Pronk L C, Schrijvers D, Schellens J H, de Bruijn E A, Planting A S, Locci-Tonelli D, Groult V, Verweij J, van Oosterom A T
Department of Medical Oncology, Rotterdam Cancer Institute (Dr. Daniel den Hoed Kliniek) and University Hospital Rotterdam, The Netherlands.
Semin Oncol. 1998 Feb;25(1 Suppl 2):23-8.
Docetaxel is a new antimicrotubule agent that has been shown to be active against a variety of solid tumors. Ifosfamide is an alkylating drug that has demonstrated activity against non-small cell lung cancer, testicular cancer, breast cancer, and soft tissue sarcoma. This phase I study of the combination of these drugs was performed to assess the feasibility of using the two agents together, to determine the maximum tolerated dose and the side effects, and to propose a safe schedule for further phase II studies. Thirty-four patients with histologically confirmed solid tumors who had not been treated previously with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-hour infusion followed by ifosfamide as a 24-hour infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg/m2 and ifosfamide doses from 2.5 to 5.0 g/m2. Grades 3 and 4 granulocytopenia were observed in 89% of courses and appeared to be of short duration and related to the ifosfamide dose. Febrile neutropenia and sepsis occurred in 17% and 2% of courses, respectively. Severe anemia and thrombocytopenia were uncommon. Nonhematologic toxicities were mild to moderate, and included alopecia, nausea, vomiting, mucositis, diarrhea, sensory neuropathy, skin and nail toxicity, hypersensitivity reactions, and edema. Schedule B appeared to induce more gastrointestinal toxicity than schedule A. One complete response in soft tissue sarcoma and two partial responses, one in cancer of unknown primary and the other in non-small cell lung cancer, were documented. The dose-limiting toxicity for schedule A was neutropenic fever at a dose of 85 mg/m2 docetaxel and 5 g/m2 ifosfamide. The dose-limiting toxicity for schedule B was neutropenic fever at a dose of 75 mg/m2 docetaxel and 4 g/m2 ifosfamide. A dose of 75 mg/m2 docetaxel combined with 5 g/m2 ifosfamide according to schedule A can be recommended for further studies.
多西他赛是一种新型抗微管药物，已显示对多种实体瘤有效。异环磷酰胺是一种烷化剂，已证明对非小细胞肺癌、睾丸癌、乳腺癌和软组织肉瘤有活性。进行这项关于这两种药物联合使用的I期研究，以评估两种药物联合使用的可行性，确定最大耐受剂量和副作用，并为进一步的II期研究提出安全的给药方案。34例组织学确诊的实体瘤患者进入研究，这些患者之前未接受过紫杉烷类或异环磷酰胺治疗，且晚期疾病接受的化疗不超过一线。治疗方案包括多西他赛静脉滴注1小时，随后异环磷酰胺静脉滴注24小时（方案A），或异环磷酰胺后接多西他赛（方案B），每3周进行一次。多西他赛剂量范围为60至85mg/m²，异环磷酰胺剂量范围为2.5至5.0g/m²。89%的疗程观察到3级和4级粒细胞减少，且似乎持续时间较短，与异环磷酰胺剂量有关。发热性中性粒细胞减少和败血症分别发生在17%和2%的疗程中。严重贫血和血小板减少并不常见。非血液学毒性为轻度至中度，包括脱发、恶心、呕吐、粘膜炎、腹泻、感觉神经病变、皮肤和指甲毒性、过敏反应和水肿。方案B似乎比方案A引起更多的胃肠道毒性。记录到1例软组织肉瘤完全缓解和2例部分缓解，1例原发灶不明癌和1例非小细胞肺癌部分缓解。方案A的剂量限制性毒性是多西他赛85mg/m²和异环磷酰胺5g/m²时的中性粒细胞减少性发热。方案B的剂量限制性毒性是多西他赛75mg/m²和异环磷酰胺4g/m²时的中性粒细胞减少性发热。可推荐按照方案A将多西他赛75mg/m²与异环磷酰胺5g/m²联合用于进一步研究。
