Palliative radiotherapy for hepatic cancer pain

A significant number of patients with liver malignancies, whether primary or metastatic, experience hepatic pain. Hepatic pain can profoundly diminish patients’ quality of life (QoL) (1,2). Unfortunately, the mechanisms underlying hepatic cancer pain remain poorly understood. It is hypothesized that this pain arises from tumor-induced stretching of the hepatic capsule, mass effect caused by a substantial tumor burden, and/or the release of pain-sensitizing cytokines. For some patients, hepatic pain manifests more as “abdominal discomfort” or “a feeling of pressure” rather than conventional “pain”, adding to the complexity of diagnosis and management (3,4).

Hepatic pain can be difficult to manage, as it can be refractory to conventional (pharmaceutical) treatments such as opioids and steroids. The management of malignancy-associated hepatic pain is often further complicated by an impaired liver function, which necessitates careful use of analgesics metabolized by the liver (1,5,6). Overuse or incorrect dosing of these medications can lead to significant adverse effects, and insufficient dosing will not alleviate the pain adequately. Although systemic therapies can alleviate hepatic cancer pain for some patients, these treatments often lack the rapid onset of pain relief sought by patients and are unsuitable for patients in poor general condition. Radiation therapy to the liver offers a promising treatment alternative. As a low-cost, relatively simple, and non-invasive intervention, palliative radiotherapy can be planned and delivered quickly and typically provides a relatively rapid effect.

Previous studies, primarily involving patients with liver metastases, have demonstrated pain reduction with various radiotherapy regimens and target volumes (7). Most importantly, a single-arm phase II clinical trial provided compelling evidence for the efficacy of a single fraction of 8 Gy radiotherapy to the whole liver (4). Based on these findings, the Canadian Cancer Trials Group (CCTG) conducted the HE1 trial—an open-label, randomized, controlled, phase III study—to evaluate the efficacy of single-dose radiotherapy plus best supportive care (BSC) versus BSC alone in patients with hepatic pain due to hepatocellular carcinoma (HCC) or liver metastases who were unsuitable for or refractory to systemic therapies (8). The primary hypothesis of this trial was that single-fraction radiotherapy would outperform BSC alone in alleviating hepatic pain caused by HCC or liver metastases. The main outcome was measured as the proportion of patients experiencing a clinically meaningful improvement in self-reported hepatic pain 1-month post-treatment, defined as an improvement in liver pain intensity by ≥2 points on the Brief Pain Inventory (BPI). Secondary pain endpoints were the proportion of patients with improvement in BPI score from baseline to 1-month and 3-month, the proportion of patients with a 25% reduction in morphine equivalent use of opioids at 1-month after randomization, and the proportion of patients with improvement in pain or discomfort intensity without increase in morphine equivalent use of opioids at 1-month. The secondary QoL endpoint measured the proportion of patients with significant QoL improvement from baseline to 1-month and 3-month using the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire. Other secondary endpoints were the proportion of patients experiencing adverse events of grade 2 or worse per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 at 1-month and 3-month after randomization, and the proportion of patients alive at 3-month. Statistical analysis was intention-to-treat, with survival assessed via the Kaplan-Meier method.

The trial enrolled 66 adult patients from nine cancer centers between 2015 and 2022. These patients had either HCC (n=23) or liver metastases (n=43) and were unsuitable for or refractory to systemic therapies. Patients exhibited a high hepatic tumor burden, stable hepatic pain/discomfort after optimization of analgesia for up to 7 days before randomization, an ECOG performance status of 0–3, a baseline pain score of ≥4/10, and had a life expectancy of >3-month. Exclusion criteria included prior hepatic radiotherapy, recent systemic anticancer therapy, or plans to start anticancer therapy in the near future.

Patients were stratified by cancer center and type of malignancy (HCC versus metastases) and were randomly assigned in a 1:1 ratio to receive either radiotherapy plus BSC or BSC alone, with all patients starting their assigned treatment. Patients in the radiotherapy group underwent a single fraction of radiotherapy of 8 Gy directed at the liver. To minimize nausea and vomiting, patients were pre-treated with 8 mg ondansetron (or an equivalent antiemetic) and 4 mg dexamethasone 1–2 hours before radiotherapy. The clinical target volume included the liver region thought to be contributing to pain, often encompassing the entire liver. Planning target volume margins ranged from 10 to 25 mm.

Both groups received BSC, including (non-)opioid and/or dexamethasone, with treatment decisions made at the physician’s discretion, although there were protocol recommendations for guidance. Pain management, QoL, laboratory tests, and adverse events were assessed at baseline, 1-month, and 3-month after randomization. Pain was evaluated using a modified BPI questionnaire, where “discomfort” replaced the term “pain” for more nuanced reporting. Daily opioid use was recorded in patient diaries, submitted at baseline and 1 and 3-month follow-ups. Notably, patients in the BSC group could cross over to receive radiotherapy after their 1-month follow-up visit. All patients were followed for a total of 3-month.

The primary analysis included data from 42 patients, 24 (73%) from the radiotherapy group and 18 (55%) from the BSC group, who completed baseline and 1-month assessments. Among the 42 evaluable patients, 16 (67%) of 24 in the radiotherapy group and 4 (22%) of 18 in the BSC group experienced at least a 2-point improvement in their worst pain intensity score on the BPI questionnaire, yielding an absolute difference of 44.4% [95% confidence interval (CI): 17.5–71.4; P=0.0042].

Additionally, patients in the radiotherapy group showed a median reduction of 6.25 morphine milligram equivalents (MME) per day in opioid use at 1-month, compared with a median increase of 34.00 MME per day in the BSC group. A 25% reduction in morphine-equivalent analgesia was achieved by 5 (36%) of 14 patients with available data in the radiotherapy group versus 3 (21%) of 14 in the BSC group (P=0.45). Furthermore, 3 (21%) of 14 patients in the radiotherapy group experienced both improved BPI scores and stable opioid usage, compared with none in the BSC group (P=0.074).

FACT-Hep completion rates were comparable at 1-month, but the radiotherapy group had fewer patients with worsening FACT-Hep HBS scores (33% vs. 61%, P=0.080) and a slight mean score improvement (0.19 vs. –6.60, P=0.071), although it is unclear whether these changes were clinically meaningful. Survival outcomes suggested a trend favoring radiotherapy, with a 3-month overall survival (OS) rate of 51% versus 33% [hazard ratio (HR) 0.56, P=0.068]. Subgroup analysis indicated potentially greater benefits in patients with HCC (HR 0.34) compared to those with liver metastases (HR 0.70). A post-hoc analysis adjusting for baseline factors confirmed this finding, with an adjusted odds ratio of 8.3 (95% CI: 1.76–39.0, P=0.0074) for pain improvement and a trend toward better OS (HR 0.57, P=0.086). However, as the study was not powered for survival outcomes, these findings should be interpreted with caution.

Adverse events were more frequent in the radiotherapy group, with 58% experiencing grade 2 or worse adverse events by 1-month versus 33% in the BSC group (P=0.083). Grade 3–4 adverse events were uncommon, occurring in 18% of patients in the radiotherapy group versus 12% in the BSC group at 1-month, and no grade 5 events or treatment-related deaths were reported. The most common grade 3–4 adverse events were ascites and abdominal pain. By 1-month, 11 (33%) of 33 patients in the BSC alone group had crossed over to the radiotherapy group.

The authors of this trial deserve recognition for conducting a phase III study in the field of palliative radiotherapy, an area of medicine where systematic research is challenging but essential. By focusing their research on patients unsuitable for or refractory to further systemic therapy, they contribute to a small but crucial body of work systematically exploring radiotherapy as a palliative treatment for those nearing the end of life. Providing robust evidence on the benefits of radiotherapy is critical, as this treatment remains underutilized, and efforts to improve referrals to radiation oncology services are insufficient (9,10). Studies like this not only educate radiation oncologists but also inform non-specialists about the advantages of radiotherapy, facilitating the development of programs that raise awareness of its safety and efficacy. Such initiatives can ultimately promote informed referral practices and increase the use of radiation oncology services.

The multiple commentaries on these findings further underscore the significance of this research and the interest it has generated among healthcare providers regarding evidence-based palliative radiotherapy (11-13). However, the attention garnered by this article also highlights key considerations for interpreting the trial’s findings.

First of all, as mentioned by the research group themselves, the accrual of patients needs to be viewed with caution (8,14). The relatively slow accrual, with 66 patients recruited from nine centers over seven years, necessitated by stringent inclusion criteria to ensure clinically significant and stable pain, may have introduced selection bias or limited the generalizability of the findings, especially as standards in supportive care may have changed in this period. Additionally, while the trial appropriately targeted patients with advanced disease and high symptom burdens, this cohort does not fully represent the broader population of individuals with hepatic malignancies, as those undergoing or planned for systemic therapy were not included in this trial. This limitation underscores the importance of future studies investigating the safety, tolerability and efficacy of large-volume liver radiotherapy in combination with systemic therapy. Expanding research in this area will help determine the optimal integration of radiotherapy into broader treatment regimens. In order to do so, an important consideration is baseline liver function, which may influence the adoption of this technique by some radiation oncologists. The study enrolled only approximately one-third of patients with Child-Pugh B liver function and almost no patients with Child-Pugh C liver function. Additionally, the study did not report longitudinal changes in liver function following radiotherapy, which could be a crucial factor for oncologists concerned about the potential for radiotherapy to exacerbate liver dysfunction and hasten mortality. For instance, clinicians at some centers may hesitate to implement this technique without clearer evidence of its impact on liver function over time. Future studies should try to also provide detailed analyses of liver function changes post-radiotherapy to better inform clinical decision-making, especially for patients who still have systemic treatment options. On the other hand, by excluding patients still eligible for systemic treatment, this trial demonstrates the tolerability and effectivity of palliative radiotherapy in a group of patients that otherwise would not have been offered any disease-specific treatment.

Furthermore, while the intervention demonstrated significant pain relief and a reduction in opioid requirements at 1-month, statistical significance for opioid use outcomes was not achieved. As Liang et al. highlighted in their correspondence, several factors could explain this result, including opioid dependence, tolerance, and the psychological dimensions of pain management (12). In the trial, patients were advised to optimize their analgesic regimens in consultation with oncologists or palliative care specialists, introducing potential variability in the administration of BSC therapies. Although the randomization process incorporated the enrolling center as a stratification factor to account for variations in local standards of care, the lack of a standardized supportive care protocol may have affected the consistency and interpretability of the radiotherapy results. Notably, there are no data on whether patients followed by palliative care specialists experienced better pain control or greater reductions in opioid use in this patient population. Palliative specialists often adopt a more holistic approach to pain management, addressing psychological and emotional aspects alongside the possible use of non-pharmacological strategies.

In response to Liang and colleagues’ assertion that there was no significant difference in opioid consumption between the two treatment groups after 1-month, the data actually indicate a median reduction in morphine equivalents of 6.25 mg/day in the radiotherapy plus BSC group, compared with a median increase of 34.00 mg/day in the BSC-alone group among patients who completed pain diaries. Although not statistically significant, a greater proportion of patients in the radiotherapy plus BSC group achieved a ≥25% reduction in opioid use at 1-month. These trends suggest potential benefits of radiotherapy that merit further investigation in a larger cohort, particularly in the context of opioid dependence and psychological factors influencing analgesic use. Future trials could benefit from standardizing and optimizing supportive/palliative care protocols to ensure uniformity and better delineate the effects of radiotherapy on pain outcomes. The importance of optimal BSC is also evident given the absence of data for a substantial number of participants at 1-month—27% (9 of 33) in the radiotherapy plus BSC group and 45% (15 of 33) in the BSC alone group, which was mainly due to patient deaths, demonstrating that in this particular patient population not all live long enough to optimally benefit from radiation treatment.

In this trial, a substantial number of patients [11 of 33 (33%)] in the BSC alone group crossed over to receive radiotherapy in addition to their BSC after 1-month. While this crossover did not affect the primary endpoint of pain response, assessed prior to the crossover, it may have diluted the observed benefits of radiotherapy plus BSC, particularly concerning OS. This highlights the challenges of maintaining distinct treatment groups in palliative care trials, where patient needs often necessitate crossover interventions. A longer follow-up period could help clarify the survival benefit of radiotherapy, particularly beyond the 3-month endpoint. Additionally, a longer follow-up, with longitudinal pain assessments beyond 1- and 3-month, could also help track pain recurrence and potential late radiotherapy effects on liver function.

Finally, subgroup analyses suggested comparable efficacy between patients with primary HCC and those with metastatic liver disease. However, the study was not powered to detect statistically significant differences between these subgroups. The observed trend toward a more favorable survival HR for patients with HCC is intriguing but merely represents a hypothesis-generating finding that warrants further investigation. Larger, diagnosis-specific trials, designed with endpoints beyond pain response, are necessary to confirm these findings and refine patient selection criteria for radiotherapy. Such studies could play a pivotal role in consolidating the currently systematically underused role of radiotherapy within comprehensive palliative care plans.

Despite some inevitable limitations, the phase 3 CCTG HE1 study provides valuable insights into pain management for patients with advanced liver cancers and lays the groundwork for optimizing palliative care by presenting evidence on the benefits of incorporating hepatic radiotherapy into treatment plans. For future research endeavors, it could be worthwhile to consider applying alternative follow-up strategies to reduce dropout rates and improve the reliability of the (secondary) outcomes, such as more frequent follow-up calls, remote pain assessments, or integrating digital pain-tracking tools.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-25-3/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-25-3/coif). C.B.S.II serves as the Editor-in-Chief of Annals of Palliative Medicine from April 2014 to April 2027. S.F.L. serves as an unpaid co-chair for the Palliative Radiotherapy Subcommittee of Annals of Palliative Medicine from October 2023 to September 2025. E.O. serves as part of the Palliative Radiotherapy Subcommittee of Annals of Palliative Medicine from December 2024 to December 2026. The other authors have no 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.

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