Advances in Clinical Medicine
Vol.08 No.01(2018), Article ID:23876,5 pages
10.12677/ACM.2018.81011

Advances in Radiotherapy for Locally Advanced Rectal Cancer

Xiaomeng Ji1, Zhenzhen Han2, Shengli Yuan2*

1Medical College of Qingdao University, Qingdao Shandong

2Department of Oncology, Qingdao Municipal Hospital, Qingdao Shandong

Received: Feb. 7th, 2018; accepted: Feb. 21st, 2018; published: Feb. 27th, 2018

ABSTRACT

Radiotherapy (RT) is an important part of the comprehensive treatment of locally advanced rectal cancer, which reduces the local recurrence rate in combination with surgery and improves survival of rectal cancer. The timing of radiotherapy, the way of radiotherapy, the needs of radiotherapy for T3N0M0 rectal cancer, the timing of surgery are summarized as follows. This review will discuss not only the basic role of RT but also the associated with controversial issues in detail.

Keywords:Rectal Neoplasms, Radiotherapy, Advanced, Chemoradiotherapy

直肠癌放射治疗研究进展

纪晓萌1,韩真真2,袁胜利2*

1青岛大学医学院,山东 青岛

2青岛市市立医院肿瘤科,山东 青岛

收稿日期:2018年2月7日;录用日期:2018年2月21日;发布日期:2018年2月27日

摘 要

放射治疗作为局部晚期直肠癌综合治疗的一个重要组成部分,联合手术治疗可降低局部复发率,提高患者总生存率。近年来多项研究对如何进一步提高放疗疗效、放疗方式、T3N0M0患者是否都需要放疗及放疗与手术时间间隔等问题进行了探索,本篇综述除讨论放疗的基本作用,并对上述研究热点做出总结分析。

关键词 :直肠肿瘤,放射治疗,进展期,同步放化疗

Copyright © 2018 by authors and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

1. 引言

结直肠癌是临床上常见的恶性肿瘤。2017年结直肠癌的新病例和死亡病例分别为135,430和50,260例 [1] 。我国直肠癌约占结直肠癌的60%以上 [2] ,且就诊时大多数直肠癌患者处于局部病变进展期。手术切除是治疗直肠癌的基石,但单纯的手术治疗疗效较差,且局部复发率较高。

近年来,放射治疗(radiotherapy, RT)在局部晚期(T3或N+)直肠癌(locally advanced rectal cancer, LARC)中已经成为标准治疗手段,放疗联合手术治疗可降低局部复发率(local recurrence rate, LRR),提高患者的无病生存期(disease free survival, DFS)和总生存期(overall survival, OS) [3] 。本综述在简要提及放疗的基本作用的同时,也将详细讨论有争议的问题,并对直肠癌放射治疗的研究热点做出总结分析。

2. 放射治疗基本作用

放疗作为辅助治疗的首要问题是能否降低LRR。1990年国家癌症研究所共识声明建议联合使用RT和5-氟尿嘧啶(5-FU)治疗局部晚期直肠癌 [4] 。共识声明基于一些国家随机研究 [5] ,结果显示辅助放疗联合5-FU为基础的化疗使盆腔复发率降低。目前放疗主要有两种方式:常规分割的长程放疗(long-course radiotherapy, LCRT),总剂量为45~50 Gy,每次1.8~2 Gy,每日1次,每周5次,持续5~6周;短程放疗(short-course radiotherapy, SCRT):总剂量为25 Gy,每次5 Gy,每日1次,连续5日。瑞典直肠癌试验 [6] 对比术前放疗组和单纯手术组,提示术前放疗对控制局部复发率有效(12% vs 25%, p < 0.001),并且显著改善患者的生存率(46% vs 39%, p < 0.03)。

随着全直肠系膜切除术(total mesorectal excision, TME)在临床上的推广应用,LRR已显著降低,放疗的地位受到了冲击,手术前后是否放疗存在争议 [7] [8] 。荷兰直肠癌试验研究 [9] 对比单纯TME和术前SCRT + TME的疗效,结果显示术前SCRT + TME在II期和III期直肠癌中LRR显著降低(2% vs 8%, p < 0.05),Stockholm TME研究也验证了相同的结果 [10] [11] [12] 。伴有高危因素的直肠癌患者仍推荐进行放疗,如环周切缘(cumferential resection margin, CRM)阳性、淋巴血管间隙浸润、较高的淋巴结分期、肠壁外血管浸润和低位肿瘤者。医学研究理事会CR07 [13] 通过对1350例患者的研究表明,对于可行手术的直肠癌患者,短期术前放疗与CRM阳性患者行术后选择性放化疗(chemoradiotherapy, CRT)相比,LRR降低(4.7% vs 11.50%, p < 0.0001)。术前放疗使局部复发的相对危险降低了61% (HR = 0.39,95% CI: 0.27~0.58, p < 0.0001)。

3. 放疗时机的选择

理论上讲,术前放疗具有生物学上的优势,完整的血管和较高的氧合状态可以提高放射敏感性,提高肿瘤切除率和保肛率,而术后放疗的益处包括局部复发高风险患者可以通过手术和/或病理发现来验证。近年来影像技术的进步使得术前临床分期更加准确,从而局部晚期直肠癌患者的术前放疗也得到广泛应用。三项随机研究比较了术前同步放化疗和术后同步放化疗的疗效 [14] [15] [16] [17] ,两项试验因入组缓慢被迫提前终止。德国CAO/ARO/AIO 94试验 [16] 是其中最经典的研究,共纳入823例cT3-4或N +直肠癌患者,平均随访时间近4年,分别接受术前同步放化疗或术后同步放化疗,手术均采用TME。术前组剂量为50.4 Gy/28 f,术后组为50.4 Gy/28 f,瘤床补量540 cGy,两组同步化疗是5-FU静脉滴注(1000 mg/m2/d,d1-5,第1和第5周),结果显示术前放疗组LRR较低(6% vs 13%, p = 0.006),且保肛率高(19% vs 39%, p = 0.004),急性和长期并发症发生率低,但两组DFS (68% vs 65%, p = 0.32)和OS(76% vs 74%, p = 0.80)无差异。另外两项随机研究也报道了术前放疗效果良好,但与德国CAO/ARO/AIO 94试验的某些方面有所不同,NSABP R-03试验 [17] 术前放化疗组与术后放化疗组LRR(10.7% vs 10.7%, p = 0.693)和保肛率(47.8% vs 39.2%, p = 0.22)的差异无统计学意义,但前者的DFS(64.7% vs 53.4%, p = 0.011)明显提高。而韩国研究报道了术前放化疗具有较高的保肛率(68% vs 42%, p = 0.008),但LRR(5% vs 6%, p = 0.335)的差异没有统计学意义 [14] [15] 。

4. SCRT还是LCRT?

较长的治疗时间和间隔时间将提供足够的时间使肿瘤明显退缩和降期,LCRT具有更高的保肛率,更高的分割数将促进正常组织和器官损伤的修复,降低并发症。一项波兰的随机临床研究 [18] 共入组200名T3-4中低位直肠癌患者,比较了术前短分割(5 × 5 Gy)和常规分割放化疗(50.4 Gy/28 f,同步5-FU化疗)的疗效,后组的病理完全缓解率(pathological complete response, pCR)较高(16.1% vs 0.7%, p = 0.017),而LRR (15.6% vs 10.6%, p > 0.05)、DFS (55.6% vs 58.4%, p > 0.05)、OS (66.2% vs 67.2%, p > 0.05)差异无统计学意义。Ngan等 [19] 报道入组326名患者,研究设计与波兰试验相同,结果同样表明两组LRR(7.5% vs 5.7%, p = 0.51)、OS (74% vs 70%, p = 0.62)的差异没有统计学意义。因此,没有证据表明一种治疗方式比另一种治疗方式要差,建议基于患者的病情和医生的偏好而定。尽管没有足够的证据支持 [20] [21] ,但肿瘤位于远端直肠并接近肛门括约肌,或者是局部晚期cT4或CRM阳性病变依然推荐LCRT进行保肛并完全切除肿瘤。

5. T3N0直肠癌患者是否都需要放疗?

在回答这个问题之前,应该区分肿瘤的病理和临床分期。在病理分期T3N0肿瘤病例中,北美的三个随机研究数据汇总分析结果显示直肠癌术后辅助放疗可能过度,因为放疗对局部复发、无病生存或总体生存没有明显影响 [22] 。目前标准手术模式TME使LRR大大降低,一部分pT3N0M0直肠癌患者在单纯手术或手术联合化疗方面有很好的疗效。但对高危因素如CRM阳性、淋巴管浸润和分化差的患者实施放疗是合理的。而临床分期cT3N0M0肿瘤患者却截然相反。近年来,术前CRT后再行手术治疗被广泛用作LARC的治疗标准,只在一些欧洲国家推荐SCRT后行手术治疗作为首选治疗方案。目前,临床治疗是依据TNM的分期来指示下一步治疗方案,问题在于影像技术在肿瘤分期上的局限性,存在对肿瘤进行过高或过低的分期,会造成过度治疗或治疗不足。瑞典直肠癌试验 [6] 提示Dukes B期患者术前放疗使LRR下降(11% vs 27%, p < 0.05),存活率也增加(58% vs 48%, p = 0.004)。荷兰研究 [11] 表明术前放疗加TME显着降低II期患者的LRR(5.7% vs 1.0%, p = 0.01)。MRC-CR07研究也观察到类似的结果,RT显著降低II期患者的LRR (6.4% vs 1.9%, p < 0.05) [13] 。

6. 放疗与手术时间间隔

理论上新辅助放化疗后一定的时间间隔会使肿瘤缩小和降期,因此我们可以期望更高的病理降期率和保肛率,但事实上一定的间隔期会使肿瘤进一步缩减和降期,并不会提高保肛率,周围正常组织有更多的时间从辐射损伤中修复,放疗并发症发生率降低,然而这种效果在临床上并不明显。且时间间隔过长会造成放射野纤维化改变,使手术切除更加困难,也会延迟伤口愈合。

Lyon 90-01 [23] 研究共纳入200多名可接受直肠指诊的cT2-3肿瘤患者,接受放疗剂量39 Gy/13 f,介于SCRT和LCRT之间,将患者随机分为短间隔组(2周后手术)和长间隔组(6~8周后手术),结果长间隔组在T期显示更高的pCR (29% vs 15%, p < 0.05),具有显著的缩小和降期效应,两组LRR均为9%,3年OS无统计学意义(78% vs 71%, p > 0.05)。Pach等 [24] 研究术前SCRT(5 × 5 Gy)患者手术时间间隔对疗效的影响,共154名患者入组,随机分至短间隔组(7~10天后手术)和长间隔组(4~5周后手术),长间隔组患者降期率高于短间隔组(44.2% vs 13%, p = 0.0001)、保肛率(p = 0.627)、治愈性切除率(p = 0.132)、5年生存率(63% vs 73%, p = 0.24)和LRR (p = 0.119)差异均无统计学意义。

7. 小结

综上所述,放疗作为是局部晚期直肠癌综合治疗重要组成部分,仍是具有争议的焦点,现阶段仍存在诸多问题需要进一步探讨,如放疗方式、放疗时机、T3N0M0患者是否都需要放疗、放疗与手术时间间隔等,这些问题的解决仍需要进行大量的临床研究,进一步为我们的临床治疗提供指导。

文章引用

纪晓萌,韩真真,袁胜利. 直肠癌放射治疗研究进展
Advances in Radiotherapy for Locally Advanced Rectal Cancer[J]. 临床医学进展, 2018, 08(01): 59-63. http://dx.doi.org/10.12677/ACM.2018.81011

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