compared adaptive SBRT to conventional SBRT and found similar local control rates between the two methods; however, treatment-related toxicity risk was lower in the adaptive group with an impressive odds ratio of 0.26 [58]. Multiple pilot studies for using MRI-guided adaptive SBRT are collecting and preparing to publish their findings. As of yet, no phase III trials have compared adaptive SBRT to conventional SBRT.

6.2 Biology-guided radiotherapy

Biology-Guided RT involves the use of advanced imaging techniques and biomarkers to personalize radiation treatment based on the unique biological characteristics of the tumor. By targeting specific molecular pathways or genetic mutations driving tumor growth, Biology-Guided RT offers the potential for more effective and precise treatment strategies [59]. While still in the early stages of development, initial studies suggest that Biology-Guided RT may lead to improved outcomes and survival rates for HCC patients.

One example of biologically guided RT in HCC is the use of positron emission tomography (PET) imaging with tracers such as fluorodeoxyglucose to identify areas of high metabolic activity that correspond to the tumor [59]. This information can then be used to target these areas with higher doses of radiation while sparing surrounding healthy tissue. Work has been published examining the use of PET-guided therapy in prostate cancer, head and neck cancer, and lymphoma with promising results [60, 61, 62]. Future work will include examining the use of this methodology in SBRT planning for lung and gastrointestinal tumors. Some papers have examined using PET-guided therapy for directing the planning of simultaneous or integrated boosts during treatment for lung cancers and nasopharyngeal carcinomas [63, 64]. Using this method, boosts could be included in treatment planning to target lymph nodal metastasis in advanced HCC.

7. Conclusions

In the management of HCC, radiation therapy has emerged as a valuable noninvasive treatment option, particularly for early or intermediate tumors that are not amenable to resection, RFA, or TACE. SBRT can be utilized in patients with complications such as tumor vascular thrombosis or those with challenging anatomical locations. SBRT has proven to be safe and effective in these cases. Combining SBRT with arterially directed and systemic therapies has shown promise and may become a standard approach in the future, especially for patients with advanced disease. Proton therapy, though less accessible than photon-based SBRT due to limited availability of major proton centers, is an effective and safe alternative. Some work comparing SBRT to RFA has been done, but no clear evidence has proven one superior to the other. As such, both remain efficacious options for appropriate patients with intermediate or early HCC. However, RT may be considered relatively contraindicated in HCC patients with Child-Pugh Class-C disease due to the increased risk for RILD.

In cases of palliative disease, patients with painful metastases should be promptly referred for palliative radiation. This approach provides significant symptom relief in 60–70% of treated patients and improves the quality (and potentially quantity) of life. Palliative RT may also be useful in patients with abdominal pain secondary to HCC tumors, especially those with reasonable baseline liver function.

It is crucial for the patient’s care team to include a radiation oncologist, as they play a pivotal role in the comprehensive treatment of HCC. It is important for clinicians treating HCC patients to be knowledgeable about the literature and indications for SBRT. These treatment options should be presented to eligible patients and discussed in multidisciplinary tumor boards to ensure comprehensive and effective care for all HCC patients.

Acknowledgments

We would like to acknowledge and thank St. Luke’s University Health Network for their support of our work.

Conflict of interest

The authors declare no conflict of interest.