University of Colorado Denver, Aurora, CO 80045, USA.
Gynecol Oncol. 2011 Oct;123(1):19-26. doi: 10.1016/j.ygyno.2011.06.022. Epub 2011 Jul 12.
Patients with persistent/recurrent epithelial ovarian cancer/primary peritoneal cancer (EOC/PPC) have limited treatment options. AKT and PI3K pathway activation is common in EOC/PPC, resulting in constitutive activation of downstream mTOR. The GOG conducted a phase II evaluation of efficacy and safety for the mTOR inhibitor, temsirolimus in EOC/PPC and explored circulating tumor cells (CTC) and AKT/mTOR/downstream tumor markers.
Eligible women with measurable, persistent/recurrent EOC/PPC who had received 1-3 prior regimens were treated with 25mg weekly IV temsirolimus until progression or intolerable toxicity. Primary endpoints were progression-free survival (PFS) ≥6-months, tumor response, and toxicity. CellSearch® system was used to examine CTC, and AKT/mTOR/downstream markers were evaluated by archival tumor immunohistochemistry. Kendall's tau-b correlation coefficient (r) and Cox regression modeling were used to explore marker associations with baseline characteristics and outcome.
Sixty patients were enrolled in a two-stage sequential design. Of 54 eligible and evaluable patients, 24.1% (90% CI 14.9%-38.6%) had PFS ≥6 months (median 3.1 months), 9.3% (90% CI 3.7%-23.4%) experienced a partial response. Grade 3/4 adverse events included metabolic (8), gastrointestinal (8), pain (6), constitutional (5) and pulmonary (4). Suggested associations were between cyclin D1 and PFS ≥6 months, PFS or survival; positive CTC pre-treatment and lack of response; and high CTC expression of M30 and PFS ≥6 months/longer PFS.
Temsirolimus appears to have modest activity in persistent/recurrent EOC/PPC; however, PFS is just below that required to warrant inclusion in phase III studies in unselected patients. Cyclin D1 as a selection marker and CTC measures merit further study.
患有持续性/复发性上皮性卵巢癌/原发性腹膜癌（EOC/PPC）的患者治疗选择有限。AKT 和 PI3K 通路的激活在 EOC/PPC 中很常见，导致下游 mTOR 的组成性激活。GOG 对 mTOR 抑制剂替西罗莫司在 EOC/PPC 中的疗效和安全性进行了 II 期评估，并探索了循环肿瘤细胞（CTC）和 AKT/mTOR/下游肿瘤标志物。
符合条件的、可测量的、持续性/复发性 EOC/PPC 患者，这些患者在之前接受过 1-3 种方案的治疗，每周静脉注射 25mg 替西罗莫司，直至疾病进展或无法耐受毒性。主要终点是无进展生存期（PFS）≥6 个月、肿瘤反应和毒性。使用 CellSearch®系统检查 CTC，并用存档肿瘤免疫组化评估 AKT/mTOR/下游标志物。Kendall's tau-b 相关系数（r）和 Cox 回归模型用于探索标志物与基线特征和结局的关联。
60 名患者按照两阶段序贯设计入组。在 54 名符合条件和可评估的患者中，24.1%（90%CI 14.9%-38.6%）的患者 PFS≥6 个月（中位 3.1 个月），9.3%（90%CI 3.7%-23.4%）的患者有部分缓解。3/4 级不良事件包括代谢（8）、胃肠道（8）、疼痛（6）、全身（5）和肺部（4）。提示关联的标志物有：cyclin D1 与 PFS≥6 个月、PFS 或生存相关；治疗前 CTC 阳性和无反应；以及高 CTC 表达的 M30 和 PFS≥6 个月/更长的 PFS。
替西罗莫司在持续性/复发性 EOC/PPC 中似乎具有适度的活性；然而，PFS 略低于在未经选择的患者中进行 III 期研究的纳入标准。cyclin D1 作为选择标志物和 CTC 测量值得进一步研究。
