Gefitinib in Combination With Oral Topotecan and Cyclophosphamide in Relapsed Neuroblastoma: Pharmacological Rationale and Clinical Response
Gefitinib in Combination With Oral Topotecan and Cyclophosphamide in Relapsed Neuroblastoma: Pharmacological Rationale and Clinical Response
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DOI：
10.1002/pbc.22219
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发表时间：
2010-01-01
影响因子：
3.2
通讯作者：
Dominici, Carlo
中科院分区：
文献类型：
--
作者：
Donfrancesco, Alberto;De Ioris, Maria Antonietta;Dominici, Carlo
瞄准在复发性神经母细胞瘤（NB）患者的病例系列中评估了吉非替尼与托泊替康和环磷酰胺（CPA）联合使用的活性和毒性。还评估了组合的体外活性。Procedure.吉非替尼（250 mg/天）、托泊替康（0.8 mg/m2/天）和CPA（50 mg/m2/天）（GTC）口服给药，共28天，连续14天。在一组NB细胞系中评估吉非替尼作为单一药剂以及与拓扑替康或CPA组合的抗肿瘤活性。结果10例患者共92个疗程。在7/92个疗程（8%）中观察到4级中性粒细胞减少，在8/92个疗程（9%）中观察到4级血小板减少。2例患者发生2级肝毒性，4例患者发生1/2级皮肤毒性，2例患者发生1/2级腹泻。8例患者需要降低托泊替康和/或CPA的剂量。四个疗程后，三名患者部分缓解（PR），四名患者病情稳定（SD），三名患者病情进展（PD）。至疾病进展时间（TTP）为9个月（范围，1-27）。在中位随访16个月（范围5-54）后，7名患者死于疾病（DOD），3名患者存活。除1例患者外，所有患者均因PD而停止口服化疗，而1例患者在27个月后因SD停止化疗。在体外，吉非替尼与拓扑替康具有协同作用，与CPA具有相加作用。结论GTC联合用药耐受性良好，TTP令人鼓舞。这些有希望的结果，也得到了体外证据的支持，应该在II期研究中进一步证实。儿科血液癌症2010;54：55-61。(C)2009 Wiley-Liss，Inc.
Aim. Activity and toxiciy of gefitinib in combination with topotecan and cyclophosphamide (CPA) were evaluated in a case-series of relapsed neuroblastoma (NB) patients. The in vitro activity of the combination was also assessed. Procedure. Gefitinib (250 mg/day), topotecan (0.8 mg/m(2)/day), and CPA (50 mg/m(2)/day) (GTC) were administered orally for 14 consecutive days out of 28 clays. Antitumor activity of gefitinib as single agent and in combination with either topotecan or CPA was assessed in a panel of NB cell lines. Results. Ninety-two courses were given in 10 patients. Grade 4 neutropenia was observed in 7/92 courses (8%) and grade 4 thrombocytopenia in 8/92 (9%). Two patients had a grade 2 liver toxicity, four a grade 1/2 skin toxicity, and two a grade 1/2 diarrhea. Dose reduction of topotecan and/or CPA was required in eight patients. After four courses, three patients were in partial response (PR) and four with a stable disease (SD), while three experienced a progressive disease (PD). Time to progression (TTP) was 9 months (range, 1-27). After a median follow-up of 16 months (range 5-54), seven patients are died of disease (DOD) and three alive with disease (AWD). All but one patient discontinued oral chemotherapy because of a PD, whilst one patient stopped chemotherapy after 27 months with a SD. In vitro, gefitinib was synergistic with topotecan and additive with CPA. Conclusion. The GTC combination was well tolerated and the TTP was encouraging. These promising results, also supported by in vitro evidence, should be further confirmed in a phase II Study. Pediatr Blood Cancer 2010;54:55-61. (C) 2009 Wiley-Liss, Inc.