Rostomily R C, Spence A M, Duong D, McCormick K, Bland M, Berger M S
Department of Neurological Surgery, University of Washington, Seattle.
Neurosurgery. 1994 Sep;35(3):378-88; discussion 388. doi: 10.1227/00006123-199409000-00004.
Fifty-one adult patients with recurrent malignant gliomas were treated in a Phase II trial of multidrug chemotherapy (6-thioguanine, dibromodulcitol, procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 5-fluorouracil, and hydroxyurea). Thirty-one patients underwent radical tumor debulking, before the administration of chemotherapy. Fifty-seven percent of all patients had either an objective radiographic response or stabilization of disease after the institution of therapy. The overall median survival time (MST) was 40 weeks; it was 79 and 33 weeks for anaplastic astrocytoma and glioblastoma patients, respectively. The overall median time to tumor progression (MTP) was 19 weeks--32 weeks for anaplastic astrocytoma patients and 13 weeks for glioblastoma patients. Serious chemotoxicity occurred in 35% of patients without permanent morbidity or mortality. The factors that affected response (including disease stabilization), MTP, and MST were identified through a multivariate statistical analysis. A longer MTP was associated with higher Karnofsky scores, lower grade initial histology, lack of prior chemotherapy, greater degree of myelotoxicity, smaller postoperative tumor volumes, greater extent of surgical resection, and a local versus diffuse recurrence pattern. A longer MST was associated with higher Karnofsky scores, lower grade histology at the time of recurrence, greater degree of myelotoxicity, and lobar versus deep tumor location. Response (including disease stabilization) correlated with higher Karnofsky scores, lower grade histology (initial and current), prior lower grade histology, smaller preoperative tumor volume, longer intervals from the time of initial diagnosis, and absence of prior chemotherapy. These results suggest that, in addition to established prognostic factors such as Karnofsky scores, other factors including prior chemotherapy administration, patterns of tumor recurrence, and tumor location may be important variables to consider in future Phase II-III clinical trials. Of the treatment variables analyzed, greater surgical debulking and smaller postoperative tumor volumes were associated with prolonged MTP but not MST, and greater myelotoxicity had a positive association with all outcomes. The significance of this latter relationship and its relevance to chemotherapy dosing will require further study. Standardization in the design and reporting of clinical trials and the use of computer-assisted tumor volume calculations to assess the extent of surgical resection and the response to therapy are advocated.
51例复发性恶性胶质瘤成年患者参加了一项多药化疗（6-硫鸟嘌呤、二溴卫矛醇、丙卡巴肼、1-(2-氯乙基)-3-环己基-1-亚硝基脲、5-氟尿嘧啶和羟基脲）的II期试验。31例患者在化疗前接受了根治性肿瘤切除。治疗开始后，所有患者中有57%出现了影像学客观缓解或疾病稳定。总体中位生存时间（MST）为40周；间变性星形细胞瘤和胶质母细胞瘤患者的MST分别为79周和33周。总体肿瘤进展中位时间（MTP）为19周，间变性星形细胞瘤患者为32周，胶质母细胞瘤患者为13周。35%的患者出现严重的化疗毒性，但无永久性发病或死亡。通过多变量统计分析确定了影响缓解（包括疾病稳定）、MTP和MST的因素。较长的MTP与较高的卡诺夫斯基评分、较低级别的初始组织学、无既往化疗、较高程度的骨髓毒性、较小的术后肿瘤体积、较大的手术切除范围以及局部复发与弥漫性复发模式相关。较长的MST与较高的卡诺夫斯基评分、复发时较低级别的组织学、较高程度的骨髓毒性以及肿瘤位于叶与深部位置相关。缓解（包括疾病稳定）与较高的卡诺夫斯基评分、较低级别的组织学（初始和当前）、既往较低级别的组织学、较小的术前肿瘤体积、从初始诊断时间起较长的间隔以及无既往化疗相关。这些结果表明，除了卡诺夫斯基评分等既定的预后因素外，其他因素，包括既往化疗给药、肿瘤复发模式和肿瘤位置，可能是未来II-III期临床试验中需要考虑的重要变量。在所分析的治疗变量中，更大范围的手术切除和更小的术后肿瘤体积与延长的MTP相关，但与MST无关，而更大程度的骨髓毒性与所有结果均呈正相关。后一种关系的意义及其与化疗剂量的相关性需要进一步研究。提倡临床试验设计和报告的标准化以及使用计算机辅助肿瘤体积计算来评估手术切除范围和对治疗的反应。
