Noda K, Hirabayashi K, Terashima Y, Ozaki M, Yakushiji M, Hatae M, Kanazawa K
Dept. of Obstetrics and Gynecology, Kinki University School of Medicine.
Gan To Kagaku Ryoho. 1997 Aug;24(10):1285-93.
A preliminary co-operative study by 7 institutes was conducted to determine the optimal dosage of the combination regimen with nedaplatin, bleomycin and ifosfamide, which is used in a phase III clinical study, to investigate its efficacy as neoadjuvant chemotherapy against advanced cervical cancer of the uterus. The drug administration consisted of 3 step; in the first step, nedaplatin and bleomycin were administered in a single dose at 80 mg/m2 and a 6-day dose at 7.5 mg/body/day, respectively, and this combination treatment was repeated every 4 weeks. After confirming the safety and efficacy of this combination regimen, the second-step treatment was started in which a 5-day dose of ifosfamide at 600 mg/m2/day was added to the combination regimen of the first step. In the third step, this three-drug combination regimen was used with the daily dose of ifosfamide increased up to 1,200 mg/m2. The drug administration was conducted in a total of 16 cases, consisting of 3 cases in the first step, 7 in the second step and 6 in the third step, which were all evaluable for tumor response and safety. Regarding tumor response, a 33.3% (1/3) of response rate was obtained in the first step, 71.4% (5/7) in the second step and 66.7% (4/6) in the third step. As for safety, bone marrow suppression indicated by grade 4 abnormal clinical laboratory test values was found in one case each in the second step (leukopenia and thrombocytopenia) and the third step (leukopenia). Thus, bone marrow suppression, mainly leukopenia and thro mbocytopenia, was regarded as the dose limiting factor of this three-drug combination regimen. The leucocyte and thrombocyte counts reached their nadirs at two weeks after administration with recovery in about two weeks. The other abnormal changes in clinical laboratory test values such as those indicating the effects on renal function were slight even in the third step. Nausea and vomiting, anorexia and fever were found in every step with high incidences. Alopecia was found in all cases of the third step. Based on the above results, the dosage of the third step (combination regimen with a single dose of nedaplatin at 80 mg/m2, 6-day dose of bleomycin at 7.5 mg/body/day and 5-day dose of ifosfamide at 1,200 mg/m2/day, repeated every 4 weeks) was considered to be the optimal dosage in the phase III clinical study for advanced cervical cancer of the uterus.
7家机构进行了一项初步合作研究，以确定用于III期临床研究的奈达铂、博来霉素和异环磷酰胺联合方案的最佳剂量，研究其作为晚期子宫颈癌新辅助化疗的疗效。给药分3个步骤进行：第一步，奈达铂和博来霉素分别以80mg/m²的单次剂量和7.5mg/体/天的6天剂量给药，这种联合治疗每4周重复一次。在确认该联合方案的安全性和疗效后，开始第二步治疗，即在第一步的联合方案中加入600mg/m²/天的5天剂量异环磷酰胺。第三步，使用这种三药联合方案，异环磷酰胺的每日剂量增加至1200mg/m²。总共对16例患者进行了给药，第一步3例，第二步7例，第三步6例，所有患者均对肿瘤反应和安全性可进行评估。关于肿瘤反应，第一步的有效率为33.3%（1/3），第二步为71.4%（5/7），第三步为66.7%（4/6）。在安全性方面，第二步（白细胞减少和血小板减少）和第三步（白细胞减少）各有1例出现4级异常临床实验室检查值提示的骨髓抑制。因此，骨髓抑制，主要是白细胞减少和血小板减少，被认为是这种三药联合方案的剂量限制因素。白细胞和血小板计数在给药后两周达到最低点，约两周后恢复。即使在第三步，其他提示对肾功能影响的临床实验室检查值的异常变化也很轻微。每一步都有高发生率的恶心、呕吐、厌食和发热。第三步的所有病例均出现脱发。基于上述结果，第三步的剂量（奈达铂单次剂量80mg/m²、博来霉素6天剂量7.5mg/体/天和异环磷酰胺5天剂量1200mg/m²/天的联合方案，每4周重复一次）被认为是晚期子宫颈癌III期临床研究的最佳剂量。
