Neoadjuvant chemoradiotherapy with capecitabine and irinotecan guided by <i>UGT1A1</i> status in patients with locally advanced rectal cancer: 5‐year update of the CinClare trial
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Bibliographic record
Abstract
Abstract Background The optimal regimen and chemotherapy intensity are still under investigation for neoadjuvant treatment of locally advanced rectal cancer (LARC). The CinClare trial has demonstrated improved pathologic complete response (pCR) with the addition of irinotecan to neoadjuvant chemoradiotherapy (CRT) guided by uridine diphosphate glucuronosyltransferase 1A1 ( UGT1A1) genotype in LARC. Here, we report the 5‐year follow‐up outcomes of the CinClare study. Methods From November 2015 to December 2017, this randomized, open‐label, multicenter, phase III trial enrolled 360 patients with LARC and assigned them in a 1:1 ratio to CapIriRT (radiation with capecitabine combined with irinotecan followed by irinotecan and capecitabine) or CapRT (radiation with concurrent capecitabine followed by oxaliplatin and capecitabine). Irinotecan dosing was guided by UGT1A1 genotype (80 mg/m 2 for *1/*1 and 65 mg/m 2 for *1/*28 ). The endpoints, including local control (LC), distant metastasis‐free survival (DMFS), disease‐free survival (DFS), and overall survival (OS), were analyzed using the log‐rank test, Cox proportional hazards regression and restricted mean survival time (RMST) test at the data cut‐off date of June 2023. Results With a median follow‐up of 60 months, the CapIriRT group showed numerically higher 5‐year LC (95.6% vs. 93.9%), 5‐year DMFS (83.9% vs. 77.9%), 5‐year DFS (77.7% vs. 70.6%), and 5‐year OS rates (82.9% vs. 76.1%) than the CapRT group. Further RMST test also showed a statistically significant difference in DFS ( P < 0.05) and a borderline difference in OS ( P = 0.050). Among the UGT1A1 *1/*1 population, the CapIriRT group had significantly improved 5‐year rates of DMFS, DFS, and OS (all P < 0.05). Patients achieving pCR also had significantly longer DFS and OS compared to non‐pCR patients ( P < 0.05). Conclusions The addition of irinotecan guided by UGT1A1 genotype to a standard capecitabine‐based scheme brings clinical benefits with improved LC, DMFS, DFS, and OS. Patients with the UGT1A1 *1/*1 genotype derived notable benefit from irinotecan, with improved survival outcomes. Achievement of pCR is crucial as it is associated with improved long‐term survival. These findings support the integration of genomic testing into clinical practice to achieve a personalized irinotecan dosing regimen, which can optimize efficacy and safety. Trial registration ClinicalTrials.gov (NCT02605265).
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| 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 | 0.000 | 0.000 |
| 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 it