Time toxicity in early phase clinical trials (EP-CTs).
Authors: Durbin Sienna , Lundquist Debra , Healy Megan , Lynch Kaitlyn , Bame Viola , Martin Tristan , Johnson Andrew , Heldreth Hope , Turbini Victoria , McIntyre Casandra , Juric Dejan , Jimenez Rachel , Nipp Ryan David 
Published: September 2022

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Background: EP-CTs are an increasingly important treatment option for patients with cancer, yet often require intensive monitoring. Little is known about the time that EP-CT participants spend in-hospital, and how that time compares to study requirements. Methods: We retrospectively reviewed the electronic health record (EHR) of consecutive patients enrolled in EP-CTs at Massachusetts General Hospital from 2017-2019 to obtain patient characteristics (demographics and clinical factors) and EP-CT investigational agent (immunomodulatory therapy [IM], targeted inhibitor [TI], antibody drug conjugate [ADC]/chemotherapy prodrug). We identified protocol requirements by reviewing the study calendar for in-hospital days for any reason, including clinician visits and diagnostic tests. We identified the real-world number of days spent at the hospital by reviewing the EHR for in-hospital days. We used descriptive statistics to compare patient characteristics and outcomes for those with higher time toxicity, defined as 5+ real-world visits during the first 28 days on trial, versus lower time toxicity. Results: Among 421 patients (median age = 63.0 years, 56.9% female, 97.6% metastatic disease), 43.2% participated in IM trials, 43.0% TI, and 13.8% ADC. Most common tumor types were gastrointestinal (GI) (22.3%) and lung (20.0%). Over the first 28 days on trial, protocol requirements listed an average of 5.2 in-hospital days, yet real-world data demonstrated that patients had an average of 6.6 in-hospital days (p < 0.001). TI trial participants had the highest average number of anticipated protocol visits compared with those on other trials (5.5 [TI] vs 5.3 [ADC] vs 5.0 [IM], p = 0.027). In real-world data, those on ADC trials had the highest average number of visits (7.5 [ADC] vs 7.1 [TI] vs 5.7 [IM], p < 0.001). Those with 5+ real-world visits during the first 28 days were more likely to have GI cancer (25.8% vs 13.9%, p = 0.011) and less likely to have lung cancer (16.7% vs 27.9%, p = 0.011). Patients with more visits were also less likely to have traveled 50+ miles to the hospital (48.8% vs 59.8%, p = 0.04). Notably, 19.5% of patients (N = 82) were hospitalized during the first 28 days on trial, with an average length of stay of 4.9 days. Those with 5+ visits had fewer days, on average, from trial start to admission (371.9 vs 650.8, p < 0.001) and fewer days on trial (mean 156.0 vs 235.0, p = 0.001). There was no significant difference in days from trial start to death for those with higher versus lower time toxicity (mean 464.6 vs 526.4, p = 0.177). Conclusions: EP-CTs represent a potentially time-intensive treatment option, as we found that patients spend over one-fifth of their first 28 days on trial at the hospital for various visits. Our findings indicate that patients may often experience more in-hospital days than what the protocol states. These data could help inform patient-clinician discussions regarding EP-CT participation and the potential time toxicity involved.