Single fraction radiation therapy (RT) outperformed best supportive care in reducing hepatic pain in patients with either end-stage hepatocellular carcinoma or liver metastases, according to a late-breaking abstract presented at 2023 ASCO Gastrointestinal Cancers symposium.1 Laura Dawson, MD, and colleagues reported a trend toward improved survival for patients receiving RT.
The randomized, multi-center, phase 3 trial conducted by Dr. Dawson and team included 66 patients with painful end-stage hepatocellular carcinoma (HCC; N=23) or liver metastases (N=43) to compare palliative radiation therapy (RT), single fraction, 8 Gy, with best supportive care (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 1 month.
The primary endpoint was met by 67% of patients in the RT arm and by 22% in the BSC arm (P=0.004). In addition, 21% of patients in the RT arm achieved the primary endpoint without increased opioid use, compared with 0% in the BSC arm, a result that trended toward significance (P=0.07). Furthermore, the authors observed a trend toward improved survival in the experimental arm, with 3-month overall survival rates of 51% and 33%, respectively (P=0.07).
Physician’s Weekly spoke with Dr. Dawson to gain her perspective on these outcomes.
PW: What is the unmet need you addressed?
LD: 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 localized cancers, however, we found that many patients weren’t eligible for curative therapies, some of whom 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 how I can help these patients. I started using low-, safe-dose radiation, but I realized there was no standardized 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 QOL 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 0-10 Likert scale. Moreover, there was a trend to an improved quality of life in these patients, which was assessed with the FACT hep tool. 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 when 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 randomized trial was needed. We designed a simple, pragmatic, randomized trial using simple radiotherapy that 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 patients randomized to RT, compared with 22% of those who received BSC 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 a clinically significant and statistically significant improvement on the BPI primary endpoint in patients receiving RT compared with those who did not (49% vs 12%). It was reassuring that sensitivity analysis was also in favor of the RT group. Moreover, there was a trend to improved QOL, consistent with the patient experiences we see in the clinic. On the downside, there were more adverse events in patients who received RT. These were predominantly grade 1 or 2 adverse events, like nausea and diarrhea, and were observed in 58% of patients receiving RT versus 33% of those in the BSC arm. Grade 3 or higher adverse events were uncommon. All in all, pain improvement far outweighed the slight increase in mild gastrointestinal toxicity. A surprise for me was that the secondary endpoint of overall survival at 3 months trended toward a benefit for patients in the experimental arm, with rates of 51% in the RT arm and 33% in the control arm.
What can you tell about the one-third of the patients who didn’t experience a benefit from RT?
The sample size was too small to perform a true subgroup analysis. It was small because we wanted to make it a pragmatic study, looking for a large effect size at 1 month. Of the 66 included patients, 43 had liver metastases and 23 had primary HCC. I would’ve hypothesized that patients with HCC would have more benefit from RT. However, there didn’t appear to be a clinically or statistically significant difference between patients who had metastases compared with those with primary HCC.
Is a follow-up study planned?
I will 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. I do know 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 them feel better in a cost-effective way.
