使用立体定向放射治疗早期非小细胞肺癌:进展与挑战

【摘要】随着诊断技术的不断发展,越来越多的早期非小细胞肺癌(Non-small Cell Lung Cancer,NSCLC)被发现。一直以来治疗早期肺癌的标准是肺叶切除联合淋巴结清扫或者亚肺叶切除。立体定向放射治疗(stereotactic body radiotherapy,SBRT)出现后,始终作为无耐受手术或者因其他原因不能手术的早期NSCLC患者的首选替代方案。近年来的研究表明,对于可手术的早期NSCLC患者来说,使用SBRT治疗可以取得与手术相同甚至更优的疗效。但是业内对使用SBRT治疗早期NSCLC的看法存在很大争议。如何选择使用SBRT治疗的早期NSCLC的最大获益人群,是目前研究的热点。相信正在进行的几项前瞻性随机对照研究可以给出答案。

【关键词】早期肺癌;立体定向放疗;手术治疗

Treatment of early stage non-small cell lung cancer with stereotactic ablation radiotherapy:progress and challenge

Lin Dong1Qingliang QinQinchuan Li

【Abstract】With the continuous development of diagnostic techniques,more and more early stage non-small cell lung cancer(NSCLC)was found.The standard for the treatment of early stage lung cancer has been treated with lobectomy combined with lymphadenectomy or sub-lobectomy.After stereotactic body radiotherapy(SBRT),it is always the preferred alternative for patients with early stage NSCLC who are unable to undergo surgery or for other reasons.Recent studies have shown that the use of SBRT treatment can achieve the same or even better efficacy as surgery for operable early stage lung cancer patients.However,there is considerable controversy regarding the use of SBRT for treatment of early stage NSCLC.How to choose the largest beneficiaries of early stage NSCLC using SBRT is the focus of the present study.I believe that several prospective randomized controlled studies are under way to give an answer.

【Key words】Early stage lung cancer;Stereotactic body radiotherapy;Surgery

肺癌仍是人类因恶性肿瘤死亡的主要原因,每年全球有超过180万人被诊断为肺癌[1]。随着人们健康意识的提高与高分辨率薄层CT的广泛使用,临床上越来越多直径<2 cm的早期肺癌被诊断。对于可手术治疗的早期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者来说,其治疗的金标准为肺叶切除加区域淋巴结清扫[2]。后来的一些研究发现,对于经过严格选择的早期周围型肺癌患者,亚肺叶切除获得了同肺叶切除类似的效果[3-5]。近几年,对于使用立体定向放疗(stereotactic body radiotherapy,SBRT)治疗可手术的早期NSCLC的争论一直存在。作为治疗方式的一种,SBRT相对于外科手术来说有非常多的优势。但最终还是要考虑患者的获益情况及相关不良反应,来选择最精确的个体化治疗方案。

1.立体定向放疗的基本内容

在过去的数十年里,放疗主要是作为手术后辅助治疗手段或者应用于无法耐受手术的肺癌患者,采用的是每天1次,每周5天,总剂量为60-70Gy的常规分割方式。从之前的文献中我们可以看出,常规分割放疗应用于早期NSCLC的患者5年生存率为10%-30%,当然其中的因素包括患者通常合并其他严重慢性内科疾病、临床分期较晚等,但与手术组五年生存率60%-70%相比有很大差距[6-9]。结合过去数十年的常规分割放疗经验,20世纪末人们开始探索减少分割次数、增加单次剂量的立体定向放疗技术(SBRT)[10]。随着工业技术的发展,SBRT的特点逐渐明显[11]:①具有高级成像定位技术(Advanced Imaging Package)联合靶区验证,可以考虑到器官的运动进行定位和复位,同时需要患者体位固定;②靶区接受照射剂量高,多束射线空间聚焦,其合成的剂量集中在肿瘤局部,而靶区之外组织接受照射剂量急剧减少,最大效率避免不良反应;③照射次数少、单次照射剂量增加,最大程度的减少肿瘤细胞增殖对疗效的影响,使用更大的处方剂量来取得更高的疗效[12]。立体定向消融放疗(stereotactic ablative radiotherapy,SABR)是SBRT中更高级的治疗方式,其放疗分割次数应不多于5次,总剂量(biologically effective dose,BED)大于100Gy,对靶区勾画的要求更严格[13]。而SBRT分割次数为10次以内,剂量无明确要求,一般大于常规分割剂量[14]。

2.早期NSCLC的诊疗现况

2.1诊断主要依靠CT的筛查及判读

目前,早期非小细胞肺癌的初次诊断主要来源于各大医院及医疗机构开展的胸部低剂量CT(low-dose computed tomography,LDCT)的肺癌筛查。LDCT显示有异常的患者至医院胸外科或呼吸内科医师处就诊,接诊医师结合患者每年随访情况等具体病情决定是否予以高分辨率CT(high-resolution CT,HRCT)检查。通过阅读患者的HRCT,医师将肺部结节分为实性或非实性。根据最新的亚洲肺部结节诊疗指南和Fleischner指南[15,16]:⑴对于直径>8mm的实性结节且有明显的恶性影像学征象或者无明显恶性影像学特征但是随访明确结节有生长情况者推荐手术切除;有条件者可行PET/CT明确高代谢后行外科活检,再决定处理方式;⑵对于直径>8mm的部分实性结节(实性成分>50%)可考虑抗生素治疗3个月后复查CT,未减小或增大者予以外科活检或直接外科手术切除。除影像学检查以外,支气管镜技术比以往更加成熟,可以用来早期诊断NSCLC;血清学肿瘤标志物,例如CEA、NSE等可以用来辅助诊断;近几年循环肿瘤细胞(circulating tumor cell,CTC)检测、循环肿瘤核酸(circulating tumor DNA,ctDNA)也逐渐进入临床应用,辅助于早期NSCLC的诊断[17-19]。

2.2放疗是辅助手术的治疗方式

手术切除高度怀疑为恶性的肺部结节可同时具有切除病灶和明确病理两种作用,所以即使是2017年更新后的Fleischner指南依然没有将SBRT/SABR作为处理早期NSCLC的方案[20]。目前对于合并有严重慢性内科疾病、高龄或者其他无法耐受手术的早期NSCLC患者,SBRT/SABR是国际上公认的的标准治疗[20-26]。2014年美国放射肿瘤治疗小组(Radiation Therapy Oncology Group,RTOG)发布报告,其0236试验发现无法手术的早期NSCLC患者使用SBRT/SABR治疗后的2年和5年局部控制率分别为97.6%和93%,3年生存率为55%,5年生存率为40%[23,27]。Solda等[28]对45份报告进行了系统分析,其中包括3771名接受了SBRT/SABR的早期肺癌患者,2年生存率及局部控制率分别为70%和91%,手术组的2年生存率为68%。2017年2月份加拿大安大略省等地的专家学者发表指南,明确的指出SBRT/SABR为无法手术治疗的早期NSCLC患者的第一选择,并且根据病灶位置、大小等不同因素给出了指导放疗方案[29]。但是这些可依据的询证医学证据普遍存在如下问题:⑴混杂因素较多,例如年龄、原有疾病等;⑵所使用的放疗设备较落后[30]。所以无法完全客观的评价SBRT/SABR与手术孰优孰劣,而临床上我们对一些处于手术临界状态的患者也只能主观遵从患者意愿予以SBRT/SABR或者手术治疗,无法明确的给出患者最优的精准治疗方案。国外学者也意识到这个问题并做相关研究,Hiroshi Onishi等[31]回顾了1995-2004的87例可耐受但拒绝手术的NSCLC患者(中位年龄74岁;T1N0M0,n=65;T2N0M0,n=22),SBRT后5年T1和T2期肿瘤的局部控制率分别为92%和73%,遗憾的是无同期手术对比而且是非前瞻性研究,而且其使用的放疗设备无呼吸门控等功能。因此,近年来随着放疗技术的不断更新,多项关于SBRT/SABR用于治疗可手术的早期NSCLC患者的前瞻性研究正在进行,其中一些已发布报告。

3.SBRT/SABR用于治疗可手术的早期NSCLC

在临床决策时,大部分医生试图将病人分布两个无形的区域内,一边是手术治疗,一边是SBRT/SABR;一边是年轻的、身体情况良好的病人,一边是伴有多种慢性疾病的高龄患者。实际上随着放疗技术的不断进步,这条“分界线”逐渐模糊,因此近几年对可手术治疗的早期NSCLC患者行SBRT/SABR治疗的对比研究比较热门,国际上争论不断。近几年的多项研究均得出了相对积极的结果,相关研究结果如表1所示[32-35]。结果显示SBRT/SABR的疗效与手术相当。另外两项荟萃分析直接比较了SBRT/SABR和手术。其中一项为上文所诉Solda等[36]对2006年至2013年期间45份研究做的系统评估,结果是3201例SABR治疗和2038例手术治疗的患者中2年生存率和局部控制率均无明显差异,注意这个3201名患者是经过调整后的假拟可手术操作的早期NSCLC患者。Zheng等[37]对2000年至2012年的研究进行分析,其中包括40项SABR研究的4,850例和23项手术研究的7,071例患者,SABR组5年平均总生存率为41.2%,肺叶切除术为66.1%。经过调整患者年龄和手术患者的比例,SABR和手术具有相似的生存率和无病生存率。加拿大学者汇总了12项比较成效研究的主要结论是在比较SABR和手术时,特别是考虑到与高龄相关的死亡风险和合并症带来的危险因素之后,有类似的治疗结果[38]。

随着越来越多结果积极的回顾性研究的发表,三项前瞻性的随机对照实验相继开展,分别是ACOSOG Z4099,ROSEL和STARS研究,但是由于经费不足、入组缓慢等原因这三项研究已经关闭。2015年Chang等[39]汇总了ROSEL和STARS两项研究数据,手术组与SBRT/SABR组的患者的基本情况在统计学上无差别。手术组采用的术式为肺叶切除术联合纵隔淋巴结清扫;SBRT/SABR组采用分割方式为外周病灶54Gy/3次,中央病灶50 Gy/4次(STARS研究)和60 Gy/5次(ROSEL研究)。手术组与SBRT/SABR组的中位随访时间分别为40.2个月和35.4个月,3年生存率分别为95%和79%,3年无复发生存率分别为86%和80%。这项研究结果首次证明对于可手术的早期NSCLC来说,SABR要优于手术治疗。2017年Chang等[40]发布了II期前瞻性随机对照试验的7年随访研究结果,是目前关于对手术与SABR相对照的前瞻性临床实验随访时间最长的临床研究。研究结果依然得出积极结论,支持对I期NSCLC的患者首选SABR治疗,而治疗失败的主原因是局部复发(3年和5年的局部复发率分别为12.3%和17.4%),但仍小于手术组的局部复发率。

综上所述,结合上海市东方医院经验,我们认为具有以下特点的患者,也许可以首选SBRT/SABR治疗:⑴结节位置位于周围型、大小≤3cm的单发结节的I期NSCLC的患者,推荐使用50 Gy/4次的分割方法;⑵结节位置位于周围型、大小≤3cm的单发结节的I期NSCLC的患者,推荐使用70 Gy/10次的分割方法;⑶多发的混合型磨玻璃结节(mixedround-grass opacity,mGGO)、影像学提示可能为早期多原发肺腺癌;⑷其他的根据最新的亚洲肺部结节诊疗指南和Fleischner指南,需要穿刺活检或外科治疗的偶然发现的肺部单发或多发结节的情况[15,16]。

4.SBRT/SABR后生活质量及相关卫生经济学

由于使用SBRT/SABR治疗的生物学剂量一般较高,同其他放射治疗一样,其治疗的相关不良反应也同样得到人们的关注。SBRT/SABR对患者的生活质量无明显的影响,不良反应较少,比较常见的为乏力、咳嗽、胸壁疼痛、放射性肺炎等,大多临床可控[41,42]。有多项研究报道,放射性肺炎(radiation pneumonitis,RP)是SBRT/SABR后最常见的不良反应,多数RP为1级或2级(根据RTOG急性放射反应评价标准)且没有明显的临床症状。在之前的大型回顾性研究中,≥2级RP的发生率低于8%[43,44]。近两年的研究,多关注于心肺功能较差的高龄NSCLC患者(中位年龄75岁),即使是在此类患者中≥3级RP的发生率约为8.35%[45,46]。Appel等[47]对122例I期NSCLC的患者进行回顾性研究,中位年龄76岁,其中胸壁疼痛8.4%,肋骨骨折0.9%,1-2级肺炎12%,3级12%,5级(死亡)0.9%。但是此研究中患者在接受SBRT/SABR治疗时都是无法耐受手术的状态,甚至有的患者当时已经有肺气肿或者肺纤维化,这与之前的研究相同,即严重的RP主要发生在先前合并肺纤维化的患者[48]。其他不良反应如肋骨骨折、臂丛神经痛、气管与食管损伤等也有相关报道,但这些反应并不常见,发生率均<1%[49,50]。Kim等[51]认为出现RP的相关因素主要是内在肿瘤靶区(internal Gross Tumor Volume,iGTV)和计划靶区(Planning Target Volume,PTV),所以对早期NSCLC的SBRT/SABR治疗应尽量使用带有成像定位、呼吸门控等功能的放疗器械,如EDGE系统等。

另外,站在公共卫生角度考虑,SBRT/SABR治疗带来的相关卫生经济学优势也凸显出来。美国的公共卫生体系比较发达,较早就开展了对手术治疗和SBRT/SABR治疗的对比研究。与手术相比,SBRT/SABR治疗的直接成本和间接成本均降低[52,53]。因为对于恶性肿瘤的患者来说,围术期的高质量护理所带来的成本比较突出,ROSEL随机对照试验的一份小型调查也验证了这个观点[54,55]。而在患者立场考虑的话,美国的另一份研究显示患者直接花费最少的是SBRT,其次是亚肺叶切除术和肺叶切除术[56]。我国目前还没有相关的调查结果发布,但虽然国情不同,但以上几个调查研究对我们依然有相对重要的指导作用。

5.展望与挑战

随着体检筛查CT越来越普遍,相信会有更多的疑似早期NSCLC的肺部结节会被发现。目前治疗的首选方案依旧是活检或手术切除,但是越来越多的证据证实SBRT/SABR可以稳定的控制病情而且无创、廉价。当然也有国外学者对“如此积极”的结论表达了一些保留意见,Brada等[57]认为其他的新方法例如VATS、射频或热消融等对肿瘤控制方面的效果与SBRT/SABR是等效的,同时还强调SBRT/SABR治疗后的局部肿瘤控制能力可能被高估,而且长期毒性可能被低估。他们质疑SBRT/SABR会对患者其他伴有疾病会产生负面的影响,需要更多地研究来明确一些问题,例如呼吸和心血管相关并发症,最佳剂量及长期毒性等。国内学者Li等[58]汇总了15项关于早期NSCLC的研究,其中包括7810例T1-3N0M0的NSCLC患者,SBRT/SABR组2986例,手术组4824例。得出的结论为手术组在生存率(OS)、无复发生存率(RFS)和局部/远程复发率方面均优于BRT/SABR组。我们需要更多、更长时间的的高质量前瞻性随机对照研究来寻找对不同患者的最佳治疗方案。几个新的比较随机研究正在进行中,例如POSTILV(NCT01753414),SABRTooth(NCT02629458),STABLE-MATES(NCT02468024;两个后续研究,包括可手术早期NSCLC的患者)和退伍军人医院的VALOR(NCT02984761,但尚未招募)。我们期望可以在未来可以根据病人的情况提出最适合最精准的治疗方案,而SBRT/SABR将会是其中某些患者首选的治疗方案。

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