Radiotherapy Department, Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital, Northwood HA6 2RN, United Kingdom.
Department of Medical Oncology, Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital, Northwood HA6 2RN, United Kingdom.
Cancer Treat Rev. 2020 Nov;90:102104. doi: 10.1016/j.ctrv.2020.102104. Epub 2020 Sep 14.
The improved overall survival (OS) after short course preoperative radiotherapy (SCPRT) using 5 × 5 Gy reported in the early rectal cancer trials could not be replicated in subsequent phase III trials. This original survival advantage is attributed to poor quality of surgery and the large differential in local recurrence rates, with and without SCPRT. Immuno-modulation during and after SCPRT and its clinical implications have been poorly investigated. We propose an alternative explanation for this survival benefit in terms of immunological mechanisms induced by SCPRT and the timing of surgery, which may validate the concept of consolidation chemotherapy.
We reviewed randomized controlled trials (RCTs) and studies of SCPRT from 1985 to 2019. We aimed to examine the precise timing of surgery in days following SCPRT and identify evidence for immune modulation, neo-antigens and memory cell induction by radiation.
Considerable variability is reported in randomised trials for median overall treatment time (OTT) from start of SCPRT to surgery (8-14 days). Only three early trials showed a benefit in terms of OS from SCPRT, although the level of benefit in preventing local recurrence was consistent across all trials. Different patterns of immune effects are observed within days after SCPRT depending on the OTT, but human leukocyte antigen (HLA)-1 expression was not upregulated.
SCPRT has a substantial immune-stimulatory potential. The importance of the timing of surgery after SCPRT may have been underestimated. An optimal interval for surgery after 5 × 5 Gy may lead to better outcomes, which is possibly exploited in total neoadjuvant therapy schedules using consolidation chemotherapy. Individual patient meta-analyses from appropriate SCPRT trials examining outcomes for each day and prospective trials are needed to clarify the validity of this hypothesis. The interaction of SCPRT with tumour adaptive immunology, in particular the kinetics and timing, should be examined further.
早期直肠癌试验中报道的 5×5 Gy 短程术前放疗（SCPRT）可提高总生存期（OS），但后续的 III 期试验未能复制这一结果。这种最初的生存优势归因于手术质量差，以及有无 SCPRT 时局部复发率的巨大差异。SCPRT 期间和之后的免疫调节及其临床意义尚未得到充分研究。我们提出了一种替代解释，即 SCPRT 诱导的免疫机制及其手术时机导致了这种生存获益，这可能验证了巩固化疗的概念。
我们回顾了 1985 年至 2019 年的 SCPRT 随机对照试验（RCT）和研究。我们旨在检查 SCPRT 后手术的确切时间，并确定放疗诱导的免疫调节、新抗原和记忆细胞的证据。
在随机试验中，SCPRT 开始到手术的中位总治疗时间（OTT）有很大的差异（8-14 天）。只有三项早期试验显示 SCPRT 在 OS 方面有获益，尽管所有试验中预防局部复发的获益水平是一致的。SCPRT 后几天内观察到的免疫效应模式因 OTT 而异，但人类白细胞抗原（HLA）-1 表达没有上调。
SCPRT 具有显著的免疫刺激潜力。SCPRT 后手术时机的重要性可能被低估了。在接受 5×5 Gy 治疗后，手术的最佳时机可能会带来更好的结果，这可能在使用巩固化疗的全新辅助治疗方案中得到利用。需要进行适当的 SCPRT 试验的个体患者荟萃分析，以检查每天的结果，并进行前瞻性试验，以澄清这一假设的有效性。应进一步研究 SCPRT 与肿瘤适应性免疫的相互作用，特别是动力学和时机。
