Wagner Lars M, McAllister Nancy, Goldsby Robert E, Rausen Aaron R, McNall-Knapp René Y, McCarville M Beth, Albritton Karen
Division of Hematology/Oncology, Primary Children's Medical Center, Salt Lake City, Utah, USA.
Pediatr Blood Cancer. 2007 Feb;48(2):132-9. doi: 10.1002/pbc.20697.
Preclinical models show sequence-dependent synergy with the combination of temozolomide and irinotecan, and a Phase I trial has demonstrated the combination to be tolerable and active in children with relapsed solid tumors. Because responses were seen in patients with Ewing sarcoma (ES) on that trial, additional patients were treated with this combination following study completion.
We reviewed data from all ES patients treated with temozolomide and irinotecan at four institutions, including seven patients treated on the above Phase I trial.
Sixteen patients received a total of 95 courses, with a median of five courses per patient. All patients had either progressive disease (PD) during initial therapy (n = 5) or relapse within 2 years of diagnosis (n = 11). Twelve patients had metastatic disease at diagnosis, including 5 with bone and/or marrow metastases. Patients received oral temozolomide 100 mg/m(2)/day on days 1-5 plus intravenous irinotecan 10-20 mg/m(2)/day on days 1-5 and 8-12, with courses repeated every 21-28 days. We observed 1 complete, 3 partial, and 3 minor responses in 14 evaluable patients, with a median duration of response of 30 weeks. Planned 21-day courses were tolerable and no more toxic than 28-day courses. Myelosuppression was minimal despite heavy pretreatment. Grade 3-4 diarrhea occurred in 11% of courses and was related to higher irinotecan doses. Over 600 irinotecan doses were administered uneventfully at home.
Temozolomide and protracted intravenous irinotecan given in 21-day courses was tolerable and active in patients with advanced ES. Home administration of irinotecan with temozolomide was safe and is reasonable palliative therapy. A formal Phase II study using a uniform dose and schedule is warranted to better define activity.
临床前模型显示替莫唑胺与伊立替康联合使用具有序列依赖性协同作用，一项I期试验已证明该联合用药对复发实体瘤儿童患者是可耐受且有效的。由于在该试验中尤因肉瘤（ES）患者出现了反应，因此在研究完成后，更多患者接受了这种联合治疗。
我们回顾了四家机构中所有接受替莫唑胺和伊立替康治疗的ES患者的数据，其中包括上述I期试验中治疗的7名患者。
16名患者共接受了95个疗程的治疗，每位患者的中位疗程数为5个。所有患者在初始治疗期间均有疾病进展（PD，n = 5）或在诊断后2年内复发（n = 11）。12名患者在诊断时有转移性疾病，其中5名有骨和/或骨髓转移。患者在第1 - 5天口服替莫唑胺100 mg/m²/天，同时在第1 - 5天和第8 - 12天静脉注射伊立替康10 - 20 mg/m²/天，疗程每21 - 28天重复一次。在14名可评估患者中，我们观察到1例完全缓解、3例部分缓解和3例轻微缓解，缓解的中位持续时间为30周。计划的21天疗程是可耐受的，且毒性不比28天疗程大。尽管预处理较重，但骨髓抑制很轻微。3 - 4级腹泻发生在11%的疗程中，与较高的伊立替康剂量有关。超过600次伊立替康剂量在患者家中顺利给药。
21天疗程的替莫唑胺和延长静脉注射伊立替康对晚期ES患者是可耐受且有效的。伊立替康与替莫唑胺在家中给药是安全的，是合理的姑息治疗方法。有必要进行一项使用统一剂量和方案的正式II期研究，以更好地确定其活性。
