关于从一个TKI靶向药交换到另一个TKI的洗脱期问题-Washout period

Washout period before going on another TKI


Evaluation of a 30-day washout before second-line sunitinib therapy in metastatic renal cell carcinoma (RCC) after progression on first-line vascular endothelial growth factor (VEGF) inhibitor.

Author(s):
A. Elfiky, D. Cho, D. McDermott, J. Rosenberg, B. Fortner, L. Antràs, K. Chen, M. Duh, M. Atkins, T. Choueiri; Dana-Farber Cancer Institute, Boston, MA; Beth Israel Deaconess Medical Center, Boston, MA; P4 Healthcare, Lakeland, TN; Analysis Group, Inc., Boston, MA

Background: Sequential therapy has been shown to be feasible with VEGF-targeted angiogenesis inhibitors (AIs) in multiple phase II trials. While the mechanisms of VEGF AI resistance remain largely unknown, preclinical models suggest that tumors may revert to VEGF-driven pathways to become "re-sensitized" to VEGF inhibition after an interval of time off treatment. We characterized the treatment response to second-line angiogenesis inhibition in a cohort of metastatic RCC patients based on time to initiate second-line therapy (≤30 days or >30 days). Methods: We identified 53 metastatic clear cell RCC patients who progressed on first line sorafenib or bevacizumab and subsequently received sunitinib as 2nd-line AI treatment between April 2003 and June 2008. We compared RECIST- defined overall response rate (ORR) (by independent radiological review) between patient groups based on time to initiate 2nd AI therapy, ≤30 days or >30 days. The two groups were evaluated for differences in baseline characteristics and known prognostic factors (PFs) in metastatic RCC using Fisher's Exact test. Results: Second-line sunitinib started after 30 days following discontinuation of front-line therapy was associated with 6/25 (24%) ORR, compared to 0/28 when therapy was started within 30 days (P=0.008). Analysis of the baseline characteristics and PFs between the two groups did not yield meaningful statistical differences that could explain the differences observed. Conclusions: Patients with metastatic RCC who fail 1st-line VEGF-targeted therapy do not appear likely to respond to 2nd-line VEGF-targeted therapy if 2nd-line therapy was initiated within 30 days. Based on this retrospective data, patients treated with sequential anti-angiogenic inhibition may need a "washout" period >30 days before initiating 2nd-line. These findings should be verified in a prospective randomized trial.

http://www.asco.org/ascov2/Meeti ... mp;abstractID=20118

也许本论坛、以致整过中国用靶向药的方法都不对？

感谢平安提供的这么重要的消息，个人感觉这样的结果可能比较偶然，样本还是有点特殊且范围不够大。

谁给翻译下？是说 换靶向药之间需要空窗30天么？

一般临床试验要求入组前停药7-21天以上。
http://cancergrace.org/lung/2011 ... rence-day-2-752011/
Dr. Weiss: "... Because these trials have a mandated washout period of 7-21 days after stopping initial TKI treatment。
举个例子：
特罗凯的半衰期是36.2小时，生物利用率是60%，血浆峰水平是4小时。
那么经过146 小时，93.75% 的特罗凯（150mg）会代谢掉，经过292小时，99.61%的特罗凯（150mg）会代谢掉。

是，参加NCI的所有靶向药临床试验的病人，都是被要求停止其他治疗药物30天左右的。
这个研究结果还是比较权威的，因为它是Dana-Farber Cancer Institute。
当然，对于患者来说，看到这样的研究结果是很难接受，关键是担心rebound。但是总体反应率（ORR）6/25 (24%) compared to 0/28！真是有点触目惊心啊。
欧美病人他们反正是一个临床试验接着一个临床试验的治疗，所以他们是严格按照洗脱期来的。可怜我们中国这些自己掏钱吃非正版的病人，谁敢停药“洗脱”啊。

同胞们，何去何从自己看着办吧，我也蒙了。

平安姐，我觉得洗脱期是临床试验的需要。
对于个体病人换药，无需严格遵守这个规定，等那么久没有必要，几天即可。按我上面的计算，只需停药7天，特罗凯的浓度就下降到6.25%。
易、特耐药后，病情通常进展非常快，如果等上10多天，甚至是一个月，将带来严重的后果，也给后面的治疗造成不利影响。

同意LS的看法

是啊，我也一直以为洗脱期是临床试验的需要，它要某药的净效果。不瞒你说，我还给患者出过馊主意，偷偷吃、不停。如此看来，要求洗脱期是出于对药效的影响的考虑。

小马，这种从药代动力学上来推算洗脱期是完全可行的！你计算一下索拉非尼、阿瓦斯丁的时间是多少？

索拉非尼生物利用度是38–49%，平均消除半衰期约为25–48小时。口服给药后，约在3小时中索拉非尼达到血浆峰水平。
半衰期按48小时计算，5个半衰期（即240小时，10天）之后，索拉非尼在体内的浓度已消除 95% 。

阿瓦斯丁的平均半衰期是20天（11-50天）。
http://www.cigna.com/assets/docs ... cizumab_avastin.pdf
5个半衰期（即100天）之后，阿瓦斯丁在体内的浓度已消除 95% 。
这个好象太长了点？！？！