Bacci G, Ferrari S, Delepine N, Bertoni F, Picci P, Mercuri M, Bacchini P, Brach del Prever A, Tienghi A, Comandone A, Campanacci M
Service de Pediatrie, Medecin Interne Oncologique, Hopital Robert Debré, Paris, France.
J Clin Oncol. 1998 Feb;16(2):658-63. doi: 10.1200/JCO.1998.16.2.658.
In osteosarcoma of the extremity, a strong correlation between chemotherapy-induced necrosis and prognosis has been reported. The aim of this study was to investigate the possible factors that influence histologic response to primary chemotherapy.
In 272 patients with high-grade osteosarcoma of the extremity preoperatively treated with high-dose methotrexate (HDMTX), cisplatin (CDP), and doxorubicin (ADM), the histologic response to chemotherapy was evaluated and graded as complete (no viable tumor cells) or incomplete (persistence of viable tumor cells). Several factors, such as metastatic disease to the lung at diagnosis, sex, age, site and tumor volume, histologic subtype, serum alkaline phosphatase, lactate dehydrogenase (LDH), and methotrexate (MTX) pharmacokinetics were investigated to test their predictive significance on histologic response.
Fifty-one patients with localized disease (20.6%) and none of the 25 patients with metastatic disease at presentation had a complete histologic response (P = .006). After multivariate analysis, performed on patients with localized disease only, MTX serum peak (> or = 700 micromol/L) and histologic subtype were proven to be significant predictive factors of histologic response. A complete response was seen in 28.8% of patients with 700 micromol/L or greater MTX serum levels and in 9.9% of those patients with lower levels (P = .001). The chondroblastic subtype was less responsive (6.1% of complete response), compared with the osteoblastic (16.3%), fibroblastic (33.3%), and telangiectatic (42.3%).
Patients with metastatic osteosarcoma and localized chondroblastic osteosarcoma have a reduced chemosensitivity to primary chemotherapy with MTX, CDP, and ADM. MTX serum peak significantly influences tumor necrosis. A dose adaptation of MTX is recommended to obtain a serum peak of 700 micromol/L or greater when MTX is infused in 6 hours.
在肢体骨肉瘤中，化疗诱导的坏死与预后之间存在密切相关性。本研究旨在探讨影响对初始化疗组织学反应的可能因素。
对272例接受高剂量甲氨蝶呤（HDMTX）、顺铂（CDP）和阿霉素（ADM）术前治疗的肢体高级别骨肉瘤患者，评估其对化疗的组织学反应，并分为完全缓解（无存活肿瘤细胞）或不完全缓解（有存活肿瘤细胞残留）。研究了几个因素，如诊断时肺转移情况、性别、年龄、部位和肿瘤体积、组织学亚型、血清碱性磷酸酶、乳酸脱氢酶（LDH）以及甲氨蝶呤（MTX）的药代动力学，以检验它们对组织学反应的预测意义。
51例局限性疾病患者（20.6%）出现完全组织学缓解，而25例初诊时有转移疾病的患者均未出现完全组织学缓解（P = 0.006）。仅对局限性疾病患者进行多因素分析后，MTX血清峰值（≥700 μmol/L）和组织学亚型被证明是组织学反应的重要预测因素。MTX血清水平≥700 μmol/L的患者中28.8%出现完全缓解，而血清水平较低的患者中这一比例为9.9%（P = 0.001）。与成骨细胞型（16.3%）、纤维母细胞型（33.3%）和毛细血管扩张型（42.3%）相比，软骨母细胞型反应较差（完全缓解率为6.1%）。
转移性骨肉瘤和局限性软骨母细胞型骨肉瘤患者对MTX、CDP和ADM的初始化疗的化疗敏感性降低。MTX血清峰值显著影响肿瘤坏死。当MTX在6小时内输注时，建议调整MTX剂量以获得≥700 μmol/L的血清峰值。
