Lessons learned: Accrual to cervical cancer studies remains a puzzling challenge given the lack of options and the dismal prognosis of this disease. The majority of patients referred for a trial such as this have very advanced disease that is difficult to manage.The observation of 4 partial responses among the 41 patients indicates that ixabepilone has some activity but not sufficient for further development without greater understanding of mechanisms of sensitivity and resistance.
Background: Ixabepilone is a microtubule-stabilizing agent approved for metastatic breast cancer. Preclinical data have shown that ixabepilone is active in taxane-sensitive and -resistant cells. Metastatic cervical carcinoma (mCC) has a poor prognosis and no established second-line therapies. This study assessed the efficacy and safety of ixabepilone in previously treated mCC.
Methods: Patients with histologically confirmed mCC and at least one prior cisplatin-containing regimen were treated with ixabepilone [6 mg/m(2) per day for 5 days] every 21 days. The primary endpoint was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were response rate, rate of tumor growth, overall survival (OS), and safety. Levels of glu-terminated and acetylated tubulin, markers of microtubule stabilization, and surrogates for target engagement were assessed by Western blot.
Results: In total, 41 patients were enrolled; 34 had tumors with primarily squamous histology. The median number of prior therapies was 2 (range 1-6). Four patients (9.7%) had a partial response. Median PFS in months was 2.3 for all, 3.84 for taxane-naïve, and 2.03 for taxane-pretreated patients (p = .13). Consistent with this, we found statistically similar (p = 1) rates of growth in taxane-naive patients (0.0035 per day) and taxane pretreated patients (0.0053 per day). Median OS was 5.84 months. G1/2 toxicities included vomiting (43%), sensory neuropathy (21%), and fatigue (60%). Bowel fistulas were observed in 7% of patients. Glu and acetylated tubulin were assessed in tumor samples from 11 patients during the first cycle of treatment. Although there was clear evidence of "target engagement" and microtubule stabilization in all tumors, a correlation between the extent of tubulin stabilization and response to therapy could not be demonstrated.
Conclusion: Ixabepilone was well tolerated but showed very modest activity in second- or later-line mCC and cannot be recommended as a therapy. Target engagement was demonstrated but was not correlated with responses, suggesting that other factors mediate drug sensitivity. New strategies are needed for refractory mCC.
学习到的经验
• 由于缺乏治疗选择以及预后极差,宫颈癌研究的患者招募仍是一个未解难题。被推荐进入临床试验的患者绝大多数处于疾病极晚期阶段,因此难以治疗。
• 在41例患者中观察到4例部分缓解,提示伊沙匹隆具有一定活性,但还不足以进入更深入的研究阶段,亟需进一步了解相关的敏感性与耐药性机制。
摘要
背景. 微管稳定剂伊沙匹隆已获准用于治疗转移性乳腺癌。临床前数据显示伊沙匹隆对紫杉烷类敏感以及耐药细胞均有效。转移性宫颈癌(mCC)预后不良,目前尚未确立二线治疗方案。本研究评估了伊沙匹隆在经治mCC患者中的疗效与安全性。
方法. 入组患者经组织学确诊为mCC,既往至少接受过1次含顺铂方案,给予伊沙匹隆治疗(每天6 mg/m2,连续5天),21天为一周期。主要终点为无进展生存(PFS),根据实体瘤疗效评估标准(RECIST)判断。次要终点为缓解率、肿瘤生长率、总生存(OS)及安全性。通过蛋白质印迹法检测糖端乙酰化微管蛋白、微管稳定性标志物、靶点攻击替代物水平。
结果. 共41例患者入组;34例肿瘤组织学类型为原发鳞癌。既往治疗周期中位数为2(范围1 ∼ 6)。4例患者(9.7%)部分缓解。总体患者中位PFS为2.3个月,既往未使用过紫杉烷类的患者中位PFS为3.84个月,既往紫杉烷类经治的患者中位PFS为2.03个月(P = 0.13)。与此相一致,我们发现紫杉烷类初治患者(0.003 5/天)与经治患者(0.005 3/天)肿瘤生长速率在统计学上相似(P = 1)。中位OS为5.84个月。1/2级毒性反应包括呕吐(43%)、感觉神经病变(21%)以及乏力(60%)。7%的患者发生肠瘘。第一个治疗周期内对11例患者的肿瘤标本进行糖化及乙酰化微管蛋白评估。尽管明确证据显示所有肿瘤均获得“靶点攻击”以及微管稳定性,微管稳定性的程度与治疗缓解之间的相关性还不能证实。
结论. 伊沙匹隆耐受良好,但用于二线或以上mCC治疗时其活性非常有限,不能推荐作为常规治疗。研究表明肿瘤获得靶点攻击但与缓解率并不相关。难治性mCC仍需要新的治疗策略。The Oncologist 2015;20:725–726
Trial registration: ClinicalTrials.gov NCT01967576.
©AlphaMed Press; the data published online to support this summary is the property of the authors.