Saif Muhammad Wasif, Juneja Vinni, Black Glenda, Thronton Jennifer, Johnson Martin R, Diasio Robert B
Yale University, New Haven, CT.
Support Cancer Ther. 2007 Sep 1;4(4):211-8. doi: 10.3816/SCT.2007.n.017.
Palmar-plantar erythordysesthesia (PPE) is the most common toxicity of capecitabine. Preclinical studies have shown that radiation therapy (RT) upregulates thymidine phosphorylase (TP), which could in turn increase the efficacy of capecitabine. Capecitabine is degraded by dihydropyrimidine dehydrogenase (DPD), and a deficiency in this enzyme can increase the toxicity of capecitabine. However, the effect of radiation therapy on frequency of PPE and association with TP and DPD has not been fully characterized.
Toxicity data were collected prospectively in 33 patients and retrospectively in 25 patients with locally advanced pancreatic cancer enrolled in 3 clinical trials who received capecitabine/RT followed by capecitabine alone. Tumor specimens on 33 patients were procured via endoscopic ultrasonography standards 1 week befoer RT and 2 weeks after RT to evaluate TP and DPD messenger RNA levels. Roche grading was used to assess PPE.
Among 58 patients, 14 (24%) developed PPE. The capecitabine group tended to have a higher incidence of PPE than the capecitabine/RT group (17.2% vs. 10.3%; P = .12). Grade 2/3 PPE, was observed in 15.5% of patients receiving capecitabine and 1.7% of patients receiving capecitabine/RT (P = .0078; overall: 17.2%). Median cumulative dose of capecitabine for first development of PPE was 235,000 mg/m2 in the capecitabine/RT group, and 3,185,000 mg/m2 in the capecitabine group, with the relative frequency of an event occurring in the capecitabine/RT arm versus capecitabine of 0.59. Time to occurrence of first episode of PPE was a median of 5 weeks with capecitabine/RT and 6 weeks with capecitabine. Log-rank test showed that neither age, sex, performance status, nor ethnicity were associated with development of PPE. There was no clear difference in tumor responses of patients who had PPE versus those who did not have PPE. Mean tumor TP level was higher among patients with versus without PPE (275.77 vs. 215.29; P = .32). Mean tumor DPD level was lower among patients with versus without PPE (55.18 vs. 63.58; P = .49). Mean TP-DPD ratio was higher among patients with versus without PPE (10.29 vs. 3.04; P = .31).
No significant association of PPE with higher tumor thymidine phosphorylase or lower tumor DPD levels was found. There was no difference in the incidence, severity, or time to occurrence of PPE with capecitabine/RT versus capecitabine, indicating no effect of RT. Further studies to evaluate the underlying mechanism of PPE are required.
手足红斑性感觉异常（PPE）是卡培他滨最常见的毒性反应。临床前研究表明，放射治疗（RT）可上调胸苷磷酸化酶（TP），进而可能提高卡培他滨的疗效。卡培他滨由二氢嘧啶脱氢酶（DPD）降解，该酶缺乏会增加卡培他滨的毒性。然而，放射治疗对PPE发生率的影响以及与TP和DPD的关联尚未完全明确。
前瞻性收集了33例患者的毒性数据，并回顾性收集了25例局部晚期胰腺癌患者的毒性数据，这些患者参加了3项临床试验，接受卡培他滨/放疗，随后单独使用卡培他滨。在放疗前1周和放疗后2周，按照内镜超声标准获取33例患者的肿瘤标本，以评估TP和DPD信使核糖核酸水平。采用罗氏分级法评估PPE。
58例患者中，14例（24%）发生了PPE。卡培他滨组的PPE发生率倾向于高于卡培他滨/放疗组（17.2%对10.3%；P = 0.12）。接受卡培他滨治疗的患者中15.5%出现2/3级PPE，接受卡培他滨/放疗的患者中1.7%出现2/3级PPE（P = 0.0078；总体：17.2%）。卡培他滨/放疗组首次发生PPE时的卡培他滨累积剂量中位数为235,000 mg/m²，卡培他滨组为3,185,000 mg/m²，卡培他滨/放疗组与卡培他滨组发生事件的相对频率为0.59。卡培他滨/放疗组首次发生PPE的时间中位数为5周，卡培他滨组为6周。对数秩检验显示，年龄、性别、体能状态和种族均与PPE的发生无关。发生PPE的患者与未发生PPE的患者在肿瘤反应方面无明显差异。发生PPE的患者的平均肿瘤TP水平高于未发生PPE的患者（275.77对215.29；P = 0.32）。发生PPE的患者的平均肿瘤DPD水平低于未发生PPE的患者（55.18对63.58；P = 0.49）。发生PPE的患者的平均TP-DPD比值高于未发生PPE的患者（10.29对3.04；P = 0.31）。
未发现PPE与较高的肿瘤胸苷磷酸化酶或较低的肿瘤DPD水平有显著关联。卡培他滨/放疗组与卡培他滨组在PPE的发生率、严重程度或发生时间上无差异，表明放疗无影响。需要进一步研究以评估PPE的潜在机制。
