Palliative radiation therapy improved hepatic pain in HCC and liver metastasis

Single fraction radiation therapy (RT) outperformed best supportive care (BSC) in reducing hepatic pain in patients with either end-stage hepatocellular carcinoma (HCC) or liver metastasis. Moreover, the authors reported a trend towards improved survival for patients receiving RT. The results were presented as a late-breaking abstract during the ASCO Gastrointestinal Cancers symposium of 2023, held in San Francisco (CA, USA) from 19 to 21 January [1]. MEDICOM interviewed Dr Laura Dawson (Princess Margaret Cancer Centre, Canada) to discuss the rationale of the study and the clinical impact of the outcomes.

A randomised multi-centre phase 3 trial (NCT02511522) included 66 patients with either painful end-stage HCC (n=23) or liver metastasis (n=43) to compare palliative RT, single fraction, 8 Gy, to BSC. The primary endpoint was the reduction of hepatic pain, defined as an improvement of at least 2 points on the ’intensity at worst‘ item of the Brief Pain Inventory (BPI) after one month.

The primary endpoint was met by 67% of the patients in the RT arm and by 22% of the patients in the BSC arm (P=0.004). In addition, 21% of the patients in the RT arm achieved the primary endpoint without increase in opioid use compared to 0% in the BSC arm, a result that trended towards significance (P=0.07). Furthermore, the authors observed a trend towards improved survival in the experimental arm, with 3-month overall survival rates of 51% and 33%, respectively (P=0.07).

MEDICOM spoke to Dr Dawson to gain her perspective on these outcomes.

MEDICOM: What is the unmet need you addressed?

Dawson: “I have an interest in delivering high dose radiation with the goal of curing patients who have unresectable primary and metastatic liver cancers. While we were treating patients with more focal or localised cancers however, we found that there were many patients who weren't eligible for curative therapies. Some of these patients were suffering from pain from their liver metastases or primary liver cancer. These are often patients with underlying liver disease. For example, many patients with primary liver cancer have cirrhosis and it's harder for them to tolerate high doses of analgesics. I asked myself the question: “How can I help these patients?” I started using low, safe-dose radiation, but I realised there was no standardised method, no guidelines, and very little literature on the topic. I decided to take on this issue.”

“We designed our first study using the simplest treatment we could think of, which was one fraction of 8 Gray radiation. We recorded patient reported outcomes on pain and quality of life in patients with end-stage primary liver cancer or liver metastases. One month after radiotherapy, approximately 50% of the included patients had a clinically important reduction in pain of more than 2 points on a Likert scale from 0 to 10. Moreover, there was a trend to an improved quality of life in these patients, which was assessed with the FACT hep tool. In fact, I have received more appreciation from patients and families regarding this therapy than for anything else I've done in my career. Obviously, reducing suffering is important and if someone can become more comfortable and enjoy their time, it's very much appreciated by patients and families.”

“However, this study didn't change practice. For this purpose, a randomised trial was needed. We designed a simple, pragmatic, randomised trial using simple radiotherapy which could be applied without CT imaging. In this way, the approach could be used in developing countries as well. We had very simple credentialing showing in what kind of cases and patients the full liver could be treated safely with the used dose. The bottom line was that there was usually no reason to not administer radiotherapy. In some cases the cancers were very large, involving most of the abdomen. For these patients, prophylactic anti-emetic treatment was needed.”

“Pain was clinically significantly improved in 67% of the patients who were randomised to radiation compared to 22% in patients who received best supportive care only, a statistically significant difference. Thus, the majority of patients who received the intervention did feel better at 1 month. Furthermore, we did a sensitivity analysis and assumed that anyone who didn't complete their questionnaires had worse pain. Strikingly, in this analysis we found there was a clinically significant and statistically significant improvement on the BPI primary endpoint in patients receiving radiation compared to those who did not (49% vs 12%). It was reassuring that that sensitivity analysis was also in favour of the radiotherapy group. Moreover, there was a trend to an improve quality of life as well, consistent with the patient experiences we see in the clinic. On the downside, there were more adverse events in patients who received radiation. These were predominantly grade 1 or 2 adverse events, like nausea, and diarrhea, and were observed in 58% of the patients receiving radiation versus 33% of the patients in the best supportive care arm. Grade 3 or higher adverse events were uncommon. All in all, pain improvement far outweighed the slight increase in mild gastro-intestinal toxicity. Something that was a surprise for me was that the secondary endpoint of overall survival at 3 months trended towards a benefit for patients in the experimental arm, with rates of 51% in the radiation arm versus 33% in the control arm.”

MEDICOM: What can you tell about the third of the patients that didn't experience a benefit from radiotherapy?

Dawson: “The sample size was too small to perform a true subgroup analysis. The number of patients was small because we wanted to make it a pragmatic study, looking for a large effect size at one month. Of the 66 included patients, 43 had liver metastasis and 23 had primary hepatocellular carcinoma. I would've hypothesised that patients with hepatocellular carcinoma would have more benefit from radiotherapy. However, there didn't appear to be a clinically or statistically significant difference between patients who had metastases compared with patients with primary liver cancer.”

MEDICOM: Is there's a follow up study plan?

Dawson: “I will definitely encourage a larger study, looking at different endpoints and perhaps investigating this treatment in combination with other therapies. However, I don't have a study design ready to go. What I do know is that many people around the world are aware that this trial was going on and there may be validation studies in different countries, perhaps even in low-income countries. Especially in patients with very advanced disease who don't have access to imaging, this approach is something that can help patients feel better in a cost effective way.”

1. Dawson LA, et al. Canadian Cancer Trials Group HE.1: A phase III study of palliative radiotherapy for symptomatic hepatocellular carcinoma and liver metastases. LBA492, Rapid Abstract Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract, ASCO-GI 2023, San Francisco, CA, USA, 19-21 January.

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Posted on 3 February 202317 March 2023