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国际视角丨关于肺癌脑转移治疗,海马保护性WBRT/PCI的已知和未知

作者:肿瘤瞭望   日期:2021/8/23 11:28:41

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脑转移(BM)在小细胞肺癌(SCLC)和非小细胞肺癌(NSCLC)患者中发生率很高,1,2,3脑转移是一个不利的预后因素,并且与生活质量(QoL)降低相关。

脑转移(BM)在小细胞肺癌(SCLC)和非小细胞肺癌(NSCLC)患者中发生率很高,1,2,3脑转移是一个不利的预后因素,并且与生活质量(QoL)降低相关。2,4因此,脑转移早期预防或治疗很重要。预防性颅脑照射(PCI)显著降低NSCLC和SCLC的脑转移发生率1,5,风险比(HR)约为0.35。然而,PCI造成的不可逆的神经认知障碍(NCD)发生率为30%6,从而对生活质量产生负面影响。1,7,8

 
在脑转移确诊后,其治疗方案取决于脑转移灶的数量、位置、转移瘤体积和患者症状; 9,10局部治疗选择包括手术或放疗(立体定向放疗[SRT]或全脑放疗[WBRT])。WBRT可带来神经认知衰退风险。11,12为了降低PCI/WBRT治疗的神经毒性风险,研究人员开展了WBRT和PCI的海马保护(HA) 临床试验(表),并讨论了未来的研究方向。
 
文章作者:马斯特里赫特大学医学中心Lizza Hendriks(左)和Dirk De Ruysscher(右)

海马保护性全脑放疗 (HA-WBRT)
 
单臂II期RTOG 0933试验中,与历史WBRT队列相比,HA-WBRT组的NCD发生率更低。13此外,随机III期RTOG 0614结果虽然为阴性,但次要终点发现WBRT+美金刚(memantine)延长了至NCD的时间。14基于这些有前景的发现,随机III期NRG CC001在多种实体恶性肿瘤脑转移患者中评估了WBRT+美金刚±海马保护,主要终点是NCD时间,结果发现海马保护使NCD风险显著降低,HR为0.74。NCD风险降低在≥4个月(执行功能)和随后6个月(学习和记忆)方面更加明显,这意味着预期寿命超过4个月的患者将受益最大。15

海马保护性预防性颅脑照射 (HA-PCI)
 
对初始治疗反应良好的局限期 SCLC患者,PCI 能够减少脑转移和提高总生存,因此成为这类患者标准治疗。16,17然而,一项日本的III期试验使PCI在广泛期SCLC中的作用受到挑战:18尽管与单用MRI随访相比,PCI+MRI随访可降低脑转移发生率,但单用PCI并未增加OS获益,此外PCI增加了NCD风险。
 
为了降低NCD风险,研究人员评估了海马保护性PCI。两项随机III期试验(NCT01780675和NCT02397733[PREMER])最近报告了相互矛盾的结果。19,20前者发现与基线相比,霍普金斯语言学习测试-(HVLT-R)修订版的评估结果在4个月时没有任何下降,两组均有约30%患者的HVLT-R下降,次要神经认知终点(如运动功能、处理速度、记忆力、执行功能和注意力)没有发现差异。19与之相反,PREMER试验发现,3个月时HA-PCI组的NCD结果更优(21.7% vs. 5.1%,p=0.01),第6个月优势持续,该试验采用了自由和提示选择性提醒测试(FCSRT)。20
 
这两项试验得出不同结论的可能原因包括:NCD评估方法、随访时间不同、放疗方面的差异。此外,基线NCD情况也对结果产生影响(基线时NCD受损多的患者的获益较少),但我们还没有获得NCT02397733的相关数据。与NRG CC001相比,NCT01780675入组患者的基线神经认知损伤较少,21而且后者仅纳入SCLC患者。一项更大规模的III期试验(NCT02635009,计划入组392例)正在进行中,可能会结束以上讨论。

未来发展方向
 
QUARTZ试验结果发布后(与单用最佳支持治疗相比,加用WBRT没有增加获益,患者预后极差),WBRT在NSCLC中的作用受到质疑。22随着SRT在SCLC多个脑转移灶治疗中应用增多以及全身性疗法(TKI和免疫检查点抑制[ICI])纳入标准方案,23晚期肺癌脑转移患者的OS显著改善。24,25,26然而,QUARTZ是在全身性疗法广泛纳入治疗之前开展,并非所有入组患者都有资格接受SRT,而且TKI对CNS患者的疗效数据仍然很少。
 
因为TKI或ICI治疗延长了生存期,24,25,26维持中枢神经系统功能和降低NCD风险的重要性增加。我们应该前瞻性地评估HA-WBRT+美金刚方案,特别是在即将接受TKI或ICI治疗,且脑转移灶不适合SRT治疗的患者亚组。对于适用SRT的患者,III期 NCT03550391试验正在非血液系统恶性肿瘤中,对比SRT vs HA-WBRT+美金刚治疗多个(5~15个)脑转移患者。
 
ICI似乎也能降低脑转移发生率。27,28目前化疗+ICI是转移性小细胞肺癌的新治疗标准,16,17因此PCI在这类患者中的作用更有争议。使用ICI的试验正在对比MRI vs PCI+MRI随访(例如NCT04155034),可能会回答PCI在使用免疫治疗的患者中的应用价值。
 
另一种可能降低NCD风险的方法是使用低剂量的PCI,因为ICI和放疗具有协同作用。29NVALT28/PRL01(NCT04597671) 试验正在III期NSCLC患者中评估低剂量PCI,该试验允许使用HA-PCI(并非强制),脑转移发生率是主要终点,NCD是关键次要终点。该试验也评估了NCD的风险因素和预测性生物标志物。30
 
总之,海马保护WBRT/PCI(尤其是与美金刚联合使用时)可能在预后良好的肺癌和脑转移患者中有应用前景。未来的试验应特别关注该患者亚组,并评估NCD的风险因素和生物标志物。
 
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