Brokaar Edwin, Knikman Jonathan, Visser Loes, van den Bos Frederiek, Henricks Linda, Lunenburg Carin, de Man Femke, Gelderblom Hans, Schellens Jan, Mathijssen Ron, Guchelaar Henk-Jan, Portielje Johanneke, Cats Annemieke, Postmus Wout, de Glas Nienke
Department of Pharmacy, Haga Teaching Hospital, The Hague, LN, the Netherlands.
Department of Internal Medicine - Medical Oncology, University Medical Center Leiden, RC, Leiden, the Netherlands.
Fundam Clin Pharmacol. 2025 Apr;39(2):e70000. doi: 10.1111/fcp.70000.
Despite the implementation of DPYD genotype-guided dosing, approximately 1 in 3 patients receiving fluoropyrimidine-containing chemotherapy continues to experience severe toxicity. While clinical studies have demonstrated a favorable tolerance among highly selected fit older adults, real-world studies have shown an increased risk of toxicity.
To identify predictors of severe toxicity or treatment deintensification in older DPYD wild-type adults receiving fluoropyrimidine-containing chemotherapy.
Patients wild type for four tested DPYD variants, aged ≥65 years, who participated in a prospective clinical trial investigating genotype-guided individualized fluoropyrimidine dosing, were eligible for the study. The association between tumor-, treatment-, and patient-related characteristics and the occurrence of severe toxicity (grade ≥3, CTCAE v5.0) was analyzed in univariate and multivariate logistic regression analyses. The same analyses were performed for a composite endpoint of severe toxicity or treatment deintensification (including dose reduction, cycle delay, or discontinuation).
A total of 311 patients were included. Median age was 71.2 years and 58.8% were male. Grade ≥3 toxicity occurred in 23.2% of patients. In multivariate analysis, none of the characteristics studied were significantly associated with the occurrence of grade ≥3 toxicity. The composite endpoint occurred in 41.2% of patients and was associated with the use of full dose monotherapy in multivariate analysis.
Despite DPYD genotype-based dosing, grade ≥3 toxicity and treatment deintensification frequently occur in older patients treated with fluoropyrimidine chemotherapy. No patient-related variables were found to be associated with grade ≥3 toxicity, but treatment with dose-reduced monotherapy resulted in fewer treatment deintensification or severe toxicity events.
尽管实施了二氢嘧啶脱氢酶（DPYD）基因型指导的给药方案，但接受含氟嘧啶化疗的患者中仍约有三分之一会出现严重毒性反应。虽然临床研究表明，在经过严格筛选的健康老年患者中耐受性良好，但真实世界研究显示毒性风险增加。
确定接受含氟嘧啶化疗的老年DPYD野生型患者发生严重毒性反应或治疗强度降低的预测因素。
参与一项前瞻性临床试验以研究基因型指导的个体化氟嘧啶给药方案、年龄≥65岁且四种检测的DPYD变体为野生型的患者符合本研究条件。在单因素和多因素逻辑回归分析中，分析肿瘤、治疗和患者相关特征与严重毒性反应（≥3级，CTCAE v5.0）发生之间的关联。对严重毒性反应或治疗强度降低（包括剂量减少、周期延迟或停药）的复合终点进行同样的分析。
共纳入311例患者。中位年龄为71.2岁，58.8%为男性。23.2%的患者发生≥3级毒性反应。在多因素分析中，所研究的特征均与≥3级毒性反应的发生无显著关联。复合终点在41.2%的患者中出现，在多因素分析中与全剂量单药治疗的使用相关。
尽管采用了基于DPYD基因型的给药方案，但接受氟嘧啶化疗的老年患者中≥3级毒性反应和治疗强度降低仍频繁发生。未发现与≥3级毒性反应相关的患者相关变量，但采用减量单药治疗导致治疗强度降低或严重毒性事件较少。
