Santana V M, Schell M J, Williams R, Bowman L C, Thompson E I, Brenner M K, Mirro J
Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38101-0318.
Bone Marrow Transplant. 1992 Nov;10(5):457-62.
Thirty patients with relapsed pediatric solid tumors received high-dose carboplatin and etoposide with autologous marrow support in a dose-escalation trial. These patients had received extensive prior treatment, which included both cisplatin and etoposide in 25 cases. Six patient cohorts received carboplatin in doses of 1200-2100 mg/m2 and etoposide in doses of 960-1500 mg/m2. All courses were associated with severe neutropenia and thrombocytopenia. The median times from bone marrow infusion to granulocyte recovery (> 0.5 x 10(9)/l) and platelet recovery (> 50 x 10(9)/l) were 33 and 28 days, respectively, with similar findings for all dosage levels. The frequency of non-hematologic toxicities was generally low, although hyponatremia (Na+ < 129 mEq/l) was seen in one-third of the courses. Hepatoxicity was dose-limiting and was significantly associated with the cumulative prior cisplatin dose (p = 0.006). There were four toxic deaths (CNS hemorrhage, alfa-streptococcal sepsis, Candida sepsis, and enterocolitis). Eleven patients received a second course of therapy; toxicity profiles and times to hematologic recovery were similar for the two courses. Clinical responses were observed at all dosage levels. Eleven of 26 evaluable patients achieved a clinical response (one complete, 10 partial). The majority of responses were in patients with neuroblastoma (six of 16) or Hodgkin's disease (two of three). For phase II clinical trials, we recommend dosages of 2100 mg/m2 of carboplatin and 1500 mg/m2 of etoposide for children with prior cumulative cisplatin exposure < 960 mg/m2. This carboplatin dose represents a three- to four-fold increase over pediatric doses tolerated without bone marrow support.
30例复发的儿童实体瘤患者在剂量递增试验中接受了大剂量卡铂和依托泊苷并辅以自体骨髓支持治疗。这些患者此前接受过广泛的治疗，其中25例患者曾接受过顺铂和依托泊苷治疗。六个患者队列接受的卡铂剂量为1200 - 2100mg/m²，依托泊苷剂量为960 - 1500mg/m²。所有疗程均伴有严重的中性粒细胞减少和血小板减少。从骨髓输注到粒细胞恢复（>0.5×10⁹/L）和血小板恢复（>50×10⁹/L）的中位时间分别为33天和28天，所有剂量水平的结果相似。非血液学毒性的发生率总体较低，尽管三分之一的疗程出现了低钠血症（Na⁺<129mEq/L）。肝毒性是剂量限制性的，且与既往顺铂累积剂量显著相关（p = 0.006）。有4例因毒性死亡（中枢神经系统出血、α-链球菌败血症、念珠菌败血症和小肠结肠炎）。11例患者接受了第二个疗程的治疗；两个疗程的毒性特征和血液学恢复时间相似。所有剂量水平均观察到临床反应。26例可评估患者中有11例获得临床反应（1例完全缓解，10例部分缓解）。大多数反应见于神经母细胞瘤患者（16例中的6例）或霍奇金病患者（3例中的2例）。对于II期临床试验，我们建议对于既往顺铂累积暴露量<960mg/m²的儿童，卡铂剂量为2100mg/m²，依托泊苷剂量为1500mg/m²。该卡铂剂量比无骨髓支持时耐受的儿童剂量增加了三至四倍。
