The combination of radiation and systemic therapy can prolong survival of patients with advanced liver cancer

The combination of radiation and systemic therapy can prolong survival of patients with advanced liver cancer

Adding radiation therapy to systemic therapy in patients with advanced liver cancer can extend overall survival and delay tumor progression without affecting patients' quality of life, a randomized phase III clinical trial shows. The results suggest that radiotherapy should be a standard treatment option for patients with liver cancer for whom resection and other standard local-regional therapies are not an option. Results from the NRG Oncology/RTOG 1112 trial (NCT01730937) will be presented today at the American Society for Radiation Oncology (ASTRO) Annual Meeting.

The addition of radiation therapy to systemic therapy delayed tumor progression and prolonged survival without increasing side effects. In all respects, the combination of radiation therapy and sorafenib appears to be more effective than the drug alone.”

Laura A. Dawson, MD, FASTRO, lead author of the study

Laura A. Dawson is a professor of radiation oncology at the University of Toronto and a practicing radiation oncologist at the Princess Margaret Cancer Centre/University Health Network in Toronto.

Liver cancer is one of the most commonly diagnosed cancers and is the third leading cause of cancer death worldwide. Incidence rates of hepatocellular carcinoma (HCC), the most common type of liver cancer, have more than tripled in the United States since 1980, and mortality rates have also increased, despite increasing availability of screening and improved treatments for the diseases that increase the risk of liver cancer.

Systemic therapy is the standard of care for patients with HCC who are not eligible for surgical resection or other invasive therapies. However, a growing number of studies indicate a benefit from radiation therapy for these patients. Those from Dr. Dawson-led study is the first North American randomized trial to focus specifically on the role of radiation therapy for these patients.

Study participants included 193 patients (177 eligible for analysis) with new or recurrent advanced HCC who were ineligible for surgical resection or other standard local or regional therapies due to underlying clinical factors or because their cancer had recurred after standard therapy. Most patients had invasion of the cancer into the hepatic vasculature (a poor prognostic factor), and a small number had metastases outside the liver. The median age was 66 years (range 27–84).

Study participants were randomized at 23 sites in the United States and Canada to receive either sorafenib alone or stereotactic body radiation therapy (SBRT) followed by sorafenib. Sorafenib was the standard systemic therapy at the start of the study. SBRT was administered in five fractions over a period of five to ten days, with total doses ranging from 27.5 to 50 Gy, individualized to each patient based on clinical factors.

Overall survival was longer in patients who received a combination of SBRT and sorafenib than in those who received sorafenib alone (15.8 vs. 12.3 months; one-sided p = 0.055). The difference was statistically significant after controlling for clinical prognostic factors such as performance status and degree of vascular invasion (p = 0.042).

"It was somewhat ambitious to design a trial with overall survival as the primary endpoint, but when we designed the trial there were limited systemic therapies available for these patients and we had strong signals from previous research that adding SBRT to sorafenib should improve." tumor control and lead to improved survival," said Dr. Dawson. "We can now say without hesitation that radiotherapy is an effective treatment for patients with unresectable liver cancer. Outcomes were better in patients treated with SBRT, despite the planned delay in starting sorafenib."

Progression-free survival was improved with the addition of SBRT, from 5.5 months with sorafenib alone to 9.2 months with combination therapy (HR = 0.92, p < 0.001). Patients in the combination arm also experienced longer intervals before their cancer progressed (18.5 vs. 9.5 months; HR = 0.69, p = 0.034).

Treatment-related side effects did not differ significantly between treatment groups. Serious adverse events (i.e., grade 3 or higher) occurred in 42% of patients in the sorafenib arm and 47% of patients in the SBRT/sorafenib arm, and there was one treatment-related death in the sorafenib-only arm.

While the study was designed to follow patients for five years, Dr. Dawson said she continues to see longer-term benefits at her clinic. “Some patients who had SBRT as part of the study still come back to my clinic more than five years after treatment and are doing very well.”

The study was completed earlier than expected, primarily due to a change in standard systemic treatment for advanced HCC. Prior to 2016, sorafenib was the only FDA-approved first-line treatment for the disease, but since then several targeted molecular drugs and, more recently, immune checkpoint inhibitors have been adopted into the standard of care.

Dr. Dawson said she hopes the results spark increased interest in future clinical trials to examine the benefits of radiation therapy in combination with newer drug therapies. “There is a growing body of preclinical and early clinical studies suggesting that SBRT may act synergistically with immunotherapy and provide more than additive benefit to patients,” she noted.

Other open questions concern the optimal dosage and sequence of radiation therapy with different therapies as well as the potential benefit of radiation alone for patients who are not candidates for standard therapies.

Source:

American Society for Radiation Oncology

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