Department of Surgery, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS One. 2012;7(2):e26331. doi: 10.1371/journal.pone.0026331. Epub 2012 Feb 7.
Sorafenib is a multi-targeted tyrosine kinase inhibitor with therapeutic efficacy in several malignancies. Sorafenib may exert its anti-neoplastic effect in part by altering vascular permeability and reducing intra-tumoral interstitial hypertension. As correlative science with a phase II study in patients with advanced soft-tissue sarcomas (STS), we evaluated the impact of this agent on intra-tumor interstitial fluid pressure (IFP), serum circulating biomarkers, and vascular density.
Patients with advanced STS with measurable disease and at least one superficial lesion amenable to biopsy received sorafenib 400 mg twice daily. Intratumoral IFP and plasma and circulating cell biomarkers were measured before and after 1-2 months of sorafenib administration. Results were analyzed in the context of the primary clinical endpoint of time-to-progression (TTP).
In 15 patients accrued, the median TTP was 45 days (range 14-228). Intra-tumoral IFP measurements obtained in 6 patients at baseline showed a direct correlation with tumor size. Two patients with stable disease at two months had post-sorafenib IFP evaluations and demonstrated a decline in IFP and vascular density. Sorafenib significantly increased plasma VEGF, PlGF, and SDF1α and decreased sVEGFR-2 levels. Increased plasma SDF1α and decreased sVEGFR-2 levels on day 28 correlated with disease progression.
Pretreatment intra-tumoral IFP correlated with tumor size and decreased in two evaluable patients with SD on sorafenib. Sorafenib also induced changes in circulating biomarkers consistent with expected VEGF pathway blockade, despite the lack of more striking clinical activity in this small series.
ClinicalTrials.gov NCT00330421.
索拉非尼是一种多靶点酪氨酸激酶抑制剂，对多种恶性肿瘤具有治疗作用。索拉非尼可能通过改变血管通透性和降低肿瘤内间质高血压来发挥其抗肿瘤作用。作为与晚期软组织肉瘤（STS）患者的 II 期研究相关的科学，我们评估了该药物对肿瘤内间质液压力（IFP）、血清循环生物标志物和血管密度的影响。
患有可测量疾病和至少一处可进行活检的浅表病变的晚期 STS 患者每天接受两次 400 毫克索拉非尼治疗。在接受索拉非尼治疗 1-2 个月前后测量肿瘤内 IFP 和血浆及循环细胞生物标志物。结果根据主要临床终点进展时间（TTP）进行分析。
在纳入的 15 名患者中，中位 TTP 为 45 天（范围 14-228）。基线时对 6 名患者进行的肿瘤内 IFP 测量显示与肿瘤大小直接相关。2 名在两个月时疾病稳定的患者进行了索拉非尼后的 IFP 评估，显示 IFP 和血管密度下降。索拉非尼显著增加了血浆 VEGF、PlGF 和 SDF1α，降低了 sVEGFR-2 水平。第 28 天血浆 SDF1α 增加和 sVEGFR-2 水平降低与疾病进展相关。
在可评估的两名疾病稳定患者中，基线时的肿瘤内 IFP 与肿瘤大小相关，且在使用索拉非尼治疗后降低。尽管在这个小系列中缺乏更明显的临床活性，但索拉非尼也诱导了循环生物标志物的变化，这些变化与预期的 VEGF 通路阻断一致。
ClinicalTrials.gov NCT00330421。
