Hoffmann E, Toepell A, Peter A, Böke S, De-Colle C, Steinle M, Niyazi M, Gani C
University Hospital for Radiation Oncology and Radiotherapy, University Hospital Tübingen, Tübingen, Germany.
Department for Diagnostic Laboratory Medicine, Institute for Clinical Chemistry and Pathobiochemistry, University Hospital Tübingen, Tübingen, Germany.
Strahlenther Onkol. 2024 Sep 4. doi: 10.1007/s00066-024-02287-7.
5‑Fluoruracil (5-FU) and its oral prodrug capecitabine are mainstays in combined chemoradiotherapy regimens. They are metabolized by dihydropyrimidine dehydrogenase (DPYD). Pathogenic variants of the DPYD gene cause a reduction in DPYD activity, leading to possibly severe toxicities. Therefore, patients receiving 5‑FU-/capecitabine-based chemoradiotherapy should be tested for DPYD variants. However, there are limited clinical data on treatment adjustments and tolerability in patients with decreased DPYP activity receiving combined chemoradiotherapy. Therefore, a retrospective analysis of the toxicity profiles of patients with decreased DPYD activity treated at our center was conducted.
For all patients receiving 5‑FU-/capecitabine-based chemo(radio)therapy at our department, DPYD activity was routinely tested. Genotyping of four DPYD variants (DPYD2A, DPYD13, c.2846A > T, and haplotype B3) was conducted according to the recommendation of the German Society for Hematooncology (DGHO) using TaqMan hydrolysis polymerase chain reaction (PCR; QuantStudy 3, Thermo FisherScientific, Darmstadt). DPYD variants and activity score as well as clinical data (tumor entity, treatment protocol, dose adjustments, and toxicity according to the Common Terminology Criteria for Adverse Events [CTCAE]) were assessed and reported.
Of 261 tested patients, 21 exhibited DPYD variants, 18 of whom received chemoradiotherapy. All but one patient was treated for rectal or anal carcinoma. The observed rate of DPYD variants was 8.0%, and heterozygous haplotype B3 was the most common (5.75%). One patient exhibited a homozygous DPYD variant. DPYD activity score was at least 0.5 in heterozygous patients; chemotherapy dose was adjusted accordingly, with an applied dose of 50-75%. CTCAE grade 2 skin toxicity (50%) and grade 3 leukopenia (33.3%) were most common. One patient experienced a transient grade 4 increase in transaminases. All high-grade toxicities were manageable with supportive treatment and transient. No CTCAE grade 5 toxicities related to 5‑FU administration were observed.
With dose reduction in heterozygous patients, toxicity was within the range of patients without DPYD variants. Our clinical data suggest that dose-adapted 5‑FU-/capecitabine-chemoradiotherapy regimens can be safely considered in patients with heterozygous clinically relevant DPYD variants, but that the optimal dosage still needs to be determined to avoid both increased toxicity and undertreatment in a curative setting.
5-氟尿嘧啶（5-FU）及其口服前体药物卡培他滨是联合放化疗方案的主要药物。它们由二氢嘧啶脱氢酶（DPYD）代谢。DPYD基因的致病变异会导致DPYD活性降低，可能引发严重毒性。因此，接受基于5-FU/卡培他滨的放化疗患者应检测DPYD变异。然而，关于DPYD活性降低的患者接受联合放化疗时治疗调整和耐受性的临床数据有限。因此，我们对在本中心接受治疗的DPYD活性降低患者的毒性特征进行了回顾性分析。
对于在我科接受基于5-FU/卡培他滨的化疗（放疗）的所有患者，常规检测DPYD活性。根据德国血液肿瘤学会（DGHO）的建议，使用TaqMan水解聚合酶链反应（PCR；QuantStudy 3，赛默飞世尔科技，达姆施塔特）对四个DPYD变异（DPYD2A、DPYD13、c.2846A>T和单倍型B3）进行基因分型。评估并报告DPYD变异、活性评分以及临床数据（肿瘤类型、治疗方案、剂量调整和根据不良事件通用术语标准[CTCAE]的毒性）。
在261例接受检测的患者中，21例存在DPYD变异，其中18例接受了放化疗。除1例患者外，所有患者均接受直肠癌或肛管癌治疗。观察到的DPYD变异率为8.0%，杂合单倍型B3最为常见（5.75%）。1例患者表现为纯合DPYD变异。杂合患者的DPYD活性评分至少为0.5；化疗剂量相应调整，应用剂量为50-75%。CTCAE 2级皮肤毒性（50%）和3级白细胞减少（33.3%）最为常见。1例患者转氨酶短暂升高至4级。所有高级别毒性通过支持治疗均可控制且为短暂性。未观察到与5-FU给药相关的CTCAE 5级毒性。
通过降低杂合患者的剂量，毒性在无DPYD变异患者的范围内。我们的临床数据表明，对于具有临床相关杂合DPYD变异的患者，可以安全地考虑采用剂量适应性5-FU/卡培他滨放化疗方案，但仍需要确定最佳剂量，以避免在根治性治疗中增加毒性和治疗不足。
