Intrapatient Variation in Response to Systemic Therapy in Advanced Hepatocellular Carcinoma.

Purpose: Progression-free survival (PFS) has been proposed as a surrogate end point in clinical trials for advanced hepatocellular carcinoma (aHCC). However, there have been concerns about the discrepancy between PFS and overall survival. Here, we aimed to characterize the behavior of individual lesions within the same patient/liver that play a key role in response assessment to a systemic treatment and how this changed temporally.

Methods: We obtained serial lesion measurement data from six clinical trials undertaken in the modern era (by which we mean since the first controlled trial in aHCC). In each patient, the percentage change of their lesion size was calculated at each visit compared with the baseline/screening phase. To assess lesion behavior, the patients were classified according to the degree of divergence (DOD) categories that ranged from 0 (all lesions behaved similarly) to 2 (completely discordant behavior). Finally, the results were summarized per treatment arm as the proportion of patients in each divergence category per follow-up visit.

Results: Of the 8,260 visits where DOD was assessed in patients, there was a considerable proportion of patients with divergent lesion behavior at the treatment arm level-approximately 58% were DOD 0, 38% were DOD 1, and 4% were DOD 2. Individually, there was evidence of lesions both increasing and decreasing in size within the same liver despite the treatment remaining the same.

Conclusion: The evidence presented here suggests that caution should be exercised in the application of progression-based metrics such as PFS as an end point in HCC clinical trials. Ultimately, there was consistently a considerable proportion of patients who were classified as having lesions within their liver which had a divergent response to treatment.