Illum Henrik, Wang David H, Dowell Jonathan E, Hittson William J, Torrisi John R, Meyer Jeffrey, Huerta Sergio
VA North Texas Health Care System Department of Hematology Oncology, Radiation Oncology, and Surgery/University of Texas Southwestern, Department of Surgery and Radiation Oncology, Dallas, TX.
VA North Texas Health Care System Department of Hematology Oncology, Radiation Oncology, and Surgery/University of Texas Southwestern, Department of Surgery and Radiation Oncology, Dallas, TX.
Surgery. 2015 Aug;158(2):460-5. doi: 10.1016/j.surg.2015.04.007. Epub 2015 May 9.
Nitric oxide donors decreased cell survival in vitro and tumor load in vivo in models of rectal cancer subjected to ionizing radiation. Nitroglycerin (NTG) transdermal patches, added to chemotherapy, have been shown to improve outcomes in lung cancer patients.
This open-label, nonrandomized, multicohort, dose escalation, phase I trial had a primary endpoint to evaluate the safety, tolerability, feasibility, dose-limiting toxicity and maximum tolerated dose of topical NTG in addition to 5-fluorouracil and radiation therapy for neoadjuvant treatment of locoregionally advanced operable rectal cancer. The secondary endpoint was rate of pathologic complete response (pCR). Patients were assigned to 3 sequential cohorts of escalating dose levels of commercially available NTG patches (0.2, 0.4, and 0.6 mg/h), each cohort was intended to consist of 3 patients.
Thirteen patients were enrolled in the trial as specified in the dose escalation protocol. They were all male with a median age of 59.4 ± 2.5 (SEM) years. The observed toxicities were mild to moderate and manageable. Four patients developed asymptomatic grade 3 lymphopenia during the chemoradiation that resolved promptly upon completion. One patient had a non-ST segment elevation MI and 1 patient developed diarrhea. None of these toxicities were attributed to NTG except for 1 patient who developed a grade 3 headache. This required an additional group of patients at the same dose and no other patient experienced headaches. pCR was 17%.
NTG patches are well-tolerated and it is feasible to proceed with a phase II trial at the maximum dose examined (0.6 mg/h).
在接受电离辐射的直肠癌模型中，一氧化氮供体可降低体外细胞存活率和体内肿瘤负荷。已证明，在化疗中添加硝酸甘油（NTG）透皮贴剂可改善肺癌患者的预后。
本开放标签、非随机、多队列、剂量递增的I期试验的主要终点是评估除5-氟尿嘧啶和放疗外，局部使用NTG用于局部晚期可手术直肠癌新辅助治疗的安全性、耐受性、可行性、剂量限制性毒性和最大耐受剂量。次要终点是病理完全缓解（pCR）率。患者被分配到3个连续队列，使用市售NTG贴剂的剂量水平递增（0.2、0.4和0.6 mg/h），每个队列计划由3名患者组成。
按照剂量递增方案，13名患者入组该试验。他们均为男性，中位年龄为59.4±2.5（SEM）岁。观察到的毒性为轻度至中度且可控制。4名患者在放化疗期间出现无症状3级淋巴细胞减少，完成后迅速缓解。1名患者发生非ST段抬高型心肌梗死，1名患者出现腹泻。除1名出现3级头痛的患者外，这些毒性均未归因于NTG。这需要同一剂量组增加一组患者，且没有其他患者出现头痛。pCR为17%。
NTG贴剂耐受性良好，在最大检测剂量（0.6 mg/h）下进行II期试验是可行的。
