Kushner B H, Meyers P A, Gerald W L, Healey J H, La Quaglia M P, Boland P, Wollner N, Casper E S, Aledo A, Heller G
Department of Medical Imaging, Memorial Sloan-Kettering Cancer Center New York, NY 10021, USA.
J Clin Oncol. 1995 Nov;13(11):2796-804. doi: 10.1200/JCO.1995.13.11.2796.
To improve the prognosis of patients with poor-risk peripheral primitive neuroectodermal tumors (pPNETs; including peripheral neuroepithelioma and Ewing's sarcoma), while testing the feasibility of intensive use in adolescents and young adults of high-dose cyclophosphamide, doxorubicin, and vincristine (HD-CAV).
This report concerns previously untreated patients with newly diagnosed pPNET deemed poor-risk because of a tumor volume more than 100 cm3 or metastases to bone or bone marrow. The P6 protocol consists of seven courses of chemotherapy. Courses 1, 2, 3, and 6 include 6-hour infusions of cyclophosphamide on days 1 and 2 for a total of 4,200 mg/m2 per course (140 mg/kg per course for patients < 10 years old), plus 72-hour infusions of doxorubicin 75 mg/m2 and vincristine 2.0 mg/m2 beginning on day 1 (HD-CAV). Courses 4, 5, and 7 consist of 1-hour infusions of ifosfamide 1.8 g/m2/d and etoposide (VP-16) 100 mg/m2/d, for 5 days. Granulocyte colony-stimulating factor (G-CSF) and mesna are used. Courses start after neutrophil counts reach 500/microL and platelet counts reach 100,000/uL. Surgical resection follows course 3 and radiotherapy follows completion of all chemotherapy.
Among the first 36 consecutive assessable patients (median age, 17 years), HD-CAV achieved excellent histopathologic or clinical responses in 34 patients and partial responses (PRs) in two patients. For 24 patients with locoregional disease, the 2-year event-free survival rate was 77%; adverse events were two locoregional relapses, one distant relapse, and one secondary leukemia. All six patients with metastatic disease limited to lungs achieved a complete response (CR) and did not relapse; one is in remission 36+ months from diagnosis, but the other patients are not assessable in terms of long-term efficacy of the P6 protocol because of short follow-up time (n = 3), additional systemic therapy (bone marrow transplantation), or septic death (autopsy showed no residual pPNET). All six patients with widespread metastases had major responses, including eradication of extensive bone marrow involvement, but distant relapses ensued. Myelosuppression was severe, but most patients received the first three courses of HD-CAV within 6 to 7 weeks. Major nonhematologic toxicities were mucositis and peripheral neuropathy.
Excellent antitumor efficacy and manageable toxicity support the dose-intensive use of HD-CAV for pPNET in children, as well as in young adults. Consolidation of remissions of pPNET metastatic to bone and bone marrow remains a therapeutic challenge.
改善高危外周原始神经外胚层肿瘤（pPNET，包括外周神经上皮瘤和尤因肉瘤）患者的预后，同时测试在青少年和年轻成人中密集使用高剂量环磷酰胺、多柔比星和长春新碱（HD-CAV）的可行性。
本报告涉及先前未经治疗、新诊断为pPNET且因肿瘤体积超过100 cm³或有骨或骨髓转移而被视为高危的患者。P6方案包括七个化疗疗程。第1、2、3和6疗程包括在第1天和第2天进行6小时的环磷酰胺输注，每个疗程总量为4200 mg/m²（10岁以下患者每个疗程为140 mg/kg），加上从第1天开始进行72小时的多柔比星75 mg/m²和长春新碱2.0 mg/m²的输注（HD-CAV）。第4、5和7疗程包括每天1小时的异环磷酰胺1.8 g/m²和依托泊苷（VP-16）100 mg/m²的输注，持续5天。使用粒细胞集落刺激因子（G-CSF）和美司钠。疗程在中性粒细胞计数达到500/μL且血小板计数达到100,000/μL后开始。第3疗程后进行手术切除，所有化疗完成后进行放疗。
在连续的前36例可评估患者（中位年龄17岁）中，HD-CAV使34例患者获得了优异的组织病理学或临床反应，2例患者获得部分反应（PR）。对于24例局部区域疾病患者，2年无事件生存率为77%；不良事件为2例局部区域复发、1例远处复发和1例继发性白血病。所有6例转移局限于肺部的患者均获得完全缓解（CR）且未复发；1例自诊断后36 +个月处于缓解期，但由于随访时间短（n = 3）、额外的全身治疗（骨髓移植）或败血症死亡（尸检显示无残留pPNET），其他患者无法评估P6方案的长期疗效。所有6例广泛转移的患者均有主要反应，包括根除广泛的骨髓受累，但随后出现远处复发。骨髓抑制严重，但大多数患者在6至7周内接受了前三个疗程的HD-CAV。主要的非血液学毒性为黏膜炎和周围神经病变。
优异的抗肿瘤疗效和可控的毒性支持在儿童以及年轻成人中对pPNET密集使用HD-CAV。巩固转移至骨和骨髓的pPNET的缓解仍然是一个治疗挑战。
