A step towards multimodality relief for painful hepatic cancer: the CCTG HE1 trial

In the absence of effective anti-cancer agents, opioids are the mainstay for patients with painful liver tumours. However, pain control can still be suboptimal in a subset of patients, and previous single arm, phase II studies on palliative, single-fraction radiotherapy showed that around 50% of patients had symptomatic improvement at one month (1,2). Building on these results, the CCTG HE1 trial, the first phase 3 trial assessing palliative radiotherapy for hepatic cancer pain, compared radiotherapy plus best supportive care (BSC) to BSC alone in patients with primary or secondary hepatic tumours who have exhausted active anti-cancer therapies and with moderate to severe hepatic cancer pain (3). A promising improvement in pain control from radiotherapy was seen, with 67% of patients receiving radiotherapy reporting an improvement in hepatic pain of at least 2 points on the Brief Pain Inventory at one month (3), compared to only 22% in the BSC group (P=0.0042). A trend towards better quality of life (QOL) was also seen, with patients receiving radiotherapy having at least stable QOL score by the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire [mean score change 0.19, standard deviation (SD) 9.43], compared to worsened score for the BSC only group (−6.60, SD 12.31, P=0.071). These results are very promising and are potentially practice-changing, specifically for patients who have stable but moderate to severe symptoms, relatively preserved liver function and absence of complications.

Interestingly, though the study was not powered for detecting differences in overall survival (OS), a trend towards improvement in OS was also seen for the radiotherapy group [3-month OS: 51% vs. 33%, hazard ratio (HR) =0.56; 95% confidence interval (CI): 0.3–1.05; P=0.068]. Though it is definitely possible, as the authors suggested, that better pain control has led to improved mobility and reduced complications, it is also possible that radiotherapy exerted certain anti-tumour effects onto hepatic tumours. Liver directed therapies in the form of hepatic arterial infusional chemotherapy (HAIC), yttrium-90 (Y90) radioembolisation or transarterial embolization have long demonstrated anti-tumour effects with delay in liver progression in colorectal liver metastases and hepatocellular carcinomas (HCCs) (4-6), benefitting even patients with extrahepatic metastasis (6). Given that liver metastasis often confers uniquely poor prognosis across many tumour types, irradiation of liver disease may in fact temporarily control the most prognosis limiting site of disease and result in better OS, though more studies are required to investigate these possibilities.

Nevertheless, several points need to be kept in mind when considering whether CCTG HE1 truly changes practice in contemporary, real-life patient populations. Firstly, CCTG HE1 targeted an extremely specific patient population, which slowed accrual to the extent that the study had to be closed early and arguably affected the generalizability of its findings. Included patients must have had a high burden of disease but limited complications [tumour involving >50% of liver, more than 10 lesions, size 10 cm (for single lesion) or 6 cm (for multiple lesions) or vascular invasion, but with only alanine aminotransferase <10× upper normal limit or bilirubin <2.5 upper normal limit, and no cholangitis within 4 weeks]. In addition, patients must not be receiving therapy but have very symptomatic visceral tumours, and at the same time having a life expectancy of ≥3 months. Such patients would be challenging to find in real life practice, in which large, highly symptomatic liver tumours are often complicated with recurrent malignant biliary obstruction and sepsis, liver failure, and rapid progression to death.

Secondly, there are potential safety concerns with radiotherapy to the liver. Radiotherapy is well known to cause radiation-induced liver disease (RILD), and the risk is proportionate to the amount of radiation received by liver parenchyma and baseline liver function (7). In the trial, adverse events also occurred at a higher percentage in the radiotherapy arm, with grade 2 and 3 all-cause adverse events of 39% and 18% within 1 month of randomization, compared to 21% and 9% in the BSC only arm. In real-life practice, patients with symptomatic liver tumours often have poor hepatic reserve due to replacement of normal liver parenchyma by intrahepatic tumours and portal vein thrombosis. In addition, patients with HCC often have concomitant cirrhosis. Hence, such patients are particularly at risk of developing RILD, and proper patient selection must be done to avoid toxicities and impairment of survival. Whether risks of toxicities for radiotherapy would be prohibitive in real-life settings, in which patients are usually less fit and selected less stringently, would be an important question to consider when translating trial results into actual practice.

Thirdly, there are study design and methodology concerns with CCTG HE1. The trial only included a total of 42 evaluable patients owing to enrollment difficulties, and effects observed may simply be due to the small numbers of patients in each treatment arm. Moreover, as highlighted by Wong et al. in their correspondence (8), there were no protocols for BSC. Variability in pharmacological and non-pharmacological pain control measures may have affected pain control, and by extension interpretation of the true effect of radiotherapy. The subjective improvement in pain from radiotherapy may also be due to placebo effect, which is known to play a considerable role in pain therapies (9). Teasing out the active role of radiotherapy may thus require future studies which account for such factors as well.

Fourthly and most importantly, concurrent anti-cancer therapy was forbidden in CCTG HE1. However, a paradigm shift in systemic HCC therapy has occurred during the enrollment of the study (from 2015 to 2022), and concurrent immune checkpoint inhibitors with radiotherapy have been demonstrated to be safe and synergistic for tumour control in HCCs by multiple studies (10,11). Symptom palliation should be an integral component of cancer care throughout all phases of therapy, instead of being reserved to patients who have exhausted active therapies. Patients with very large HCCs often suffer from significant pain even at diagnosis, and therefore it would be of great interest to see if single-fraction radiotherapy, given alongside contemporary oncological HCC treatments such as immunotherapies, would also be effective in pain control in these patients.

Patients with painful hepatic tumours have high unmet needs for symptomatic relief, and the CCTG HE1 trial is a big step forward towards improving their well-being. In real-life practice, clinicians should explore considerations in patient selection, potential toxicities and concurrent anti-tumour therapies, to maximize the benefit of radiotherapy for more patients.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

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