Thread by @kharofaJ

Short #tweetorial on issues related to toxicity in oncology trials. How do we conclude Tx A is more/less toxic than Tx B? Room for improvement when you look at how we collect and report toxicity. Vital for both therapy escalation and de-escalation trials [Thread]

https://twitter.com/kharofaJ/status/1308550109240713216

Do we consistently grade events? Answer is no for retrospective and even prospectively this is a challenge with CTCAE. High grade events also require adjudication and attribution which is inherently a challenge. Nice study here pubmed.ncbi.nlm.nih.gov/32371073/ @julian_hong @mpalta1098

We don't do well with chronicity of AE (CTCAE or PRO). Daily pads due to fecal incontinence for life (CTCAE grade 2) better or worse than grade 3 admit? One pt with a grade 3 for 2 weeks may be counted the same as another with the same AE for 6 months. "AUC" models needed

Are all AE created equally? No. Patients may preferentially weight one type of AE worse than another but our analyses do not account for this. Even within PRO scores. Nice example from @MarkMishraMD using EPIC Bowel. Fecal control most valued

The timing of assessment is critical. If only one time point is selected care must be taken to ensure you aren’t too soon or too late for CTCAE or PRO-CTCAE events. The dynamics are important. Nice example from TIME-C @AnamariaYeung @AnnKloppMD

Looking at max grade between arms (ex 3+) ignores differences in number of AEs the same grade (ex 9 grade 3 GI events probably worse than 1 grade 3 GI event). Also ignores events of lower grade. Problematic for treatments that cause AEs across many organ systems (ex anal cancer)

There are now many well-developed tools to assess toxicity directly from patients (Ex PRO-CTCAE) and several studies have illustrated benefits of asking patients directly. See NRG 1203 PRO-CTCAE continence scores vs clinician reported. Underappreciate problem!

Despite utility of PRO instruments, need to evaluate how we use these as endpoints. Does statistical difference in scores (ex MDASI, EPIC-Bowel, etc) = clinically meaningful difference? How do we best use PRO-CTCAE data? Max grade differences have challenges. what about duration?

Several Novel composite toxicity endpoints may enhance data collection and reporting are being studied. Some include the Toxicity index (CTCAE or PRO-CTAE data), TAME, Total Toxicity Burden.
academic.oup.com/jnci/advance-a…
pubmed.ncbi.nlm.nih.gov/17543584/
redjournal.org/article/S0360-…

@HinaSaeedMD @SprakerMDPhD @KrishanJethwa