Time toxicity of patients with cancer enrolled in clinical trials: a systematic review and meta-analysis

Clinical Snapshot

Key Findings

• P Value: Not reported in abstract

• Effect Size: Mean 7.6 total days/month; mean 2.2 planned days/month; mean 2.0 unplanned days/month; approximately twice the time toxicity of non-trial participants

• Primary Outcome: Mean total time toxicity of 7.6 calendar days with healthcare contact per month among cancer patients enrolled in pharmacotherapy clinical trials; highest burden observed in the first month of trial participation

• Nnt Or Sensitivity: Not applicable for this descriptive meta-analysis; the ratio of planned to unplanned days (approximately 1.1:1) remained consistent over time, suggesting a stable pattern of healthcare utilisation throughout trial participation

• Confidence Interval: Not reported in abstract

Clinical Application

Time toxicity measurement is feasible using existing administrative health data and electronic medical records. Integration into trial design requires prospective data collection frameworks. Mitigation strategies (e.g., telehealth substitution, home-based monitoring, consolidated visit scheduling) are operationally implementable within existing healthcare infrastructure. Incorporation into informed consent processes requires minimal additional resource investment. In the Australian context, time toxicity is particularly relevant given geographic barriers to trial participation for patients in regional, rural, and remote areas. The majority of cancer clinical trials are conducted at metropolitan academic centres (e.g., Peter MacCallum Cancer Centre, Royal Prince Alfred Hospital, Princess Alexandra Hospital), creating substantial travel and accommodation burdens for non-metropolitan patients. The RACGP and Cancer Australia have emphasised equitable access to clinical trials as a priority. PBS-listed cancer pharmacotherapies increasingly include agents first evaluated in trials, making trial participation a pathway to early access. The TGA's regulatory framework does not currently mandate time toxicity reporting in trial submissions, representing a policy gap. Medicare Benefits Schedule (MBS) data linkage could facilitate retrospective time toxicity quantification in Australian trial cohorts. The Australian Clinical Trials Alliance (ACTA) and Australasian Gastro-Intestinal Trials Group (AGITG) frameworks could incorporate time toxicity metrics into trial design standards. Telehealth expansion post-COVID-19 under MBS item numbers provides an existing infrastructure to reduce planned healthcare contact days. Adult patients with cancer being considered for or enrolled in pharmacotherapy clinical trials, particularly those with significant comorbidities, limited social support, geographic remoteness, or reduced functional capacity where healthcare contact burden may be disproportionately impactful

Abstract

PURPOSE: Time toxicity-the time patients spend receiving treatment, managing side effects, attending follow-ups and undergoing rehabilitation-is increasingly recognised as an important burden of cancer care. While time toxicity has been studied in routine clinical settings, it has rarely been quantified among patients with cancer enrolled in pharmacotherapy clinical trials. This systematic review aims to quantify time toxicity in this population. DESIGN: We searched Ovid MEDLINE, Embase and Cochrane CENTRAL from inception to 12 June 2025. Studies were included if they reported time toxicity among patients with cancer enrolled in clinical trials. Time toxicity was defined as calendar days with healthcare contact. Primary outcomes were (1) total days, (2) planned days and (3) unplanned days per month. Study quality was assessed using the Joanna Briggs Institute's (JBI) Checklist for Cohort Studies. RESULTS: Four retrospective studies reporting on an aggregate of 1809 patients were included. Two studies had low risk for bias and two had unclear risk of bias. Patients experienced time toxicity a mean of 7.6 days per month, with the highest burden in the first month of trial participation. Planned and unplanned days averaged 2.2 and 2.0 days per month, respectively. The ratio of planned to unplanned days remained consistent over time. CONCLUSIONS: Time toxicity is a substantial, under-recognised burden in cancer pharmacotherapy trials-approximately two times that experienced by non-participants. Its measurement and mitigation should be prioritised to improve patient-centred care, support shared decision-making and inform trial design, policy and consent processes. REGISTRATION: Study protocol preregistration: https://doi.org/10.17605/OSF.IO/BVY7C.

References

1. 1.Chow, R., Im, J. H. B., Richards, G. C., Zimmermann, C., & Heneghan, C. (2026). Time toxicity of patients with cancer enrolled in clinical trials: a systematic review and meta-analysis. BMJ Supportive & Palliative Care. https://doi.org/10.1136/spcare-2025-006038