Lawrie Theresa A, Green John T, Beresford Mark, Wedlake Linda, Burden Sorrel, Davidson Susan E, Lal Simon, Henson Caroline C, Andreyev H Jervoise N
Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group, 1st Floor Education Centre, Royal United Hospital, Combe Park, Bath, UK, BA1 3NG.
Cochrane Database Syst Rev. 2018 Jan 23;1(1):CD012529. doi: 10.1002/14651858.CD012529.pub2.
BACKGROUND: An increasing number of people survive cancer but a significant proportion have gastrointestinal side effects as a result of radiotherapy (RT), which impairs their quality of life (QoL). OBJECTIVES: To determine which prophylactic interventions reduce the incidence, severity or both of adverse gastrointestinal effects among adults receiving radiotherapy to treat primary pelvic cancers. SEARCH METHODS: We conducted searches of CENTRAL, MEDLINE, and Embase in September 2016 and updated them on 2 November 2017. We also searched clinical trial registries. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of interventions to prevent adverse gastrointestinal effects of pelvic radiotherapy among adults receiving radiotherapy to treat primary pelvic cancers, including radiotherapy techniques, other aspects of radiotherapy delivery, pharmacological interventions and non-pharmacological interventions. Studies needed a sample size of 20 or more participants and needed to evaluate gastrointestinal toxicity outcomes. We excluded studies that evaluated dosimetric parameters only. We also excluded trials of interventions to treat acute gastrointestinal symptoms, trials of altered fractionation and dose escalation schedules, and trials of pre- versus postoperative radiotherapy regimens, to restrict the vast scope of the review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. We used the random-effects statistical model for all meta-analyses, and the GRADE system to rate the certainty of the evidence. MAIN RESULTS: We included 92 RCTs involving more than 10,000 men and women undergoing pelvic radiotherapy. Trials involved 44 different interventions, including radiotherapy techniques (11 trials, 4 interventions/comparisons), other aspects of radiotherapy delivery (14 trials, 10 interventions), pharmacological interventions (38 trials, 16 interventions), and non-pharmacological interventions (29 trials, 13 interventions). Most studies (79/92) had design limitations. Thirteen studies had a low risk of bias, 50 studies had an unclear risk of bias and 29 studies had a high risk of bias. Main findings include the following:Radiotherapy techniques: Intensity-modulated radiotherapy (IMRT) versus 3D conformal RT (3DCRT) may reduce acute (risk ratio (RR) 0.48, 95% confidence interval (CI) 0.26 to 0.88; participants = 444; studies = 4; I = 77%; low-certainty evidence) and late gastrointestinal (GI) toxicity grade 2+ (RR 0.37, 95% CI 0.21 to 0.65; participants = 332; studies = 2; I = 0%; low-certainty evidence). Conformal RT (3DCRT or IMRT) versus conventional RT reduces acute GI toxicity grade 2+ (RR 0.57, 95% CI 0.40 to 0.82; participants = 307; studies = 2; I = 0%; high-certainty evidence) and probably leads to less late GI toxicity grade 2+ (RR 0.49, 95% CI 0.22 to 1.09; participants = 517; studies = 3; I = 44%; moderate-certainty evidence). When brachytherapy (BT) is used instead of external beam radiotherapy (EBRT) in early endometrial cancer, evidence indicates that it reduces acute GI toxicity (grade 2+) (RR 0.02, 95% CI 0.00 to 0.18; participants = 423; studies = 1; high-certainty evidence).Other aspects of radiotherapy delivery: There is probably little or no difference in acute GI toxicity grade 2+ with reduced radiation dose volume (RR 1.21, 95% CI 0.81 to 1.81; participants = 211; studies = 1; moderate-certainty evidence) and maybe no difference in late GI toxicity grade 2+ (RR 1.02, 95% CI 0.15 to 6.97; participants = 107; studies = 1; low-certainty evidence). Evening delivery of RT may reduce acute GI toxicity (diarrhoea) grade 2+ during RT compared with morning delivery of RT (RR 0.51, 95% CI 0.34 to 0.76; participants = 294; studies = 2; I = 0%; low-certainty evidence). There may be no difference in acute (RR 2.22, 95% CI 0.62 to 7.93, participants = 110; studies = 1) and late GI toxicity grade 2+ (RR 0.44, 95% CI 0.12 to 1.65; participants = 81; studies = 1) between a bladder volume preparation of 1080 mls and that of 540 mls (low-certainty evidence). Low-certainty evidence on balloon and hydrogel spacers suggests that these interventions for prostate cancer RT may make little or no difference to GI outcomes.Pharmacological interventions: Evidence for any beneficial effects of aminosalicylates, sucralfate, amifostine, corticosteroid enemas, bile acid sequestrants, famotidine and selenium is of a low or very low certainty. However, evidence on certain aminosalicylates (mesalazine, olsalazine), misoprostol suppositories, oral magnesium oxide and octreotide injections suggests that these agents may worsen GI symptoms, such as diarrhoea or rectal bleeding.Non-pharmacological interventions: Low-certainty evidence suggests that protein supplements (RR 0.23, 95% CI 0.07 to 0.74; participants = 74; studies = 1), dietary counselling (RR 0.04, 95% CI 0.00 to 0.60; participants = 74; studies = 1) and probiotics (RR 0.43, 95% CI 0.22 to 0.82; participants = 923; studies = 5; I = 91%) may reduce acute RT-related diarrhoea (grade 2+). Dietary counselling may also reduce diarrhoeal symptoms in the long term (at five years, RR 0.05, 95% CI 0.00 to 0.78; participants = 61; studies = 1). Low-certainty evidence from one study (108 participants) suggests that a high-fibre diet may have a beneficial effect on GI symptoms (mean difference (MD) 6.10, 95% CI 1.71 to 10.49) and quality of life (MD 20.50, 95% CI 9.97 to 31.03) at one year. High-certainty evidence indicates that glutamine supplements do not prevent RT-induced diarrhoea. Evidence on various other non-pharmacological interventions, such as green tea tablets, is lacking.Quality of life was rarely and inconsistently reported across included studies, and the available data were seldom adequate for meta-analysis. AUTHORS' CONCLUSIONS: Conformal radiotherapy techniques are an improvement on older radiotherapy techniques. IMRT may be better than 3DCRT in terms of GI toxicity, but the evidence to support this is uncertain. There is no high-quality evidence to support the use of any other prophylactic intervention evaluated. However, evidence on some potential interventions shows that they probably have no role to play in reducing RT-related GI toxicity. More RCTs are needed for interventions with limited evidence suggesting potential benefits.
背景:越来越多的癌症患者得以存活,但相当一部分人因放疗(RT)出现胃肠道副作用,这损害了他们的生活质量(QoL)。 目的:确定哪些预防性干预措施可降低接受原发性盆腔癌放疗的成年人胃肠道不良反应的发生率、严重程度或两者。 检索方法:我们于2016年9月对Cochrane中心对照试验注册库(CENTRAL)、医学文献数据库(MEDLINE)和荷兰医学文摘数据库(Embase)进行了检索,并于2017年11月2日更新。我们还检索了临床试验注册库。 入选标准:我们纳入了干预措施的随机对照试验(RCT),这些干预措施旨在预防接受原发性盆腔癌放疗的成年人盆腔放疗的胃肠道不良反应,包括放疗技术、放疗实施的其他方面、药物干预和非药物干预。研究需要样本量为20名或更多参与者,并需要评估胃肠道毒性结局。我们排除了仅评估剂量学参数的研究。我们还排除了治疗急性胃肠道症状的干预措施试验、分割方式改变和剂量递增方案试验以及术前与术后放疗方案试验,以限制综述的广泛范围。 数据收集与分析:我们采用标准的Cochrane方法。所有荟萃分析均使用随机效应统计模型,并使用GRADE系统对证据的确定性进行评级。 主要结果:我们纳入了92项RCT,涉及10000多名接受盆腔放疗的男性和女性。试验涉及44种不同的干预措施,包括放疗技术(11项试验,4种干预措施/比较)、放疗实施的其他方面(14项试验,10种干预措施)、药物干预(38项试验,16种干预措施)和非药物干预(29项试验,13种干预措施)。大多数研究(79/92)存在设计局限性。13项研究的偏倚风险较低,50项研究的偏倚风险不明确,29项研究的偏倚风险较高。主要研究结果如下: 放疗技术:调强放疗(IMRT)与三维适形放疗(3DCRT)相比,可能降低急性(风险比(RR)0.48,95%置信区间(CI)0.26至0.88;参与者 = 444;研究 = 4;I² = 77%;低确定性证据)和晚期胃肠道(GI)2级及以上毒性(RR 0.37,95% CI 0.21至0.65;参与者 = 332;研究 = 2;I² = 0%;低确定性证据)。适形放疗(3DCRT或IMRT)与传统放疗相比,可降低急性2级及以上GI毒性(RR 0.57,95% CI 0.40至0.82;参与者 = 307;研究 = 2;I² = 0%;高确定性证据),并可能导致较少的晚期2级及以上GI毒性(RR 0.49,95% CI 0.22至1.09;参与者 = 517;研究 = 3;I² = 44%;中等确定性证据)。在早期子宫内膜癌中,使用近距离放疗(BT)代替外照射放疗(EBRT),证据表明可降低急性GI毒性(2级及以上)(RR 0.02,95% CI 0.00至0.18;参与者 = 423;研究 = 1;高确定性证据)。 放疗实施的其他方面:降低放射剂量体积,急性2级及以上GI毒性可能几乎没有差异(RR 1.21,95% CI 0.81至1.81;参与者 = 211;研究 = 1;中等确定性证据),晚期2级及以上GI毒性可能也没有差异(RR 1.02,95% CI 0.15至6.97;参与者 = 107;研究 = 1;低确定性证据)。与上午进行放疗相比,晚上进行放疗可能降低放疗期间急性2级及以上GI毒性(腹泻)(RR 0.51,95% CI 0.34至0.76;参与者 = 294;研究 = 2;I² = 0%;低确定性证据)。膀胱容量准备为1080毫升与540毫升之间,急性(RR 2.22,95% CI 0.62至7.93,参与者 = 110;研究 = 1)和晚期2级及以上GI毒性(RR 0.44,95% CI 0.12至1.65;参与者 = 81;研究 = 1)可能没有差异(低确定性证据)。关于球囊和水凝胶间隔器的低确定性证据表明,这些用于前列腺癌放疗的干预措施对GI结局可能几乎没有影响。 药物干预:氨基水杨酸类、硫糖铝、氨磷汀、皮质类固醇灌肠剂、胆汁酸螯合剂、法莫替丁和硒的任何有益效果的证据确定性低或非常低。然而,关于某些氨基水杨酸类(美沙拉嗪、奥沙拉嗪)、米索前列醇栓剂、口服氧化镁和奥曲肽注射剂的证据表明,这些药物可能会加重GI症状,如腹泻或直肠出血。 非药物干预:低确定性证据表明,蛋白质补充剂(RR 0.23,95% CI 0.07至0.74;参与者 = 74;研究 = 1)、饮食咨询(RR 0.04,95% CI 0.00至0.60;参与者 = 74;研究 = 1)和益生菌(RR 0.43,95% CI 0.22至0.82;参与者 = 923;研究 = 5;I² = 91%)可能降低急性放疗相关腹泻(2级及以上)。饮食咨询也可能长期(五年时)降低腹泻症状(RR 0.05,95% CI 0.00至0.78;参与者 = 61;研究 = 1)。一项研究(108名参与者)的低确定性证据表明,高纤维饮食可能对一年时的GI症状(平均差(MD)6.10,95% CI 1.71至10.49)和生活质量(MD 20.50,95% CI 9.97至31.03)有有益影响。高确定性证据表明,谷氨酰胺补充剂不能预防放疗引起的腹泻。缺乏关于各种其他非药物干预措施(如绿茶片)的证据。 纳入研究中生活质量的报告很少且不一致,现有数据很少足以进行荟萃分析。 作者结论:适形放疗技术比旧的放疗技术有所改进。在GI毒性方面,IMRT可能优于3DCRT,但支持这一点的证据不确定。没有高质量证据支持使用所评估的任何其他预防性干预措施。然而,关于一些潜在干预措施的证据表明,它们可能在降低放疗相关GI毒性方面不起作用。对于证据有限但提示有潜在益处的干预措施,需要更多的RCT。
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