McDonald S, Meyerowitz C, Smudzin T, Rubin P
Department of Radiation Oncology, University of Rochester Medical and Dental Center, NY 14642.
Int J Radiat Oncol Biol Phys. 1994 Jul 1;29(4):747-54. doi: 10.1016/0360-3016(94)90562-2.
Based on in vivo evidence of radioprotection of the salivary glands using WR-2721, a pilot study was undertaken to determine the feasibility, toxicity, and salivary function of patients receiving WR-2721, while undergoing radiation therapy to the head and neck.
Patients undergoing radiation therapy for cancer of the head and neck were eligible if the major salivary glands received more than 45 Gy. WR-2721 was administered over 6 min IV, 10-15 min prior to each dose of radiation five times per week. Saliva was collected and measured prior to radiation therapy, weekly during radiation therapy, 1 month postradiation therapy, and every 3 months thereafter. Flow rates of unstimulated whole saliva, stimulated whole saliva, and stimulated parotid saliva were measured using standard techniques. 99mTc salivary scintiscans were performed prior to radiation therapy, 1 month postradiation therapy and every 3 months thereafter. Nine patients are presently enrolled on the first dose level (100 mg/m2) of this study. Eight completed per protocol, two with minor decreases of total WR-2721 doses. Two patients progressed with distant metastases soon after completion of therapy. All available data are included in the analysis. Median follow-up for all patients is 18 months.
Flow rates of unstimulated whole saliva decreased significantly during radiation therapy reaching 5.6% of baseline at 9 months postradiation therapy, subsequently recovering to 20% of baseline, then remaining stable over time. Stimulated whole salivary flow rate similarly decreased during radiation therapy and reached its nadir (11% of baseline) at 3 months postradiation therapy, improving to 27% of baseline by 2 years. The stimulated parotid flow rate decreased during radiation therapy to 1.4% of pretreatment levels. Significant recovery took place 6 months postradiation therapy and by 18 months values had recovered to 54% of baseline. 99mTc salivary scintiscans confirmed this rebound of parotid function postradiation therapy. Toxicity was minimal with the exception of one patient who received only 27% of the planned total drug dose due to grade 3 hypotension after the eighth treatment. No recovery of salivary function has been seen in this patient; flow rates remain zero in all three areas tested 21 months after radiation.
Administration of WR-2721 prior to each dose of radiation was feasible and without significant toxicity at 100 mg/m2. Salivary gland function improved over time after completion of radiation, particularly the parotid. Future directions include escalation of WR-2721 dose to 200 mg/m2 and then 300 mg/m2, and a Phase III randomized trial will be undertaken once the optimal dose is established.
基于WR-2721对唾液腺具有辐射防护作用的体内证据，开展了一项初步研究，以确定接受WR-2721治疗的头颈部放疗患者的可行性、毒性和唾液功能。
如果主要唾液腺接受的辐射剂量超过45 Gy，则接受头颈部癌症放疗的患者符合条件。WR-2721在每次放疗剂量前10 - 15分钟静脉注射，持续6分钟，每周5次。在放疗前、放疗期间每周、放疗后1个月以及此后每3个月收集并测量唾液。使用标准技术测量未刺激全唾液、刺激全唾液和刺激腮腺唾液的流速。在放疗前、放疗后1个月以及此后每3个月进行99mTc唾液闪烁扫描。目前有9名患者登记参加本研究的第一剂量水平（100 mg/m2）。8名患者按方案完成研究，2名患者的WR-2721总剂量略有减少。2名患者在治疗完成后不久出现远处转移进展。所有可用数据均纳入分析。所有患者的中位随访时间为18个月。
放疗期间未刺激全唾液流速显著下降，在放疗后9个月降至基线的5.6%，随后恢复至基线的20%，然后随时间保持稳定。刺激全唾液流速在放疗期间同样下降，在放疗后3个月达到最低点（基线的11%），到2年时改善至基线的27%。刺激腮腺流速在放疗期间降至治疗前水平的1.4%。放疗后6个月出现显著恢复，到18个月时恢复至基线的54%。99mTc唾液闪烁扫描证实了放疗后腮腺功能的这种反弹。除一名患者外，毒性极小，该患者在第八次治疗后因3级低血压仅接受了计划总药物剂量的27%。该患者未观察到唾液功能恢复；放疗后21个月，所有三个测试区域的流速仍为零。
在每次放疗前给予WR-2721是可行的，在100 mg/m2剂量下无明显毒性。放疗结束后，唾液腺功能随时间改善，尤其是腮腺。未来的方向包括将WR-2721剂量逐步提高至200 mg/m2，然后提高至300 mg/m2，一旦确定最佳剂量，将开展III期随机试验。
