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Clinical Trial
. 2023 Dec;8(6):102046.
doi: 10.1016/j.esmoop.2023.102046. Epub 2023 Nov 16.

Time toxicity associated with early phase clinical trial participation

U Nindra  1 , G Shivasabesan  2 , S Childs  2 , R Yoon  3 , S Haider  4 , M Hong  5 , A Cooper  5 , A Roohullah  3 , K Wilkinson  5 , A Pal  6 , W Chua  5
Affiliations
Clinical Trial

Time toxicity associated with early phase clinical trial participation

U Nindra et al. ESMO Open. 2023 Dec.

Abstract

Background: Early phase cancer clinical trials (EPCTs) involve experimental drugs being used for the first time in humans. These studies are designed for dose determination and safety, and represent the most time intensive of all clinical trials for both clinicians and patients. We sought to quantify the amount of patient time consumed through EPCT participation.

Patients and methods: A retrospective audit of patients treated in the EPCT unit at Liverpool Hospital, Sydney was carried out from 2013 to 2023. We defined 'time toxicity' (TT) as a composite measure where time-toxic days were considered days with any health care system contact, including clinic visits, infusions, procedures or blood work.

Results: A total of 219 patients across 36 EPCTs were included. The median age was 65 years (range 31-81 years). Patients spent a median of 29% (range 4%-100%) of their days in direct contact with the health care system during their study. Protocol-specified visits accounted for the greatest contribution to total TT in 101 (46%) patients. In 7% (n = 16) of patients, unscheduled visits due to either adverse events or cancer-related symptoms accounted for the greatest TT. TT reduced as patients completed additional cycles of treatment. Patients who completed >10 cycles spent 14% of their days interacting with health care systems compared with 35% for those who completed ≤2 cycles. No statistically significant difference in TT was noted between dose-expansion and dose-escalation studies or trials focusing on immune-oncology versus targeted therapy.

Conclusions: Our study is the first to report TT in EPCTs with an extended follow-up. Clinicians should be aware of TT when discussing risks and benefits. TT also may not be the appropriate term when describing the time patients invest during EPCTs. Toxicity implies a negative impact, but for many patients, trial participation would be seen as positive. There should be efforts to streamline health care visits to limit TT in EPCTs.

Keywords: early phase clinical trials; phase 1; risk versus benefit; shared decision making; time toxicity.

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Conflict of interest statement

Disclosure The authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
Example schema for enrolling into and completing the first cycle of an early phase study. AE, adverse event; ECG, electrocardiogram; PK, pharmacokinetic.
Figure 2
Figure 2
Time toxicity burden during cycles 1-2 compared with cycles 3+.
See this image and copyright information in PMC

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