Teo Mark T W, McParland Lucy, Appelt Ane L, Sebag-Montefiore David
Radiotherapy Research Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Leeds Cancer Centre, St James University Hospital, Leeds, UK.
Radiotherapy Research Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.
Int J Radiat Oncol Biol Phys. 2018 Jan 1;100(1):146-158. doi: 10.1016/j.ijrobp.2017.09.042. Epub 2017 Sep 29.
Multiple phase 2 trials of neoadjuvant treatment intensification in locally advanced rectal cancer have reported promising efficacy signals, but these have not translated into improved cancer outcomes in phase 3 trials. Improvements in phase 2 trial design are needed to reduce these false-positive signals. This systematic review evaluated the design of phase 2 trials of neoadjuvant long-course radiation or chemoradiation therapy treatment intensification in locally advanced rectal cancer.
The PubMed, EMBASE, MEDLINE, and Cochrane Library databases were searched for published phase 2 trials of neoadjuvant treatment intensification from 2004 to 2016. Trial clinical design and outcomes were assessed, with statistical design and compliance rated using a previously published system. Multivariable meta-regression analysis of pathologic complete response (pCR) was conducted.
We identified 92 eligible trials. Patients with American Joint Committee on Cancer stage II and III equivalent disease were eligible in 87 trials (94.6%). In 43 trials (46.7%), local staging on magnetic resonance imaging was mandated. Only 12 trials (13.0%) were randomized, with 8 having a standard-treatment control arm. Just 51 trials (55.4%) described their statistical design, with 21 trials (22.8%) failing to report their sample size derivation. Most trials (n=84, 91.3%) defined a primary endpoint, but 15 different primary endpoints were used. All trials reported pCR rates. Only 38 trials (41.3%) adequately reported trial statistical design and compliance. Meta-analysis revealed a pooled pCR rate of 17.5% (95% confidence interval, 15.7%-19.4%) across treatment arms of neoadjuvant long-course radiation or chemoradiation therapy treatment intensification and substantial heterogeneity among the reported effect sizes (I = 55.3%, P<.001). Multivariable meta-regression analysis suggested increased pCR rates with higher radiation therapy doses (adjusted P=.025).
Improvement in the design of future phase 2 rectal cancer trials is urgently required. A significant increase in randomized trials is essential to overcome selection bias and determine novel schedules suitable for phase 3 testing. This systematic review provides key recommendations to guide future treatment intensification trial design in rectal cancer.
多项局部晚期直肠癌新辅助治疗强化的2期试验报告了有前景的疗效信号，但这些信号在3期试验中并未转化为改善的癌症结局。需要改进2期试验设计以减少这些假阳性信号。本系统评价评估了局部晚期直肠癌新辅助长程放疗或放化疗强化治疗的2期试验设计。
检索PubMed、EMBASE、MEDLINE和Cochrane图书馆数据库，查找2004年至2016年发表的新辅助治疗强化的2期试验。评估试验临床设计和结局，使用先前发表的系统对统计设计和依从性进行评分。对病理完全缓解（pCR）进行多变量Meta回归分析。
我们确定了92项符合条件的试验。87项试验（94.6%）纳入了美国癌症联合委员会II期和III期等效疾病的患者。43项试验（46.7%）要求进行磁共振成像局部分期。仅12项试验（13.0%）为随机试验，其中8项有标准治疗对照臂。仅51项试验（55.4%）描述了其统计设计，21项试验（22.8%）未报告样本量推导过程。大多数试验（n = 84，91.3%）定义了主要终点，但使用了15种不同的主要终点。所有试验均报告了pCR率。仅38项试验（41.3%）充分报告了试验统计设计和依从性。Meta分析显示，新辅助长程放疗或放化疗强化治疗各治疗组的合并pCR率为17.5%（95%置信区间，15.7%-19.4%），报告的效应大小之间存在实质性异质性（I² = 55.3%，P <.001）。多变量Meta回归分析表明，放疗剂量越高，pCR率越高（校正P = 0.025）。
迫切需要改进未来的直肠癌2期试验设计。显著增加随机试验对于克服选择偏倚和确定适合3期试验的新方案至关重要。本系统评价提供了关键建议，以指导未来直肠癌治疗强化试验设计。
