Centre Antoine-Lacassagne, Epidemiology and Biostatistics Unit, Université Côte d'Azur, 33 Avenue de Valombrose, 06189 Nice Cedex 2, Nice, France.
Centre Antoine-Lacassagne, Medical Oncology, Université Côte d'Azur, Nice, France.
BMC Cancer. 2020 May 18;20(1):436. doi: 10.1186/s12885-020-06907-0.
Dihydropyrimidine dehydrogenase (DPD) status is an indicator of a marked risk for toxicity following fluoropyrimidine (FP)-based chemotherapy. This notion is well-established for low DPD status but little is known about the clinical impact of high DPD activity. This study examined the possible link between high intrinsic lymphocytic DPD activity and overall survival, progression free survival and response to FP-based treatment in patients treated in our institution.
Lymphocytic DPD activity was assessed in a group of 136 patients receiving FP-based chemotherapy from 2004 to 2016. There were 105 digestive (77.2%), 24 breast (17.6%) and 7 head and neck cancers (5.2%). Cox or logistic regression models were applied with adjustment on all confounding factors that could modify OS, PFS or response. All models were stratified on the three cancer locations. A cut-off for DPD activity was assessed graphically and analytically.
An optimal cut-off for DPD activity at 0.30 nmol/min/mg protein was identified as the best value for discriminating survivals and response. In multivariate analysis, individual lymphocytic DPD activity was significantly related to overall survival (p = 0.013; HR: 3.35 CI95%[1.27-8.86]), progression-free survival (p < 0.001; HR: 3.15 CI95%[1.75-5.66]) and response rate (p = 0.033; HR: 0.33 CI95%[0.12-0.92]) with a marked detrimental effect associated with high DPD activity.
DPD status screening should result in a two-pronged approach with FP dose reduction in case of low intrinsic DPD and, inversely, an increased FP dose for high intrinsic DPD. In a context of personalized FP-based treatment, this innovative strategy needs to be prospectively validated.
二氢嘧啶脱氢酶（DPD）状态是氟嘧啶（FP）为基础的化疗后发生毒性的显著风险指标。这种观念在低 DPD 状态下已经得到充分确立，但对于高 DPD 活性的临床影响知之甚少。本研究在我院接受 FP 为基础化疗的 136 例患者中，评估了高内在淋巴细胞 DPD 活性与总体生存率、无进展生存率和对 FP 为基础治疗反应之间的可能联系。
2004 年至 2016 年期间，我们评估了一组接受 FP 为基础化疗的 136 例患者的淋巴细胞 DPD 活性。其中有 105 例消化系统（77.2%）、24 例乳腺癌（17.6%）和 7 例头颈部癌症（5.2%）。应用 Cox 或逻辑回归模型，对所有可能改变 OS、PFS 或反应的混杂因素进行调整。所有模型均按三个癌症部位进行分层。通过图形和分析评估 DPD 活性的最佳截断值。
确定 DPD 活性的最佳截断值为 0.30nmol/min/mg 蛋白，可最佳区分生存和反应。多变量分析显示，个体淋巴细胞 DPD 活性与总生存期（p=0.013；HR：3.35CI95%[1.27-8.86]）、无进展生存期（p<0.001；HR：3.15CI95%[1.75-5.66]）和反应率（p=0.033；HR：0.33CI95%[0.12-0.92]）显著相关，高 DPD 活性与显著的不良影响相关。
DPD 状态筛查应采用双管齐下的方法，低内在 DPD 时减少 FP 剂量，反之，高内在 DPD 时增加 FP 剂量。在个性化 FP 为基础治疗的背景下，这种创新策略需要前瞻性验证。
