Prognostic value of unplanned hospital attendances in early phase cancer trial participants

Background Early phase cancer trials (EPCTs) are critical for assessing safety and early efficacy of new therapies. While treatment-related toxicities are routinely evaluated, the burden of healthcare attendance (time toxicity) is less understood. We investigated the relationship between excess healthcare visits and clinical outcomes in EPCT participants. Methods We retrospectively analysed patients enrolled in EPCTs at two European centres (Imperial College London and Gemelli Hospital Rome). Time toxicity was defined as the number of healthcare visits exceeding those mandated by protocol. Adjusted attendance rates (% days attended/days on trial) were calculated. The primary endpoint was overall survival (OS). Multivariable Cox models included centre-level frailty terms and were adjusted for age, sex, ECOG performance status (PS), primary tumour type, administration route, trial type, and enrolling centre. Results Among 272 patients (mean age 59.5±13.1 years; 58.5% female; ECOG 1 50.7%), median time on trial was 128 days (95%CI: 106-147). Median planned attendance was 11 days (IQR: 8-16.2) while median crude attendance was 15 days (IQR: 11-22). In total, 175 patients (64.3%) required at least one day of additional attendance. Median days of additional attendance were 5 days (IQR: 2-9). Adjusted crude attendance rate was higher in ECOG 1 vs 0 (15.0% vs 11.1%, p<0.001), and in those with grade ≥3 TRAEs (14.8% vs 12.1%, p=0.034). In our population excess attendance (≥1 day) was independently associated with worse OS (HR:2.26; 95%CI:1.42-3.59; p<0.001), and ECOG PS 1 (HR:1.84; 95%CI:1.16-2.91; p=0.009). On the other hand, severe TRAEs did not significantly affect OS (353 vs 572 days, HR 0.75, 95%CI: 0.48-1.17, p=0.2). Conclusions In this EPCT cohort, time toxicity, quantified as excess healthcare visits, was common and independently associated with worse OS, even after adjusting for ECOG PS, primary tumour type, and other baseline clinical variables. While associated with TRAEs, excess attendance emerged as a distinct marker of patient trajectories and vulnerability, capturing elements of clinical fragility not explained by toxicity or protocol-defined factors.