Platelet-derived growth factor receptor inhibition and chemotherapy for castration-resistant prostate cancer with bone metastases
Platelet-derived growth factor receptor inhibition and chemotherapy for castration-resistant prostate cancer with bone metastases
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DOI：
10.1158/1078-0432.ccr-07-1269
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发表时间：
2007-10-01
影响因子：
11.5
通讯作者：
Logothetis, ChristopherJ.
中科院分区：
文献类型：
--
作者：
Mathew, Paul;Thall, Peter F.;Logothetis, ChristopherJ.
目的：为了进一步评估甲磺酸伊马替尼（一种血小板衍生生长因子受体（PDGFR）抑制剂）调节前列腺癌和骨转移中紫杉烷活性的临床前和早期临床证据，进行了一项随机研究。患有进行性去势抵抗性前列腺癌伴骨转移的男性（n = 144）计划随机接受静脉注射30 Mg/m（2）每42天在第1、8、15和22天给予氯塞韦，每天给予600 mg伊马替尼或安慰剂，中位无进展生存期从4.5个月改善至7.5个月（双侧α = 0.05和β = 0.20）。次要终点包括差异毒性和骨转换标志物，肿瘤磷酸化PDGFR（p-PDGFR）的表达，和调制p-PDGFR在外周血leukemics.Results：Accrual停止早期，因为不良胃肠道事件。在116名可评估的男性（57名氯塞韦+伊马替尼; 59名氯塞韦+安慰剂）中，各自的中位进展时间为4.2个月（95%置信区间，3.1-7.5）和4.2个月（95%置信区间，3.0-6.8; P = 0.58，对数秩检验）。氯塞韦+伊马替尼组的3级以上毒性（n = 23）主要是疲劳和胃肠道。在12/14例（86%）可评价骨标本中观察到肿瘤p-PDGFR表达。在外周血白细胞中，与多西他赛+安慰剂相比，氯塞替尼+伊马替尼治疗的患者更可能降低p-PDGFR（P < 0.0001），尿N-端肽减少（P = 0.004），而非血清骨特异性碱性磷酸酶（P = 0.099）。这些临床和转化结果质疑紫杉烷化疗抑制PDGFR在前列腺癌骨转移中的价值，进行临床前研究。这种不一致需要解释。
Purpose: To further assess preclinical and early clinical evidence that imatinib mesylate, a platelet derived growth factor receptor (PDGFR) inhibitor, modulates taxane activity in prostate cancer and bone metastases, a randomized study was conducted.Experimental Design: Men with progressive castration -resistant prostate cancer with bone metastases (n = 144) were planned for equal randomization to i.v. 30 Mg/m(2) clocetaxel on days 1, 8,15, and 22 every 42 days with 600 mg imatinib daily or placebo, for an improvement in median progression-free survival from 4.5 to 7.5 months (two-sided alpha = 0.05 and beta = 0.20). Secondary end points included differential toxicity and bone turnover markers, tumor phosphorylated PDGFR (p-PDGFR) expression, and modulation of p-PDGFR in peripheral blood leukocytes.Results: Accrual was halted early because of adverse gastrointestinal events. Among 116 evaluable men (57 clocetaxel + imatinib; 59 clocetaxel + placebo), respective median times to progression were 4.2 months (95% confidence interval, 3.1-7.5) and 4.2 months (95% confidence interval, 3.0-6.8; P = 0.58, log-rank test). Excess grade 3 toxicities (n = 23) in the clocetaxel + imatinib group were principally fatigue and gastrointestinal. Tumor p-PDGFR expression was observed in 12 of 14 (86%) evaluable bone specimens. In peripheral blood leukocytes, p-PDGFR reduction was more likely in clocetaxel + imatinib- treated patients compared with docetaxel + placebo (P < 0.0001), as were reductions in urine N-telopepticles (P = 0.004) but not serum bone-specific alkaline phosphatase (P = 0.099).Conclusions: These clinical and translational results question the value of PDGFR inhibition with taxane chemotherapy in prostate cancer bone metastases and are at variance with the preclinical studies. This discordance requires explanation.