Epstein A H, Lebovics R S, Goffman T, Teague D, Fuetsch E S, Glatstein E, Okunieff P, Cook J A
Radiation Oncology Branch, National Cancer Institute, Bethesda, Md.
J Natl Cancer Inst. 1994 Dec 7;86(23):1775-80. doi: 10.1093/jnci/86.23.1775.
The halogenated pyrimidines 5'-iododeoxyuridine (IdUrd) and 5'-bromodeoxyuridine (BrdUrd) are under active study as radiation sensitizers for a variety of malignancies. Head and neck neoplasms may also be suitable for halogenated pyrimidine-mediated sensitization; previous regimens using intra-arterial BrdUrd delivery, however, were poorly tolerated.
A pilot study was undertaken with the use of intravenous IdUrd with hyperfractionated radiotherapy to assess tolerance. In addition, serial tumor biopsy specimens were obtained to determine the kinetics of IdUrd labeling and incorporation.
Twelve patients with squamous cell carcinomas of the head and neck (one patient had stage II cancer, one had stage III, and 10 had stage IV) were treated with hyperfractionated radiation therapy at a dose of 1.2 or 1.5 Gy twice a day, to a total dose in the range of 70-76 Gy. IdUrd (1000 mg/m2 per day) was infused for a maximum of 14 days at the beginning and then again during the middle of the radiotherapy. A tumor biopsy specimen was obtained from 11 patients following initiation of treatment with IdUrd. Eight patients consented to serial biopsy to allow the study of IdUrd-labeling indices and thymidine replacement over time. Incorporation of IdUrd into tumor DNA was determined by high-performance liquid chromatography, and cell labeling was determined with the use of an anti-BrdUrd/IdUrd monoclonal antibody in conjunction with flow cytometry. Patients continue to be followed to assess local control.
A plot of corrected IdUrd replacement as a function of infusion time suggests the possibility of a plateau after 5-7 days of infusion at 7.5%-8%. The average rate of replacement from days 1 to 5 was 1.3% per day and was determined by linear regression analysis. Acute toxic effects, especially mucositis, were severe enough to require delays in the radiation therapy. Eleven of 12 patients treated had complete clinical remissions. Seven of these patients remain clinically free of local disease at the time of death or most recent follow-up.
The level of IdUrd incorporation and cell labeling should be adequate to produce sensitization. However, the treatment as prescribed in this study (two 14-day infusions of IdUrd during radical radiotherapy with only one planned split) was not completed in a single patient because of either dose-limiting hematologic toxicity or severe mucositis necessitating treatment break. Since this particular regimen is not tolerable, future protocols will have shorter exposures to IdUrd.
Previous regimens using halogenated pyrimidine radiosensitizers have generally used protracted drug delivery schedules. In this study, a high level of IdUrd labeling was measured after 5-7 days of drug infusion. The halogenated pyrimidines deserve further study with the use of repetitive short courses to reduce toxicity and possibly improve efficacy.
卤代嘧啶5'-碘脱氧尿苷（IdUrd）和5'-溴脱氧尿苷（BrdUrd）作为多种恶性肿瘤的辐射增敏剂正在积极研究中。头颈部肿瘤也可能适用于卤代嘧啶介导的增敏作用；然而，先前使用动脉内注射BrdUrd的方案耐受性较差。
进行一项试点研究，使用静脉注射IdUrd联合超分割放疗来评估耐受性。此外，获取系列肿瘤活检标本以确定IdUrd标记和掺入的动力学。
12名头颈部鳞状细胞癌患者（1例为II期癌症，1例为III期，10例为IV期）接受超分割放射治疗，剂量为每天两次，每次1.2或1.5 Gy，总剂量在70 - 76 Gy范围内。IdUrd（每天1000 mg/m²）在放疗开始时最多输注14天，然后在放疗中期再次输注。在开始使用IdUrd治疗后，从11例患者中获取肿瘤活检标本。8例患者同意进行系列活检，以便研究IdUrd标记指数和随时间的胸腺嘧啶替代情况。通过高效液相色谱法测定IdUrd掺入肿瘤DNA的情况，并使用抗BrdUrd/IdUrd单克隆抗体结合流式细胞术测定细胞标记情况。继续对患者进行随访以评估局部控制情况。
将校正后的IdUrd替代量作为输注时间的函数作图表明，在以7.5% - 8%的速率输注5 - 7天后有可能达到平台期。通过线性回归分析确定，第1天至第5天的平均替代率为每天1.3%。急性毒性作用，尤其是粘膜炎，严重到足以导致放疗延迟。接受治疗的12例患者中有11例实现了完全临床缓解。这些患者中有7例在死亡或最近一次随访时临床上无局部疾病。
IdUrd的掺入水平和细胞标记应该足以产生增敏作用。然而，本研究中规定的治疗方案（在根治性放疗期间两次输注IdUrd，每次14天，仅计划一次分割）没有一名患者完成，原因是出现了剂量限制性血液学毒性或严重粘膜炎需要中断治疗。由于这种特定方案不可耐受，未来的方案将缩短IdUrd的暴露时间。
先前使用卤代嘧啶放射增敏剂的方案通常采用长期给药方案。在本研究中，药物输注5 - 7天后测量到高水平的IdUrd标记。卤代嘧啶值得进一步研究，采用重复短疗程以降低毒性并可能提高疗效。
