Mapping PRO-CTCAE responses to clinician-graded adverse events, dose reductions, interruptions, and discontinuations in phase I cancer trials.
Bibliographic record
Abstract
2014 Background: Typically symptomatic adverse events (sy-AEs) on clinical trials are reported by clinicians using the CTCAE. To complement clinician collected sy-AEs and understand tolerability better, the patient report outcome version of the CTCAE (PRO-CTCAE) has been developed to provide the patient (pt) perspective on severity of AEs (graded scale 0-4) and their interference in daily life (scale 0-4). The aim of this study was to correlate PRO responses with the grade (G) of AEs, dose interruptions/reductions and dose limiting toxicities (DLTs). Methods: Pts enrolled on phase 1 clinical trials at Princess Margaret were surveyed electronically on tablet using the full library of items for PRO-CTCAE. The PRO-CTCAE was administered at baseline (prior to therapy), mid-cycle 1, and mid-cycle 2. AEs on study were recorded by physicians using the CTCAE. The electronic medical records were analyzed for an association between reported sy-AEs and PRO score. Summary statistics were used to describe patient and disease characteristics, as well as the outcomes. Spearman’s method was used to correlate PRO severity and interference responses. Logistic regression was used to assess which factors were associated with CTCAE G 3-4 vs G 2 AEs. Results: We analyzed 158 pts: median age 60yrs, 77 (49%) were male; all were ECOG ≤1 and 22, 55 and 81 pts completed 1, 2 and 3 surveys, respectively. Clinician reported G2, 3 and 4 sy-AEs occurred in 81, 47 and 3 pts, respectively and all of these were related to a PRO item except 5% (4/81), 9% (4/47) and 33% (1/3), respectively because either the AE occurred after 3 rd time point or patient not able to complete the PRO (encephalitis). Sy-AEs causing dose interruptions, reductions, DLTs and discontinuations occurred in 45 (28%), 12 (7.5%), 5 (3%) and 12 (7.5%) pts, respectively; with a corresponding PRO item in 40 (89%), 12 (100%), 4 (80%) and 11(92%) pts, respectively. For patients who had CTCAE G2, G3/4 AEs, interruptions and discontinuations, their severity and inference levels were positively correlated (coefficient 0.49, p < 0.001; 0.45, p < 0.001 0.59, p < 0.001, 0.86, p < 0.001). Dose interruptions (p = 0.0027) and reductions (p = 0.0061) were significantly associated with G3-4 compared to G2 AEs. Conclusions: This is the first time an association between PRO-CTCAE severity and interference; and CTCAE G2, 3, 4 AEs, dose interruptions and discontinuations has been demonstrated. Additional modelling and more patient data are being analyzed to explore the relationship.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.042 | 0.722 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.004 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; both teacher heads agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".