Measuring What Matters: RECIST Response Does Not Predict HRQoL in Early-Phase Clinical Trials

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Abstract
Background/Objectives: Early-phase clinical trials (EPCTs) focus on safety and preliminary efficacy, often assessed by RECIST (Response Evaluation Criteria in Solid Tumours) tumour response. Health-related quality of life (HRQoL) is rarely evaluated in EPCTs and may not align with radiological outcomes. Methods: The PEARLER (Patient Experience in Early-Phase Cancer Clinical Trials) study evaluated the demographics, tumour response, HRQoL, and therapy type in two early-phase trial units in Australia between August 2023 and 2024. Patients completed the EORTC QLQ-C30 at baseline and follow-ups. The Global Health Status (GHS) score was selected as the primary HRQoL measure. Tumour response was assessed using RECIST 1.1. Spearman correlation and Kruskal–Wallis testing assessed the associations between RECIST, cross-sectional GHS change (ΔGHS; follow-up minus baseline), and therapy types. Multilevel models were used to evaluate longitudinal GHS values per RECIST category. Results: Of 122 patients recruited to the PEARLER study, 74 patients had paired RECIST and HRQoL data (complete response (CR) n = 0; partial response (PR) n = 15; stable disease (SD) n = 39; progressive disease (PD) n = 20). The median change in GHS was zero across RECIST groups, with broad individual variability. Notably, 18 of 54 patients (33.3%) with stable or responding disease experienced HRQoL decline. Meanwhile, 10 of 20 (50%) patients with PD experienced stable or improving HRQoL. The best RECIST response and ΔGHS showed a weak but statistically significant negative relationship (Spearman ρ = −0.28, p = 0.017), with the Kruskal–Wallis test demonstrating χ2 = 6.20 (p = 0.045), indicating modest group differences driven by the deterioration in PD patients. The multilevel model demonstrated a lower GHS in patients with PD, with no statistically significant interaction of GHS change over time with the RECIST response (p = 0.226). Conclusions: HRQoL change is largely independent of radiologic tumour response and therapy type in EPCT participants. Patients experienced a HRQoL decline despite tumour response. Incorporating patient-reported outcomes alongside RECIST and safety outcomes is important to fully capture the impact of investigational therapies and guide patient-centred trial designs.

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