Ferreira Lopes, Joao Andre; (2024) A framework to quantify the quality-of-life value of progression-free survival in cancer clinical trials. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background: Progression-Free Survival (PFS) is a key outcome in cancer treatment trials, but its clinical value is unclear, particularly when there is a benefit on PFS but not for Overall Survival (OS). Considering PFS and Health-Related Quality-of-Life (HRQoL) together can help confirm PFS as a valuable outcome, but quantifying their relationship is challenging. Objective: To develop a new estimand that quantitatively combines PFS and HRQoL across the follow-up period for a patient: Time of Accumulated Quality of Life during PFS (TAQL PFS). Methods: The research involved literature reviews and development and evaluation of the TAQL PFS estimand. TAQL PFS incorporates PFS and HRQoL, considering HRQoL duration and intensity until a PFS event. A STATA command was developed for TAQL PFS analysis, which includes imputing censored PFS times, fitting mixed models, predicting HRQoL trajectories, and implementing bootstrapping for inference. The TAQL PFS analysis was validated using simulations and real-world trial data. Results: Among 13 studies, evidence of a link between progressive disease (PD) and HRQoL decline was mixed. A review of 20 colorectal cancer trials found a lack of standardisation in HRQoL assessment and reporting. It was unclear whether improved PFS or OS equated to HRQoL benefit, highlighting the need for a combined metric. Simulations confirmed sensitivity of TAQL PFS measure to PFS time and HRQoL scores and its robustness across different model specifications. TAQL PFS can be computed from published summary data using individual-level data reconstruction. Analysis of the ABC-02 trial identified PD as a factor in HRQoL decline and showed that extending PFS in the CisGem arm corresponded to a longer 12-month TAQL PFS across assessed HRQoL dimensions (treatment difference: 0.98-1.32 HRQoL-corrected PFS months, p<0.05). Conclusion: TAQL PFS combines PFS-HRQoL in a new way to quantify patient outcomes in cancer trials. It enhances the relevance of PFS as an outcome measure for clinicians, patients, and regulators. Further validation is needed to confirm robustness and generalisability across a range of cancer types and interventions.

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