Coleman C N, Noll L, Riese N, Buswell L, Howes A E, Loeffler J S, Alexander E, Wen P, Harris J R, Kramer R A
Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA 02115.
Int J Radiat Oncol Biol Phys. 1992;22(3):577-80. doi: 10.1016/0360-3016(92)90880-q.
Seventy-eight patients have been treated on a Phase I trial using continuous infusion etanidazole while undergoing brachytherapy for locally advanced tumors. There were two sequential schemata, the first treated 63 patients with doses ranging from 8-23 g/m2 over 48 hr and the second treated 15 patients with doses ranging from 20-23 g/m2 over 96 hr. The tumor sites were: brain (n = 42), cervix (n = 22), and breast (n = 14). Patients received a loading dose of etanidazole of 2 g/m2 followed by a continuous infusion for a total of 48 or 96 hr while radioactive implants were in place. Of the 63 patients in the 48-hr study, 52 were entered at doses of less than or equal to 21 g/m2 and there were no definite neuropathies but two patients with the cramping/arthralgia syndrome. Of the 11 patients entered at 22-23 g/m2, 1 patient had symptoms of peripheral neuropathy (Grade II) and 6 had the cramping/arthralgia syndrome. This is a new syndrome, distinct from the peripheral neuropathy, characterized by transient alterations in sensations consisting of cramping, arthralgias, or tingling that resolved completely at intervals varying from a few hours to about 1 week post-treatment. The cramping/arthralgia syndrome limited dose escalation; therefore, the maximum tolerated dose over 48 hr was determined to be 20-21 g/m2. The 96-hr infusion was limited to patients with recurrent gliomas undergoing stereotactic implantation. To date, 15 patients have been treated with doses of 20-23 g/m2. No toxicity was encountered at doses less than or equal to 22 g/m2. At 23 g/m2, one patient developed Grade III neuropathy and three patients had mild cramping/arthralgia syndrome, for whom the drug was discontinued. Therefore, it appears the maximum tolerated dose at 96 hr will be approximately 23 g/m2, which is 10-15% higher than for the 48-hr infusion.
78例患者在一项I期试验中接受了持续输注乙磺硝唑治疗，同时接受近距离放射治疗以治疗局部晚期肿瘤。试验采用了两个连续的方案，第一个方案治疗了63例患者，剂量在48小时内为8 - 23 g/m²，第二个方案治疗了15例患者，剂量在96小时内为20 - 23 g/m²。肿瘤部位包括：脑（n = 42）、宫颈（n = 22）和乳腺（n = 14）。患者先接受2 g/m²的乙磺硝唑负荷剂量，然后在放射性植入物在位期间持续输注48或96小时。在48小时研究的63例患者中，52例的输入剂量小于或等于21 g/m²，未出现明确的神经病变，但有2例患者出现痉挛/关节痛综合征。在输入剂量为22 - 23 g/m²的11例患者中，1例出现周围神经病变症状（II级），6例出现痉挛/关节痛综合征。这是一种不同于周围神经病变的新综合征，其特征为感觉的短暂改变，包括痉挛、关节痛或刺痛，在治疗后数小时至约1周的不同间隔时间内完全缓解。痉挛/关节痛综合征限制了剂量递增；因此，48小时内的最大耐受剂量被确定为20 - 21 g/m²。96小时输注仅限于接受立体定向植入的复发性胶质瘤患者。迄今为止，15例患者接受了20 - 23 g/m²的剂量治疗。在剂量小于或等于22 g/m²时未出现毒性反应。在23 g/m²时，1例患者出现III级神经病变，3例患者出现轻度痉挛/关节痛综合征，这3例患者的药物治疗被停用。因此，96小时时的最大耐受剂量似乎约为23 g/m²，比48小时输注时高10 - 15%。
