TABLE 4.
Detailed data from included DPD phenotype studies
| First author, year published (PMID) | Study design | Pre‐treatment dose reduction based on phenotype | n with phenotype data | Data using the [U]/[UH2] or [UH2]/[U] ratio | Data using plasma uracail concentration [U] |
|---|---|---|---|---|---|
| Ciccolini 2006 (17038885) | Retrospective | No | 140 | U/UH2 ratio: 80 patients with grade ≥ 3 toxicity were compared to 60 patients with no toxicity. The mean [U]/[UH2] ratio in the reference population was 1.4 (±0.6) compared to 3.8 in the toxicity group. 57 of 80(71%) of the patients in the toxicity group had a [U]/[UH2] ratio above 2 (cut‐off value) | |
| Boisdron‐Celle 2007 (17064846) | Retrospective | No | 252 | [UH2]/[U] ratio: A significant correlation was found between the [UH2]/[U] ratio and treatment toxicity. The mean [UH2]/[U] ratio decreased with toxicity grade: grade 0, 8 ± 2.5; grade I, 6.5 ± 3.2; grade II, 6.7 ± 1.7; grade III, 5 ± 3.1; grade IV, 3.7 ± 2.7. | The mean [U] increased with toxicity grade: grade 0, 14 ± 6.7 μg/L; grade I, 14 ± 2.6 μg/:L; grade II, 17.5 ± 4.8 μg/L; grade III, 25 ± 11 μg/L; grade IV, 24.4 ± 10 μg/L |
| Cai 2017 (28278081) | Retrospective | No | 244 | [UH2]/[U] ratio: Only subgroup analysis was reported in the study. UH2/U comparison between different CSN‐38 1.5 h and CSN‐38 49 h subsets with or without adverse effects: The [UH2]/[U] ratio in patients with toxcity were statistically lower than those in patients without toxcity in CSN‐38 1.5 h > 50.24 ng/ml (B) p < 0.001 for bone marrow hypocellular, p < 0.001 for diarrhoea and p < 0.001 for oral mucositis and CSN‐38 49 h > 15.25 ng/ml subgroups (C) p = 0.005 for bone marrow hypocellular, p = 0.001 for diarrhoea, and p = 0.002 for oral mucositis. | |
| Meulendijks 2017 (28427087) | Retrospective | No | 550 | Odds ratio (OR) for global severe toxcity was reported for different [U] intervals: [U] < 13 n = 500 OR = 1 (reference)|[U] 13–13. 8 n = 16 OR1.2(0.24–6.14)|[U] = 13.9–16 n = 17 OR 8.2(2.55–26.1)|[U] > 16 n = 17 OR 5.3 (1.53–18.7) | |
| Etienne‐Grimaldi 2017(28 481 884) | Retrospective | No | 205 | [UH2]/[U] ratio: In patients with validated phenotypic data, distribution of [UH2]/[U] was not different according to toxicity. No specific data is reported | Relative risk (RR) for grade 3 and 4 toxicity was reported. RR for Grade 3–4 toxicity. [U] > 16 n = 18 , RR 1.47(0.48–4.45)|RR for Grade 4 toxicity. [U] > 16 n = 18 RR 20.56(1.96–215.8) |
| Boisdron‐Celle 2017 (28395758) | Prospective with control arm. | Patented treatment algorithm. A Multiparametric approach | 1116 | [UH2]/[U] ratio: A Multiparametric approach was used including genotyping and UH2/U ratio. Risk of ≥ grade 3 toxicity was compared between the two arms in the study. Arm with intervention (Multiparametric approach) n = 718 / 10.8% ( n = 78 )|Arm without MAP n = 398 /17.6% ( n = 70 ). The percentage of death was reduced from 2.5/1000 in arm B to 0 in arm with intevtion | |
| Launay 2017 (29682445) | Prospective | [UH2]/[U] ratio| > 4 Standard dose|3–4 Alert for reduced activity, without systematic dose reduction |2–3 20% dose reduction |1–2 30% dose reduction |0.5–1 50% dose reduction| < 0.5 5‐FU precluded | 221 | [UH2]/[U] ratio: Extensive metabolizers (normal) [UH2]/[U] ratio > 4. 13% of 200 patients ( n = 26 ) suffered severe toxicity. Poor metabolizers [UH2]/[U] ratio < 4 < 18 ( n = 2 ) 11% suffered severe toxcity. In the poor metabolizers revived a 20–50% reduced dose of 5‐FU compared to extensive metabolizers. Mean dose of 5‐FU was 19% lower in the poor metabolizers group | |
| Capitain 2020 (32973417) | Retrospective | No | 472 | [UH2]/[U] ratio: Incidence of overall grade 3 ≥ toxicity was compared across different [UH2]/[U] ratio intervals|[UH2]/[U] ≥ 6 n = 267 /25.1% ( n = 67 )| [UH2]/[U] ≥ 2 ‐ < 6 n = 180 /96.7% ( n = 174 )|[UH2]/[U] < 2 n = 25 /100% ( n = 25 ) | Incidence of overall grade ≥ 3 toxicity was compared across different [U] intervals|[U] < 16 n = 280 /39% ( n = 108 )| [U] ≥ 16 ‐ < 150 n = 178 /80.9% ( n = 144 )|[U] > 150 n = 14 /100% ( n = 14 ) |
| With 2022 (35397172) | Retrospective | No | 955 | DPYD variants carriers were excluded as they had received prereceivedemtive dose reductions based. The median pretreatment [U] was 10.10 ng/ml in patients without grade ≥ 3 overall severe toxicity compared to 10.35 ng/ml in the patients with severe toxicity (P = 0.73) |
Abbreviations: Toxcity grading, Common Terminology Criteria for Adverse Events (CTCAE); DPYD, gene encoding dihydropyrimidine dehydrogenase; [U], plasma uracil concentration; [UH2], plasma dihydrouracil concentration.
[Correction added on 26 September 2022, after first online publication: Author entries in Table 4 (rows 2, 5) have been amended.]