Radiation therapy reduces pain in advanced hepatocellular carcinoma
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Single-fraction radiation therapy reduced hepatic pain among most patients with end-stage hepatocellular carcinoma or liver metastases, according to randomized phase 3 study results presented at ASCO Gastrointestinal Cancers Symposium.
Researchers also observed a trend toward longer survival among those assigned radiation.
“I absolutely believe this is practice-changing,” researcher Laura A. Dawson, MD, FRCPC, FASTRO, chair of the department of radiation oncology at University of Toronto and practicing radiation oncologist at Princess Margaret Cancer Centre, told Healio. “We routinely treat patients with bone metastases or bleeding from lung metastases or with primary metastatic brain cancer. We don’t routinely treat patients who are having pain or discomfort in the liver. This study shows a very simple one-dose intervention can help patients.”
Background and methods
Patients experiencing pain from end-stage HCC or liver metastases who are not eligible for systemic therapies — such as immunotherapy, targeted therapy or chemotherapy — receive best supportive care. This typically consists of analgesics. However, because these patients often have cirrhosis or poor liver function, high-dose pain medications often are less effective, leading to poorer quality of life.
“These patients with end-stage primary or metastatic cancer are underserved. The majority are treated by palliative care physicians or in hospice, so many medical oncologists, radiation oncologists and surgeons don’t see patients at the end of life when they’re suffering,” Dawson said. “A substantial portion are bothered by pain or discomfort from the burden of disease in the liver.”
Prior single-arm studies showed single-dose radiotherapy reduced pain at 1 month.
The Canadian Cancer Trials Group supported the HE.1 trial to definitively determine whether the addition of radiotherapy to best supportive care reduced pain for patients with primary liver cancer or liver metastases.
The multicenter trial included patients with painful end-stage HCC or liver metastases who were not candidates for local, regional or systemic therapies.
At least 4 weeks had elapsed since last chemotherapy or transarterial chemoembolization, and at least 2 weeks had passed since last targeted therapy or immunotherapy.
Researchers randomly assigned trial participants to best supportive care alone or with single-fraction radiotherapy (8 Gy), with the clinical target volume irradiated being the whole liver or near-whole liver.
Improved liver cancer pain “intensity at worst” — measured by at least a two-point improvement on the Brief Pain Inventory from baseline to 1 month — served as the primary outcome.
Secondary outcomes included proportion of patients alive at 3 months; proportion of those with at least a two-point improvement in Brief Pain Inventory at 1 month and 3 months; proportion of those with a 25% reduction in opioids at 1 month; and proportion who reported improved quality of life as determined by at least a five-point change on the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) hepatobiliary subscale and at least a seven-point change in the FACT-Hep Trial Outcome Index score at 1 month.
Researchers enrolled 66 patients. Twenty-three had HCC and 43 had liver metastases (colorectal, n = 12; breast, n = 5; pancreas, n = 4; lung, n = 3; other, n = 19).
More than half (59%) of patients had ECOG performance status 2 or 3. Two-thirds (64%) had Child-Pugh score A, and one-third (36%) had Child-Pugh score B or C.
All had stable pain rated at least a 4 on a 10-point Likert scale.
Results
The final analysis included 42 patients who completed baseline and 1-month assessments; 24 had received radiation therapy and 18 had received best supportive care alone.
Researchers reported an average baseline “pain at worst” score of 7 out of 10.
Several outcomes at 1 month favored the radiation therapy group, including percentage of those who exhibited significant improvement in “worst” pain score as assessed by Brief Pain Inventory (67% vs. 22%; P = .004); percentage who reported improved “worst” pain with no increase in opioid use (21% vs. 0%); proportion who reported significant improvement in Brief Pain Inventory “pain at its least” (63% vs. 28%; P = .03); Brief Pain Inventory “percentage relief in pain by treatment” (59% vs. 25%; P = .04).
A sensitivity analysis of all patients — which classified those who did not complete 1-month assessments as having no improvement — showed 49% of those who received radiation therapy plus best supportive care and 12% of those assigned best supportive care alone exhibited improvements in Brief Pain Inventory “worst” pain (P = .002).
“The fact we still saw statistically significant and clinically important improvement in the sensitivity analysis was quite reassuring,” Dawson said.
Eleven patients assigned best supportive care alone crossed over to receive radiation therapy at 1 month.
Despite the crossover, results showed 3-month survival rates of 51% with radiation therapy and 33% with best supportive care alone.
“This was a little surprising, but certainly I was pleased to see that result,” Dawson said. “This was close to statistical significance with a P value of .07. It suggests there was no increased serious toxicity that we couldn’t see. I suggests for some patients there may be a little bit more than a pain benefit, or perhaps by helping patients not need as many pain medications, that led them to have fewer downstream side effects from analgesia. I’m not quite sure of the pathophysiology of that and the numbers are low, but it deserves validation in future studies.”
Researchers observed a trend toward improvement in FACT-Hep hepatobiliary subscale at 1 month among those who received radiation therapy.
A higher percentage of those assigned radiation therapy experienced grade 2 or higher adverse events by day 30 (58% vs. 33%; P = .05). The most common included nausea, vomiting, diarrhea and other gastrointestinal events; however, most were short-lasting, Dawson said. Researchers also observed transient fatigue among patients assigned radiation therapy.
Grade 3 or higher adverse events were uncommon, according to investigators.
Investigators plan correlative studies of blood samples to in hopes they offer insights into why some patients derived benefit and others did not.
“I think this study also begs the question whether we can help more patients,” Dawson told Healio. “There may be patients who are still tolerating targeted therapy or immunotherapy who may derive benefit from radiation. ... There also are patients with smaller burden of disease than those enrolled in this study, and perhaps those patients could benefit from this type of treatment or even higher-dose treatment.”
Perspective
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Mary Feng, MD
Dawson and colleagues must be congratulated for initiating and completing this meaningful trial. For these patients at the end of their lives, often with concomitant liver dysfunction, pain control is a real challenge. It causes both physical and emotional distress for the patient, and it also is very stressful for their loved ones. In this trial, a single, simple radiation treatment provided a meaningful improvement in pain, which is so welcome to the patients and their families. It is important that oncologists and practitioners of symptom management are familiar with the final results of this study, to refer and treat patients with this simple and effective palliative method.
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Dawson LA, et al. Abstract LBA492. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 19-21, 2023; San Francisco.
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