5PSQ-041 Safety and efficacy of high doses of irinotecan in patients with metastatic colorectal cancer treated with FOLFIRI scheme based on UGT1A1 genotype: a systematic review
Bibliographic record
Abstract
Background and importance Irinotecan’s antineoplastic activity, as well as its safety, depends on the action of its active metabolite, SN-38, which is inactivated by UDP-glucuronosyltransferase (UGT), an enzyme encoded by the UGT1A1 gene. The presence of the *28 allele decreases the elimination of SN-38. Some studies have shown the possibility of using doses of irinotecan higher than 180 mg/m2 in patients with the UGT1A1*1/*1 and *1/*28 genotypes. Aim and objectives To analyse published data about the use of a higher dose than 180 mg/m2 of irinotecan and its relationship with the efficacy and safety in metastatic colorectal cancer (mCRC) patients with the UGT1A1*1/*1 and *1/*28 genotypes treated with the FOLFIRI scheme. Material and methods A systematic review was carried out in Medline. The quest was done for articles published up to November 2020. MeSH terms used were: irinotecan and UGT1A1. Methods used were based on those recommended according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched for randomised clinical trials (RCTs) and observational studies. Four reviewers independently assessed the eligibility of each study. To assess the methodological quality of the RCT and the observational studies included, the Jadad and the Newcastle-Ottawa (NOS) scales were used, respectively. Results Search strategy reported 595 references, of which 13 were selected for analysis, 7 (53.8%) evaluating both efficacy and safety and 6 (46.2%) only safety. In relation to the studies that evaluated efficacy and safety, 6 (85.7%) were in favour of increasing the dose in terms of objective response rate (ORR) and progression-free survival (PFS), and even in one of them, in overall survival (OS). Studies evaluating safety suggested that doses of irinotecan greater than 180 mg/m2 are tolerated by most UGT1A1*1/*1 and *1/*28 patients. Of all the studies analysed, only one of them showed greater toxicity (grade ≥3) in the group with increased doses of irinotecan compared to the control group. Conclusion and relevance The present systematic review shows the convenience of assessing the irinotecan dose adjustment within the FOLFIRI scheme based on UGT1A1 polymorphisms, with a potential increase in the probabilities of an adequate clinical response. References and/or acknowledgements Conflict of interest No conflict of interest
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.015 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.007 | 0.008 |
| Bibliometrics | 0.006 | 0.006 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
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".