Glynne-Jones R, Mawdsley S, Pearce T, Buyse M
Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex, UK.
Ann Oncol. 2006 Aug;17(8):1239-48. doi: 10.1093/annonc/mdl173.
In rectal cancer a high risk of local recurrence has been reported for patients treated by surgery alone. It is also recognised that 20%-40% of rectal cancer patients continue to develop distant metastases and die, even when a very low risk of local recurrence has been achieved with the use of preoperative radiotherapy and total mesorectal excision (TME). Hence, the current design of randomised trials in rectal cancer continues to use the standard end points of local control and survival. This strategy is time-consuming. The recently published EORTC 22921 trial, which compared radiotherapy with chemoradiotherapy and tested the role of postoperative adjuvant chemotherapy, has taken 14 years from planning to results. The aim of this review was to use the evidence from both phase II and phase III trials to provide a comprehensive survey of alternative clinical trial end points in rectal cancer, where preoperative chemoradiation has now become the standard treatment. We describe their strengths and weaknesses. Some are clearly defined, easy to assess and can be obtained early, because surgical resection usually takes place within 6-8 weeks of the completion of treatment. Some pathological response end points reflect biological activity, although their effect on survival has yet to be validated in randomised controlled trials. We will propose measurement and analytical techniques for minimising bias and intra- and inter-observer variability of the non-validated end points in the hope of basing these judgements on as firm a ground as possible.
A literature search identified both randomised and non-randomised trials of preoperative radiation therapy (RT) and chemoradiation therapy (CRT) in rectal cancer from 1993 to 2005. The aim was to find those studies that documented potential alternative end points.
Pathological parameters have been used as early end points to compare studies of preoperative radiotherapy or chemoradiation. In the light of the German CAO/ARO/AIO-94 study, which demonstrated an improved therapeutic ratio for preoperative treatment, enthusiasm for preoperative chemoradiation in the management of rectal cancer is increasing. Current evidence cannot indicate whether the degree of response to chemoradiation (e.g. complete pathological response; downsizing the primary tumour; sterilizing the regional nodes; tumour regression grades or residual cell density) or the achievement of a curative resection (CRM/R0 resection) is the best early clinical end point. Problems with these end points include lack of structured measurement and analysis techniques to control for intra- and inter-observer variation and lack of validation as surrogates for long-term clinical end points such as local control and survival. However, retrospective studies in rectal cancer have confirmed a strong association between the presence of microscopic tumour cells within 1 mm of the CRM and increased risks of both local recurrence and distant metastases. Further end points of current clinical relevance for which adequate methodologies for assessment are lacking include sphincter sparing end points, and assessment of long-term toxicities, ano-rectal function and their specific impact on quality of life. Recommendations are made as to the most appropriate information, which should be documented in future trials.
Pathological complete response following preoperative chemoradiation does not reliably predict late outcome. There are other events not mediated through this end point and there are also unintended effects (often an excess of non-cancer related deaths). Disease-free survival currently remains the best (because it is relatively quick) primary end point in designing randomised phase III studies of preoperative chemoradiation in rectal cancer, although it is necessary to control for postoperative adjuvant chemotherapy. However, the CRM status can substantially account for effects on disease-free and overall survival after chemoradiation, radiation or surgery alone. Hopefully, randomised controlled trials, which utilise these alternative clinical end points, will in future determine the precise percentages of the effect of different chemoradiation schedules on disease-free and overall survival.
据报道，单纯手术治疗的直肠癌患者局部复发风险较高。人们也认识到，即使术前放疗和全直肠系膜切除术（TME）已使局部复发风险非常低，但仍有20%-40%的直肠癌患者会继续发生远处转移并死亡。因此，目前直肠癌随机试验的设计仍继续采用局部控制和生存这两个标准终点。这种策略耗时较长。最近发表的EORTC 22921试验比较了放疗与放化疗，并测试了术后辅助化疗的作用，从规划到得出结果耗时14年。本综述的目的是利用II期和III期试验的证据，全面调查直肠癌替代临床试验终点，目前术前放化疗已成为标准治疗方法。我们描述了它们的优缺点。有些终点定义明确、易于评估且能早期获得，因为手术切除通常在治疗完成后的6-8周内进行。一些病理反应终点反映了生物学活性，尽管它们对生存的影响尚未在随机对照试验中得到验证。我们将提出测量和分析技术，以尽量减少未经验证终点的偏差以及观察者内和观察者间的变异性，希望能尽可能可靠地做出这些判断。
通过文献检索确定了1993年至2005年期间直肠癌术前放射治疗（RT）和放化疗（CRT）的随机和非随机试验。目的是找到那些记录了潜在替代终点的研究。
病理参数已被用作早期终点，以比较术前放疗或放化疗的研究。鉴于德国CAO/ARO/AIO-94研究表明术前治疗的治疗比有所提高，直肠癌治疗中对术前放化疗的热情正在增加。目前的证据无法表明对放化疗的反应程度（例如完全病理反应；原发肿瘤缩小；区域淋巴结清除；肿瘤消退分级或残留细胞密度）或根治性切除（CRM/R0切除）的实现是否是最佳的早期临床终点。这些终点存在的问题包括缺乏结构化的测量和分析技术来控制观察者内和观察者间的差异，以及缺乏作为局部控制和生存等长期临床终点替代指标的验证。然而，直肠癌的回顾性研究证实，CRM周围1毫米内存在微小肿瘤细胞与局部复发和远处转移风险增加之间存在密切关联。目前具有临床相关性但缺乏充分评估方法的其他终点包括保留括约肌终点，以及长期毒性、肛门直肠功能及其对生活质量的特定影响的评估。针对未来试验应记录的最适当信息提出了建议。
术前放化疗后的病理完全缓解并不能可靠地预测晚期结局。还有其他未通过此终点介导的事件，也存在意外影响（通常是非癌症相关死亡过多）。无病生存目前仍然是设计直肠癌术前放化疗随机III期研究的最佳（因为相对较快）主要终点，尽管有必要控制术后辅助化疗。然而，CRM状态在很大程度上可以解释放化疗、单纯放疗或手术后对无病生存和总生存的影响。希望利用这些替代临床终点的随机对照试验未来能确定不同放化疗方案对无病生存和总生存影响的确切百分比。
