Combining immunotherapy and radiotherapy in hepatocellular carcinoma: the importance of irradiated tumor burden and the possible role of a low dose radiotherapy induction strategy
Year: 2023
Type: article
Abstract: We congratulate Juloori et al. for their recently published phase I study (1) on stereotactic body radiotherapy (SBRT) followed by nivolumab plus ipilimumab or nivolumab alone in hepatocellular carcinoma (HCC).Their results are an excellent example of both the promise of combining radiotherapy (RT) with immune checkpoint inhibitors (ICI) in HCC, as well the pitfalls of analyzing and interpreting the results of RT/ICI combination trials.The authors report the outcomes of thirteen randomly assigned patients, six in the nivolumab alone and seven in the nivolumab/ipilimumab arm.They report a higher rate of toxicities and higher overall response rates (4/7 vs. 0/6) in the dual ICI arm, with two patients alive after at least 3 years without progression and a negative PET scan.As the trial was powered for evaluation of dose-limiting toxicity and enrolled less than a quarter of the planned 50 patients, these results cannot be used to accurately assess the absolute or relative efficacy of these two combination regimens.This point is well made by the authors, as they mention that the observed overall response rate in the SBRT + nivolumab arm (0%) was lower than the 15-20% observed in CheckMate-040 nivolumab monotherapy trial encompassing 262 patients (2).Particularly when evaluating immunotherapy, where response varies widely, a few outliers in a small population can invalidate the assumption of proportional hazards required by the log-rank test.However, we would like to look past the small cohort size and discuss the results of this trial despite its lack of statistical power.What can this trial teach us about the way forward for RT/ICI combination trials in HCC?When comparing the populations in the two trial arms, there is a large discrepancy in the extent of disease, with 50% of patients in the nivolumab only arm presenting with extra-hepatic disease, compared to only 14% in the dual-ICI arm.This is particularly important for this trial because only intrahepatic disease was irradiated.Furthermore, the maximum GTV was mostly restricted to 100 cc and in the case of multiple lesions, the RT target was left to investigator discretion.This means that the fraction of tumor burden irradiated in these patients varied widely and was lower in the patients in the nivolumab arm, as half of them had extrahepatic metastases, which by design, were not included in the target volume.This is an important distinction, and crucial for two reasons.First, these limitations restrict the usefulness of metrics such as overall response rate and waterfall plots.
Source: Translational Cancer Research
DOI: 10.21037/tcr-23-192
Institutions: University of Washington, Fred Hutch Cancer Center
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
Funder: National Cancer Institute
Awards: Bio-Physical Modeling of Immuno-Radiotherapy Combinations based on Patient Data, A Computational Method to Calculate the Radiation Dose to CirculatingLymphocytes, Integrating patient-specific clinical and biological factors towards individualizing utilization of proton and photon radiation therapy.
OpenAlex ID: W4362684563