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Abstract Background Administration of single-agent docetaxel in a weekly schedule may offer similar efficacy, with a more favorable toxicity profile, compared to a three-weekly schedule in patients with metastatic breast cancer. Methods The original search of Medline, Embase, and Scopus was performed in September 2018 and references were updated with additional searches up to January 2021. Two reviewers independently screened the identified literature based on a predefined set of criteria. Randomized controlled trials investigating the use of weekly versus three-weekly docetaxel in metastatic breast cancer patients were included. Results Four randomized controlled trials (N = 459 patients) were included in the final analyses. No significant differences were found in terms of objective response rate (risk ratio (RR) 0.75, 95% confidence interval (CI): 0.54 – 1.05), progression-free survival (hazard ratio (HR) 0.95, 95% CI: 0.71 – 1.26) or overall survival (HR 0.95, 95% CI: 0.70 – 1.29) between weekly and three-weekly docetaxel, respectively. Weekly docetaxel was associated with a significantly lower risk of grade 3/4 neutropenia (RR 0.16, 95% CI: 0.10 – 0.27), febrile neutropenia (RR 0.21, 95% CI: 0.08 – 0.55), and neuropathy (RR 0.29, 95% CI: 0.11 – 0.78). Although the risk of epiphora (≥ grade 3/leading to treatment withdrawal, RR 3.62, 95% CI: 1.07–12.22) and onycholysis (≥ grade 2/leading to treatment withdrawal, RR 3.90, 95% CI: 1.34 – 11.32) was increased. Conclusions Weekly docetaxel is associated with a lower risk of neutropenia, febrile neutropenia and neuropathy than the three-weekly docetaxel schedule in metastatic breast cancer patients. However, the risk of onycholysis, epiphora, and treatment discontinuation seems increased with weekly administration. No significant differences in efficacy outcomes were found. Weekly docetaxel might be an alternative for patients at risk for developing neutropenia.

Abstract Background Awareness of model-based designs for dose-finding studies such as the Continual Reassessment Method (CRM) is now becoming more commonplace amongst clinicians, statisticians and trial management staff. In some settings toxicities can occur a long time after treatment has finished, resulting in extremely long, interrupted, CRM design trials. The Time-to-Event CRM (TiTE-CRM), a modification to the original CRM, accounts for the timing of late-onset toxicities and results in shorter trial duration. In this article, we discuss how to design and deliver a trial using this method, from the grant application stage through to dissemination, using two radiotherapy trials as examples. Methods The TiTE-CRM encapsulates the dose-toxicity relationship with a statistical model. The model incorporates observed toxicities and uses a weight to account for the proportion of completed follow-up of participants without toxicity. This model uses all available data to determine the next participant’s dose and subsequently declare the maximum tolerated dose. We focus on two trials designed by the authors to illustrate practical issues when designing, setting up, and running such studies. Results In setting up a TiTE-CRM trial, model parameters need to be defined and the time element involved might cause complications, therefore looking at operating characteristics through simulations is essential. At the grant application stage, we suggest resources to fund statisticians’ time before funding is awarded and make recommendations for the level of detail to include in funding applications. While running the trial, close contact of all involved staff is required as a dose decision is made each time a participant is recruited. We suggest ways of capturing data in a timely manner and give example code in R for design and delivery of the trial. Finally, we touch upon dissemination issues while the trial is running and upon completion. Conclusion Model-based designs can be complex. We hope this paper will help clinical trial teams to demystify the conduct of TiTE-CRM trials and be a starting point for using this methodology in practice.