Division of Surgical Oncology and General Surgery, Princess Margaret Hospital and University Health Network, University of Toronto, Toronto, ON, Canada.
Manchester Cancer Research Centre and NIHR Manchester Biomedical Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, UK.
Lancet Gastroenterol Hepatol. 2018 Dec;3(12):825-836. doi: 10.1016/S2468-1253(18)30301-7. Epub 2018 Oct 12.
In patients with rectal cancer who achieve clinical complete response after neoadjuvant chemoradiotherapy, watch and wait is a novel management strategy with potential to avoid major surgery. Study-level meta-analyses have reported wide variation in the proportion of patients with local regrowth. We did an individual participant data meta-analysis to investigate factors affecting occurrence of local regrowth.
We updated search results of a recent systematic review by searching MEDLINE and Embase from Jan 1, 2016, to May 5, 2017, and used expert knowledge to identify published studies reporting on local regrowth in patients with rectal cancer managed by watch and wait after clinical complete response to neoadjuvant chemoradiotherapy. We restricted studies to those that defined clinical complete response using criteria equivalent to São Paulo benchmarks (ie, absence of residual ulceration, stenosis, or mass within the rectum on clinical and endoscopic examination). The primary outcome was 2-year cumulative incidence of local regrowth, estimated with a two-stage random-effects individual participant data meta-analysis. We assessed the effects of clinical and treatment factors using Cox frailty models, expressed as hazard ratios (HRs). From these models, we derived percentage differences in mean θ as an approximation of the effect of measured covariates on between-centre heterogeneity. This study is registered with PROSPERO, number CRD42017070934.
We obtained individual participant data from 11 studies, including 602 patients enrolled between March 11, 1990, and Feb 13, 2017, with a median follow-up of 37·6 months (IQR 25·0-58·7). Ten of the 11 datasets were judged to be at low risk of bias. 2-year cumulative incidence of local regrowth was 21·4% (random-effects 95% CI 15·3-27·6), with high levels of between-study heterogeneity (I=61%). We noted wide between-centre variation in patient, tumour, and treatment characteristics. We found some evidence that increasing cT stage was associated with increased risk of local regrowth (random-effects HR per cT stage 1·40, 95% CI 1·00-1·94; p=0·048). In a subgroup of 459 patients managed after 2008 (when pretreatment staging by MRI became standard), 2-year cumulative incidence of local regrowth was 19% (95% CI 13-28) for stage cT1 and cT2 tumours, 31% (26-37) for cT3, and 37% (21-60) for cT4 (random-effects HR per cT stage 1·50, random-effects 95% CI 1·03-2·17; p=0·0330). We estimated that measured factors contributed 4·8-45·3% of observed between-centre heterogeneity.
In patients with rectal cancer and clinical complete response after chemoradiotherapy managed by watch and wait, we found some evidence that increasing cT stage predicts for local regrowth. These data will inform clinician-patient decision making in this setting. Research is needed to determine other predictors of a sustained clinical complete response.
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在接受新辅助放化疗后达到临床完全缓解的直肠癌患者中，观察等待是一种具有避免重大手术潜力的新型管理策略。研究水平的荟萃分析报告了局部复发患者的比例存在广泛差异。我们进行了一项个体参与者数据荟萃分析，以调查影响局部复发发生的因素。
我们通过检索 MEDLINE 和 Embase，更新了最近一项系统评价的搜索结果，检索时间为 2016 年 1 月 1 日至 2017 年 5 月 5 日，并利用专家知识确定了已发表的研究报告，这些研究报告报告了在新辅助放化疗后临床完全缓解的直肠癌患者中通过观察等待管理后局部复发的情况。我们将研究限制在那些使用相当于圣保罗基准（即直肠临床和内镜检查无残留溃疡、狭窄或肿块）的标准来定义临床完全缓解的研究中。主要结局是 2 年累积局部复发发生率，采用两阶段随机效应个体参与者数据荟萃分析进行估计。我们使用 Cox 脆弱性模型评估临床和治疗因素的影响，用风险比（HRs）表示。从这些模型中，我们得出了平均θ的百分比差异，作为衡量协变量对中心间异质性影响的近似值。本研究在 PROSPERO 注册，编号 CRD42017070934。
我们从 11 项研究中获得了个体参与者数据，包括 1990 年 3 月 11 日至 2017 年 2 月 13 日期间入组的 602 名患者，中位随访时间为 37.6 个月（IQR 25.0-58.7）。11 个数据集中有 10 个被判定为低偏倚风险。2 年局部复发累积发生率为 21.4%（随机效应 95%CI 15.3-27.6），研究间异质性水平较高（I=61%）。我们注意到患者、肿瘤和治疗特征方面存在广泛的中心间差异。我们发现一些证据表明，cT 分期的增加与局部复发风险的增加相关（每增加一个 cT 分期的随机效应 HR 为 1.40，95%CI 1.00-1.94；p=0.048）。在 2008 年（当 MRI 术前分期成为标准时）管理的 459 名患者的亚组中，cT1 和 cT2 肿瘤的 2 年局部复发累积发生率为 19%（95%CI 13-28），cT3 为 31%（26-37），cT4 为 37%（21-60）（每增加一个 cT 分期的随机效应 HR 为 1.50，随机效应 95%CI 1.03-2.17；p=0.0330）。我们估计，测量因素占观察到的中心间异质性的 4.8-45.3%。
在接受新辅助放化疗后达到临床完全缓解并接受观察等待的直肠癌患者中，我们发现一些证据表明 cT 分期的增加预测了局部复发。这些数据将为这一环境下的医患决策提供信息。需要研究来确定其他预测持续临床完全缓解的因素。
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