Voss Stephan D, Glade-Bender Julia, Spunt Sheri L, DuBois Steven G, Widemann Brigitte C, Park Julie R, Leary Sarah E S, Nelson Marvin D, Adamson Peter C, Blaney Susan M, Weigel Brenda
Department of Radiology, Boston Children's Hospital Dana -Farber Cancer Institute, Boston, Massachusetts.
Pediatr Blood Cancer. 2015 Jan;62(1):45-51. doi: 10.1002/pbc.25229. Epub 2014 Sep 24.
Pre-clinical studies suggest that anti-angiogenic agents may be toxic to the developing growth plate. The purpose of this study was to evaluate the incidence of growth plate abnormalities in children with refractory cancer undergoing anti-angiogenic therapy.
Targeted radiographic studies from 53 subjects enrolled on six separate Children's Oncology Group Phase 1 and Pilot Consortium clinical trials evaluating new anti-cancer agents interfering with angiogenesis were reviewed. Subjects received tyrosine kinase inhibitors with anti-angiogenic effects (n = 35), monoclonal antibodies targeting vascular endothelial growth factor (VEGF) (n = 13), or angiopoietin (n = 5). Radiographs of their distal femur/proximal tibia were obtained at baseline. Follow-up radiographs were obtained after odd-numbered treatment cycles in patients with open growth plates who did not experience disease progression prior to cycle 3.
Baseline and follow-up growth plate radiographs were acquired in 48/53 (90%) of patients. Five patients (9.4%), all of whom received a specific VEGF/VEGFR blocking agent (sunitinib [n = 1] or pazopanib [n = 4]), had growth plate abnormalities. Four patients had growth plate widening that was apparent on at least two successive radiographs, but was not confirmed by MRI. The fifth patient had progressive growth plate widening and evidence of physeal cartilage hypertrophy on MRI. Subsequent off treatment radiographs showed that the growth plate changes were reversible.
Growth plate abnormalities occur in a small, but relevant number of patients undergoing anti-angiogenic therapy. These results support the need for growth plate monitoring in children with open growth plates who are receiving anti-angiogenic therapy, and for improved methods to assess toxicity of anti-angiogenic agents to the developing skeleton.
临床前研究表明，抗血管生成药物可能对发育中的生长板有毒性。本研究的目的是评估接受抗血管生成治疗的难治性癌症儿童生长板异常的发生率。
回顾了53名受试者的靶向放射学研究，这些受试者参加了六项独立的儿童肿瘤学组1期和试点联盟临床试验，评估干扰血管生成的新型抗癌药物。受试者接受具有抗血管生成作用的酪氨酸激酶抑制剂（n = 35）、靶向血管内皮生长因子（VEGF）的单克隆抗体（n = 13）或血管生成素（n = 5）。在基线时获取他们股骨远端/胫骨近端的X线片。对于生长板未闭合且在第3周期前未出现疾病进展的患者，在奇数治疗周期后获取随访X线片。
48/53（90%）的患者获得了基线和随访生长板X线片。五名患者（9.4%）出现生长板异常，他们均接受了特定的VEGF/VEGFR阻断剂（舒尼替尼[n = 1]或帕唑帕尼[n = 4]）治疗。四名患者的生长板增宽在至少两张连续的X线片上明显，但MRI未证实。第五名患者生长板逐渐增宽，MRI显示有骺软骨肥大的证据。随后的停药后X线片显示生长板变化是可逆的。
接受抗血管生成治疗的患者中，虽有一小部分但数量可观的患者会出现生长板异常。这些结果支持对接受抗血管生成治疗且生长板未闭合的儿童进行生长板监测，并需要改进评估抗血管生成药物对发育中骨骼毒性的方法。
