Gok Beril, McGirt Matthew J, Sciubba Daniel M, Garces-Ambrossi Giannina, Nelson Clarke, Noggle Joseph, Bydon Ali, Witham Timothy F, Wolinsky Jean-Paul, Gokaslan Ziya L
Department of Neurosurgery, The Johns Hopkins University, Baltimore, Maryland, USA.
Neurosurgery. 2009 Jul;65(1):193-9; discussion 199-200. doi: 10.1227/01.NEU.0000345948.54008.82.
OBJECTIVE: The optimal management of spinal column metastatic disease is controversial. Local chemotherapy delivery systems allow targeted high-dose adjuvant therapy. We evaluated whether injection of OncoGel paclitaxel-releasing biodegradable polymer (Protherics, Inc., West Valley City, UT) into the tumor resection cavity at the time of surgery would improve the efficacy of surgical resection with or without external beam radiotherapy (XRT) in a rat model of spinal column metastases. METHODS: Fischer-344 rats (Charles River Laboratories, Wilmington, MA) underwent a transabdominal approach for implantation of a CRL-1666 breast adenocarcinoma cell line within the L6 vertebral body. In experiment 1, 7 days after tumor implantation, animals underwent 1 of 2 treatments or no treatment (n = 8 per group): control (no treatment); surgery alone (L6 corpectomy); or surgery + OncoGel (L6 corpectomy with OncoGel implantation into the resection cavity). In experiment 2, 7 days after tumor implantation, animals underwent 1 of 2 treatments or no treatment (n = 8 per group): control (no treatment); surgery + XRT (L6 corpectomy followed by XRT [total 20 Gy]); or surgery + XRT + OncoGel (L6 corpectomy with OncoGel implantation followed by XRT). In experiment 3, 7 days after tumor implantation, animals underwent 1 of 2 treatments or no treatment (n = 8 per group): control (no treatment); XRT alone (total 20 Gy); or XRT + OncoGel. Daily hindlimb function was assessed using the Basso, Beattie, and Bresnahan (BBB) scale (range, 1-21). RESULTS: In experiment 1, both treatment groups had delayed onset of paresis compared with control. Compared with surgery alone, surgery + OncoGel resulted in superior median BBB scores on posttreatment days 9 (21 versus 19, P < 0.001) through 14 (11 versus 8, P < 0.005). In experiment 2, both treatment groups had delayed onset of paresis compared with control. Compared with surgery + XRT, surgery + XRT + OncoGel resulted in superior median BBB scores on posttreatment days 13 (21 versus 19, P < 0.001) through 17 (12 versus 8, P < 0.005). Median time to loss of ambulation (BBB scale score </=7) was maximized by the addition of OncoGel to surgery plus XRT: control (8.5 days), surgery alone (13.5 days), surgery + OncoGel (16 days), surgery + XRT (17 days), and surgery + XRT + OncoGel (19 days). In experiment 3, both treatment groups had delayed onset of paresis compared with control. Compared with XRT alone, XRT + OncoGel resulted in superior median BBB scores on posttreatment days 6 (21 versus 19, P < 0.001) through 11 (13 versus 8, P < 0.005). However, compared with surgery + XRT + OncoGel, XRT + OncoGel resulted in worse median BBB scores on posttreatment days 8 (20 versus 21, P < 0.01) through 13 (7 versus 19, P < 0.005). CONCLUSION: In a rat model of spinal metastatic disease, local delivery of OncoGel increased the efficacy of surgery and radiotherapy and delayed the onset of neurological decline. These results suggest that OncoGel may be an effective adjuvant therapy in the operative management of metastatic spinal column tumors and that combining local chemotherapy with surgery and adjuvant radiotherapy may improve outcomes of this disease.
目的：脊柱转移性疾病的最佳治疗方法存在争议。局部化疗给药系统可实现靶向高剂量辅助治疗。我们评估了在手术时将载有紫杉醇的可生物降解聚合物OncoGel（Protherics公司，犹他州西谷城）注入肿瘤切除腔，是否会提高脊柱转移大鼠模型中手术切除联合或不联合外照射放疗（XRT）的疗效。 方法：Fischer - 344大鼠（查尔斯河实验室，马萨诸塞州威尔明顿）经腹途径将CRL - 1666乳腺癌细胞系植入L6椎体。在实验1中，肿瘤植入7天后，动物接受以下2种治疗之一或不治疗（每组n = 8）：对照（不治疗）；单纯手术（L6椎体次全切除术）；或手术 + OncoGel（L6椎体次全切除术并将OncoGel植入切除腔）。在实验2中，肿瘤植入7天后，动物接受以下2种治疗之一或不治疗（每组n = 8）：对照（不治疗）；手术 + XRT（L6椎体次全切除术后行XRT [总量20 Gy]）；或手术 + XRT + OncoGel（L6椎体次全切除术并植入OncoGel后行XRT）。在实验3中，肿瘤植入7天后，动物接受以下2种治疗之一或不治疗（每组n = 8）：对照（不治疗）；单纯XRT（总量20 Gy）；或XRT + OncoGel。每天使用Basso、Beattie和Bresnahan（BBB）量表（范围1 - 21）评估后肢功能。 结果：在实验1中，与对照组相比，两个治疗组的轻瘫发作均延迟。与单纯手术相比，手术 + OncoGel在治疗后第9天（21对19，P < 0.001）至第14天（11对8，P < 0.005）的BBB评分中位数更高。在实验2中，与对照组相比，两个治疗组的轻瘫发作均延迟。与手术 + XRT相比，手术 + XRT + OncoGel在治疗后第13天（21对19，P < 0.001）至第17天（12对8，P < 0.005）的BBB评分中位数更高。通过在手术加XRT中添加OncoGel，可使失去行走能力（BBB量表评分≤7）的中位时间最大化：对照组（8.5天）、单纯手术组（13.5天）、手术 + OncoGel组（16天）、手术 + XRT组（17天）和手术 + XRT + OncoGel组（19天）。在实验3中，与对照组相比，两个治疗组的轻瘫发作均延迟。与单纯XRT相比，XRT + OncoGel在治疗后第6天（21对19，P < 0.001）至第11天（13对8，P < 0.005）的BBB评分中位数更高。然而，与手术 + XRT + OncoGel相比，XRT + OncoGel在治疗后第8天（20对21，P < 0.01）至第13天（7对19，P < 0.005）的BBB评分中位数更低。 结论：在脊柱转移性疾病大鼠模型中，局部应用OncoGel可提高手术和放疗的疗效，并延迟神经功能衰退的发作。这些结果表明，OncoGel可能是转移性脊柱肿瘤手术治疗中的一种有效辅助治疗方法，并且将局部化疗与手术及辅助放疗相结合可能改善该疾病的治疗效果。
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