背景

发病率与死亡率

结直肠癌(CRC)列全球最常见恶性肿瘤第三位[1],列美国癌症死因第二位(不分性别)[2]。据估计,2013年美国将有142,820例结直肠癌新发病例,50,830例结直肠癌死亡病例[2]。2005-2009年,美国50岁以上成人结直肠癌发病率每年降低4.1%[2]。在过去20年内,男性与女性死亡率均有所降低。2005-2009年,男性死亡率每年降低2.4%,女性死亡率每年降低3.1%。50岁以下成年人的结直肠癌发病率每年增加约1.1%[2]。结直肠癌的5年生存率为64%。5%的美国人一生中可能患上结直肠癌[2][3]。 结直肠癌发病风险从40岁开始升高,在50-55岁之间急剧升高;此后每10年风险加倍,呈指数级升高。尽管手术与辅助治疗有了长足发展,但晚期肿瘤患者的生存率只有微弱改善[4][5]。因此必须开展有效的一级和二级预防措施以降低结直肠癌发病与死亡。

预防的定义

一级预防包括在出现结直肠癌临床症状前,使用药物或其他干预措施,以预防临床结直肠癌发生和死亡。

结直肠癌的病因和发病机制

遗传学[6][7]、实验[8][9]、与流行病学[10][11][12]研究均表明结直肠癌是遗传易感性和环境因素共同作用的结果。然而。具体因素及其在结直肠癌的发生和死亡中的作用有待进一步的研究。

结直肠癌危险因素

有证据表明结直肠癌与饮酒有关。一项综合8项队列研究的荟萃研究发现,与不饮酒者相比,每天摄入45g酒精(相当于每天3杯酒)人群结直肠癌发病相对风险(RR)为1.41(95% CI,1.16-1.72)[13]。1项病例对照研究发现饮酒与结直肠癌之间存在中度-高度正相关性[14][15]。一项荟萃分析发现这一相关性与年龄及病变部位无关[16]

5项研究发现饮酒与结直肠腺瘤之间存在正相关性[17]。一项旨在探讨饮食、遗传因素、腺瘤-癌之间相关性的病例对照研究在勃艮第进行[18],研究人员以腺瘤大小为10.0mm为临界值进行分层分析,发现饮酒与腺瘤的相关性仅出现在大腺瘤组,提示饮酒可能作用于腺瘤-癌变过程的促进阶段[18]

一项大规模队列研究发现饮酒与结直肠癌死亡存在剂量反应关系,与不饮酒者相比,每天摄入至少4杯酒,死亡RR为1.2(95%CI,1.0-1.5)[19]

多数关于吸烟与腺瘤的病例对照研究发现吸烟者腺瘤发病风险升高[20]。此外,有研究发现不论男性或女性腺瘤患者,吸烟者息肉切除术后腺瘤复发风险明显增加[20]。“护士健康研究”发现癌症诱导期需要至少35年[21]。“健康专家随访研究”发现类似结论,吸烟史与小腺瘤、大腺瘤均有关,结直肠癌的诱导期至少35年[22]。癌症预防研究II(CPS II)是一项大型全国队列研究,该研究发现,多变量调整结直肠癌死亡率现吸烟者最高,曾吸烟者居中,不吸烟者最低。男性与女性全人群中,有至少20年吸烟史者风险增高[23]。根据CPS II提供的数据,1997年美国12%的结直肠癌死亡归因于吸烟。一项在瑞典双生儿中开展的大规模队列研究发现,烟龄35年以上可使结肠癌发病风险增加2倍,对发病部位进行分层后,吸烟仅增加直肠癌发病风险,对结肠癌没有左右[24]。另一项病例对照研究发现,现在吸烟与过去10年内有吸烟史也增加结肠癌发病风险。和从不吸烟者相比,每天吸烟大于1包者发病风险可增加50%[25]。但芬兰一项对57,000人随访28年的研究发现,结直肠癌发病风险与基线吸烟情况无关,持续吸烟者结直肠癌发病风险可升高57%到71%[26]。另一项对首次结肠镜检查后病人进行4年随访的研究发现,吸烟、甚至长期吸烟与腺瘤复发没有相关性[27]

对106项观察性研究荟萃分析后发现,与不吸烟人群相比,吸烟人群结直肠癌发病相对风险为1.18(95%CI,1.11-1.25),绝对风险增加10.8/10万人年(95%CI,7.9-13.6),且发病与吸烟城剂量反应关系。另一项综合17项结直肠癌死亡率相关研究,发现结直肠癌死亡与吸烟和具有相关性,与从不吸烟者相比,曾吸烟者死亡RR为1.25(95%CI,1.14-1.37),死亡率绝对增加6.0/10万人年。无论是发病率还是死亡率,吸烟与直肠癌关联强度大于结肠癌[28]

3项以上大规模队列研究已证实结直肠癌的发病或死亡与肥胖相关[29][30][31]。“护士健康研究”发现体重指数(BMI)大于29的女性与BMI低于21的女性相比,结直肠癌调发病调整RR值值为1.45(95%CI,1.02-2.07)[27]。CPS II研究中[31],BMI为30-34.9的男性与女性的结直肠癌死亡调整RR值(与BMI为18.5-24.9的人相比)为1.47(95%CI,1.30-1.66),且死亡与BMI之间存在剂量反应关系[31],但无性别差异。

结直肠癌保护因素

有研究发现[32][33]久坐会增加结直肠癌发病风险,但也有研究得出不同结论[34]。大量观察性研究曾探讨结肠癌风险与体力活动之间的相关性[35]。其中,多数研究发现结肠癌发生与体力活动呈负相关,平均RR降低40%-50%。美国多项大型队列研究发现,经常运动与少量运动者的结肠癌发病调整RR值分别是0.54(95%CI,0.33-0.90)[29]与0.53(95%CI,0.32-0.88)[30],具有统计学差异。对52项观察性研究行荟萃分析发现,体力活动对结肠癌的发生调整RR值值为0.76(95%CI,0.72-0.81),男性与女性无差异[36]

结直肠癌预防性干预措施:获益与危害

一项大型队列研究(301,240人,其中3,894例结直肠癌患者)发现,每日或每周服用非阿司匹林(非乙酰水杨酸[非ASA])的非甾体类抗炎药(NSAID)可降低近端和远端结肠癌10年发病率,但不影响直肠癌发病率;其中每日用药结肠癌的风险比(HR)为0.67(95%CI,0.58-0.77)。该研究中,非阿司匹林的非甾体类抗炎药暴露史经通过自我报告评估一次,同时缺少用药剂量和用药时间的信息,故该单项研究的可靠性相对较低。因此该研究结果需要进一步研究证实[37]

虽然现在缺乏可靠证据支持非甾体类抗炎药可降低结直肠癌发病率,但一些支持者认为这些药物都是通过抑制环氧化酶(COX)活性来降低结直肠癌发病的。COX在花生四烯酸转化为前列腺素类、前列腺素与血栓素A2的过程中发生重要作用。非甾体类抗炎药药物,不仅包括阿司匹林,还包括非选择性COX一代抑制剂(抑制COX的两种功能性异构体COX-1与COX-2)和COX2的二代抑制剂。COX-1可在多种组织中表达,发挥管家作用(即保护消化道粘膜和促进血小板聚集);COX-2在应激反应中发挥作用,同时介导并扩散疾病的疼痛与炎症,如关节炎[38]

非选择性COX抑制剂包括吲哚美辛(消炎痛)、舒林酸(奇诺力)、吡罗昔康(费啶)、二氟尼柳(Dolobid)、布洛芬(艾德维尔、美林)、酮洛芬(Orudis)、萘普生(消痛灵)与萘普生钠(Aleve、Anaprox)。选择性COX-2抑制剂包括塞来昔布(西乐葆)、罗非考昔(万络)与伐地考昔(Bextra)。罗非考昔与伐地考昔因增加心血管事件发生风险不再上市。

塞来昔布与罗非考昔与严重心血管事件相关,包括与剂量相关的心血管疾病死亡、心肌梗死、卒中或心力衰竭[39][40][41][42]。下表总结了证实用药会增加并发症风险的4项试验。此外,对在不同非甾体类抗炎药间,或者非甾体类抗炎药与安慰剂之间进行研究的大规模RCT行网络荟萃分析,提示所有非甾体类抗炎药都可造成心血管不良事件。相对而言,萘普生的风险最低[43]

塞来昔布与罗非考昔用药相关的心血管风险
塞来昔布与罗非考昔用药相关的心血管风险
作者 剂量/试验用药 风险 适应证
bid=每日2次;qd=每日1次;CI=置信区间;HR=风险比;OR=比值比;RR=相对风险。
[40] 罗非考昔<25 mg/qd;罗非考昔>25 mg/qd OR = 1.47 (0.99–2.17) 3与58 (1.27–10.17) ​巢式病例对照研究所有用户
[42] 塞来昔布200 mg/qd与400 mg bid 3.4%;HR = 3.4 (95% CI, 1.4–7.8) 散发性腺瘤预防试验(N=2,035)
[41] 罗非考昔25 mg/qd RR = 1.92 (95% CI,1.19–3.11;P=0.008) 化学预防散发性腺瘤
[39] 罗非考昔25 mg/qd RR(估值)=2.66(95% CI,1.03–6.86;P=0.04) 化学预防散发性腺瘤中位数研究,用药7.4个月

非甾体类抗炎药的常见副作用还包括胃肠道出血和肾损伤。研究报道,胃肠道出血发生率可能与用药剂量呈正相关[44]

塞来昔布可降低腺瘤发病率,但不能降低散发性结直肠癌发生风险。因该药会增加心血管事件风险,且存在其他降低结直肠癌死亡率的有效方式,例如筛查,故该药预防结直肠癌的长期效果尚未证实[45]。一项基于人群的回顾性队列研究发现,在65岁以上人群中使用非甾体类抗炎药可减低结直肠癌风险,长期用药者中效应尤甚[46]

一些严格设计的研究已证实舒林酸能有效降低家族性息肉病患者腺瘤的大小和数目[47][48]。一项随机、双盲、以安慰剂作对照的研究,纳入77例家族性腺瘤性息肉病患者,在每日2次服用塞来昔布400 mg的患者组中,结直肠腺瘤的平均数目减少28.0%(与安慰剂组比,P=0.003),息肉负荷(息肉直径总和)降低30.7%(与安慰剂组比,P=0.001),而安慰剂组结直肠腺瘤平均数目减少4.5%,息肉负荷减少4.9%。100 mg塞来昔布每日2次用药组这两个比例分别为11.9%(与安慰剂组相比,P=0.33)与14.6%(P=0.09)。各组的不良事件发生率相近[49]

对于有腺瘤病史患者,服用吡罗昔康20 mg/日平均可降低直肠前列腺素浓度达50%[50]。一些研究试图评估水杨酸或其他非甾体类抗炎药在息肉切除术后息肉复发中的作用,目前仍在进行中[51],其中一些研究测量了粘膜前列腺素浓度。

非甾体类抗炎药作为一级预防措施的潜在应用正在研究。但有些问题尚未解决,因此目前不能推荐常规使用非甾体类抗炎药。存在的问题包括药物的最佳剂量和使用时间尚不明确,同时对预防措施潜在的获益有所担心,如以降低筛查/监测频率或强度的获益能否抵消个体的长期风险,例如胃肠道溃疡和出血性卒中发生风险[52]

来自观察性研究和RCT长期随访的大多数证据表明,每日服用水杨酸类药物持续至少5年可降低结直肠癌发病率。美国癌症协会的一项研究招募了超过600,000成年人,常规服用水杨酸人群的结肠癌和直肠癌死亡率降低约40%[53][54]。“健康专家随访研究”共有47,000例男性入组,该研究发现常规服用水杨酸(每周至少2次)可降低30%结直肠癌发病,其中晚期发病可降低50%[55]。“女性健康研究”(WHS)是一项2x2因素设计的随机试验研究,实验组患者每2日服用100 mg 水杨酸,平均服药10年,发现水杨酸组与安慰剂组的乳腺癌、结直肠癌或其他部位癌症的发病率接近[56]。“护士健康研究”对82,911例女性随访20年,该研究的一项报告发现常规服用水杨酸(每周≥2片标准325 mg片剂)的女性与不常规用药者相比,结肠癌发病多因素RR为0.77(95%CI,0.67-0.88)。仅当用药超过10年后,才观察到显著的RR。该获益似可能与剂量相关(例如,每周服用超过14片水杨酸、用药超过10年的女性患癌症的多因素RR为0.47[95%CI,0.31-0.71])。

2007年一篇总结46项水杨酸与结直肠癌发病的观察性研究的系统综述发现,服用水杨酸后结直肠癌发病率降低(任何形式服药的比值比[OR]为0.80[0.73-0.87])[57]。继该系统综述之后发表的一项大型队列研究(301,240例观察对象,3,894例结直肠癌患者)发现,每周或每日水杨酸用药与远端结肠癌及直肠癌(但非近端结肠)的10年发病率降低有关,每日用药后直肠癌的风险比为0.76(95%CI,0.64-0.90)。但该研究仅评估了一次,并未提供剂量、用药时间信息[37]

“医师健康研究”中,22,000例40-84岁男性被随机分配等到安慰剂组或水杨酸组(隔日325 mg水杨酸),该研究进行了5年,中位随访时间为4.5年,发现侵袭性癌症或腺瘤发病率并未降低[58]。一项汇总超过12年的随机试验与观察性研究的后续分析表明,水杨酸用药与结直肠癌发病率不相关。水杨酸使用剂量较低与治疗时间较短可能是导致阴性结果的原因[59]

一项随机研究共招募了曾患结直肠癌(T1-T2 N0 M0)并接受治愈性切除术的患者635例。每日服用水杨酸 325 mg,与安慰剂组相比,中位服药时间31个月的患者,复发性腺瘤调整RR值降低(0.65;95%CI,0.46-0.91)。水杨酸组首个腺瘤的检出时间长于安慰剂组(检测出新息肉的HR为0.54;95%CI,0.43-0.94,P=0.022)。治疗并发症包括上消化道出血和出血性卒中[60]。对近期患结直肠腺瘤的1,121例患者进行研究,平均治疗时间持续33个月,81 mg水杨酸组中任何分期腺瘤的非调整RR值为0.81(与安慰剂组相比),325 mg水杨酸组任何分期腺瘤的非校正RR为0.96(95%CI,0.81-1.13)。对于晚期肿瘤(腺瘤直径至少10.0 mm,或伴绒毛管状或绒毛状特征,或侵袭性癌),81 mg水杨酸组的RR为0.59(95%CI,0.38-0.92),325 mg水杨酸组的RR为0.83(95%CI,0.55-1.23)[61]。这两组的治疗风险相似,包括上消化道出血与出血性卒中。

2007、2010、2011与2012年分别发表的4篇文章[57][62][63][64]都是对每日服用水杨酸与安慰剂的人群进行长期随访的RCT。2007年分析报道了2项随访时间超过20年的可靠RCT,该报告发现每日使用至少300 mg 水杨酸持续5年,可降低10年后结直肠癌发病率(10-19年RR[0.60;95%CI,0.42-0.87])。2010年分析报道了4项RCT的长期随访数据,服用水杨酸至少5年可降低近端结肠癌的20年发病率与死亡率(调整发病率HR=0.35;95%CI,0.20-0.63;调整死亡率HR=0.24;95%CI,0.11-0.52),亦可降低20年直肠癌风险(RR=0.58;95%CI,0.36-0.92),但不影响远端结肠癌风险。剂量大于75 mg/日并不增加获益。致死性结直肠癌20年风险绝对降低1.76%(95%CI,0.61-2.91)。

2011年分析综合了8项RCT的数据,其中7项研究提供了原始数据,其中3项研究提供了20年随访数据。包含水杨酸服用至少5年组的研究中,20年结直肠癌死亡HR为0.60(95%CI,0.45-0.81)。一项荟萃分析共纳入6项RCT,其中5项来自于英国人群,这些研究中患者被随机分配到阿司匹林组或安慰剂组,平均治疗时间≥4年。同时研究提供了研究期间所有患者癌症数据。3项英国试验随访20年,试验结束后的癌症死亡数据通过死亡证明及癌症登记中心获得。根据各项试验比值比(OR)荟萃分析,而非考虑更为敏感的患者个例数据实际分析,发现RCT中阿司匹林组20年结直肠癌(与食管癌)死亡风险降低。最大剂量阿司匹林使用组结直肠癌死亡风险OR为0.55(95%CI,0.41–0.76),食管癌死亡风险OR为0.57(95% CI,0.27–0.81)。合计阿司匹林使用组的结直肠癌风险OR为0.58(95% CI,0.44–0.78),食管癌风险OR为0.51(95% CI, 0.31–0.83)。

美国癌症协会于1982年启动的大型CPS II营养队列中,共纳入100,139例合格参与者分析发现,近期每日服用阿司匹林的参与者消化道癌(RR = 0.61;95% CI,0.47–0.78)、肝癌(RR = 0.52;95% CI,0.30–0.93)与胆囊癌(RR = 0.52;95% CI,0.28–0.97)的死亡率均降低。研究排除标准为:1997年(基线年)调查既往癌症病史者;1999、2001与2003年邮寄的随访问卷中阿司匹林服用、吸烟状况信息缺失者。通过自动链接美国国家死亡状态索引与死因编码数据库(ICD-10),死亡随访更新至2008年12月31日,其中99.3%死亡证明可知明确死因[65]

WHS是迄今最大规模的阿司匹林随机临床试验(N=39,876),发现持续10年主动干预并不能降低结肠癌或其他癌症的发病率。但对自愿参加延长随访的女性人群(N=33,682;干预组16,913例,安慰剂组15,769例)进行长达8年(中位随访时间)随访,观察到结直肠癌发病率的显著降低(HR= 0.58;95% CI,0.42–0.8,P<0.001)。从干预开始到延长随访时间结束(中位数18年),WHS试验观察到结直肠癌发病率整体下降(HR=0.80;95%CI,0.67-0.97;P=0.021;干预期和延长随访期相比,P=0.012)。干预期内女性被随机分配到阿司匹林组或安慰组剂,隔天服用100 mg。延长随访期内,停止干预。通过相同的调查问卷记录进行18年研究方案依从性及医疗事件记录。根据随机盲法原则,一组专家对医疗记录进行审核并确认报告终点事件。对曾有每日服用阿司匹林的随机临床试验荟萃分析报道,延长随访期内结肠癌发病率有所降低,这与WHS隔日服用阿司匹林试验的结果相似[66]

一些观察性研究发现绝经后补充雌激素的女性患结肠癌的风险降低[67][68][69][70]。对于直肠癌而言,多数研究发现绝经后补充雌激素不降低或轻微增加直肠癌风险[71][72][73]

女性健康倡导(WHI)临床研究分别评估雌孕激素联合治疗和单纯雌激素治疗对结直肠癌发病率及死亡率的影响,并作为该研究的第二结局指标。WHI雌孕激素联合治疗组延长随访(平均11.6年)研究发现,与安慰剂组相比,激素联合治疗组的结直肠癌发病率更低(HR=0.72;95%CI,0.56-0.94);患结直肠癌后淋巴结更易受累(分别50.5%与28.6%;P<0.001);结直肠癌诊断分期较晚(局部与远处转移)(分别68.8%与51.4%;P=0.003)。且联合组结直肠癌死亡人数大于安慰剂组(分别37例与27例),但该差异无统计学意义(HR=1.29;95%CI,0.78-2.11)[74]

WHI实验单纯雌激素治疗组仅纳入子宫切除术后女性患者,将结直肠癌发病率作为第二结局指标。研究发现雌激素服用女性的结直肠癌发病率并没有不降低,中位随访7.1年后,雌激素组新发58例侵袭性癌症,而安慰剂组新发53例侵袭性癌症(HR=1.12;95%CI,0.77-1.63)。两组的肿瘤分期与分级相似,激素组结直肠癌死亡率为34%,安慰剂组为30%(HR=1.34;95%CI,0.58-3.19)[75]

源自一项包含外部对照和历史对照的美国全国息肉研究(NPS)的数据曾被多次引用说明,与3个历史对照组相比,结肠镜下息肉切除术后结直肠癌发病率降低76%-90%。 [76]但该研究可能存在一些偏倚,高估息肉切除的作用。主要偏倚是NPS试验组未纳入基线调查时已诊断的结肠癌患者,而对照组中并未排除此类患者,也未行基线结肠镜检查,进而导致对照组中基线已患结直肠癌的患者被认为是后续随访的新发病人。尽管研究人员对数据进行了调整,但结直肠癌临床前期时间不明确,因此无法确定该问题对结果的影响大小。

NPS队列长期随访研究(中位随访15.8年;最长23年)发现息肉切除术可降低53%的结直肠癌死亡率(排除包括初次检查发现的结直肠癌患者)。但该研究并无设置直接对照组,主要通过与医疗保险监督、流行病学和最终结果(SEER)数据库的预期数据进行比较,因此需慎重对待死亡率降低结果。此外,仍不明确何种结肠镜检查方案可能导降低死亡率。NPS患者在第1、3年接受结肠镜检查,2个对照组中1个对照组在第1年接受结肠镜检查,所有参与者第6年均接受结肠镜检查。但第6年之后,仍不确定具体如何监测患者以及监测对降低结直肠癌死亡率的意义[77]

我们希望英国软式乙状结肠镜筛查试验的进一步随访能够为息肉切除术的长期作用提供更多信息,至少对左半结肠的长期作用[77]

有研究表明乙状结肠镜筛查(应在息肉和早期癌变已经切除后进行)至少对左半结肠能带来长期明显益处。一项170,000例参与者的RCT将研究对象随机分配到乙状结肠镜组(单次)和常规医疗组。若镜下如发现息肉则行切除术,如发现肿瘤则转诊进行治疗。乙状结肠镜检结果为正常或仅有1-2个小(<1 cm)管状腺瘤,则认为对象属于低危人群,且不再接受结肠镜检查或结肠镜监测。随访10年发现,低危人群组(约95%的参与者属于低危人群)的左半部结肠癌年均发病率约为0.02%-0.04%,与平均风险人群相比结直肠癌发病风险极低。目前尚不明确风险降低的原因是检出并切除了大息肉或者小息肉,还是选择了低危人群[78]。目前,大息肉的自然史尚未明确,但有证据表明每年约有1%大息肉可进展为临床结直肠癌[79]。已有大量证据证实内镜在左半结肠的积极作用,但内镜检查能否降低右半结肠癌死亡率尚存疑问[80][81][82]。即目前内镜检查(例如结肠镜筛查)的整体作用以及对左半结肠和右半结肠作用是否存在较大差异尚不明确[80]

有研究发现最有可能进展为CRC的息肉为较大息肉(即直径>1 cm),包括绒毛状息肉或高级别组织学息肉。一些回顾性队列研究也发现息肉切除术存在相关并发症,包括出血等[83][84]

综上,证据表明他汀类药物对结直肠癌发病与死亡没有作用。尽管一些病例对照研究得出保护性的结论,但大型队列研究[148]与RCT的荟萃分析[149]均未发现两者间的相关性。

参考文献

1. Shike M, Winawer SJ, Greenwald PH, et al.: Primary prevention of colorectal cancer. The WHO Collaborating Centre for the Prevention of Colorectal Cancer. Bull World Health Organ 68 (3): 377-85, 1990.[PUBMED Abstract]

2. American Cancer Society.: Cancer Facts and Figures 2013. Atlanta, Ga: American Cancer Society, 2013. Available online. Last accessed January 10, 2014.

3. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2008. Bethesda, Md: National Cancer Institute, 2011. Also available online. Last accessed February 10, 2014.

4. Moertel CG, Fleming TR, Macdonald JS, et al.: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322 (6): 352-8, 1990.[PUBMED Abstract]

5. Krook JE, Moertel CG, Gunderson LL, et al.: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324 (11): 709-15, 1991.[PUBMED Abstract]

6. Willett W: The search for the causes of breast and colon cancer. Nature 338 (6214): 389-94, 1989.[PUBMED Abstract]

7. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61 (5): 759-67, 1990.[PUBMED Abstract]

8. Reddy B, Engle A, Katsifis S, et al.: Biochemical epidemiology of colon cancer: effect of types of dietary fiber on fecal mutagens, acid, and neutral sterols in healthy subjects. Cancer Res 49 (16): 4629-35, 1989.[PUBMED Abstract]

9. Reddy BS, Tanaka T, Simi B: Effect of different levels of dietary trans fat or corn oil on azoxymethane-induced colon carcinogenesis in F344 rats. J Natl Cancer Inst 75 (4): 791-8, 1985.[PUBMED Abstract]

10. Potter JD: Reconciling the epidemiology, physiology, and molecular biology of colon cancer. JAMA 268 (12): 1573-7, 1992 Sep 23-30.[PUBMED Abstract]

11. Wynder EL, Reddy BS: Dietary fat and fiber and colon cancer. Semin Oncol 10 (3): 264-72, 1983.[PUBMED Abstract]

12. Chen CD, Yen MF, Wang WM, et al.: A case-cohort study for the disease natural history of adenoma-carcinoma and de novo carcinoma and surveillance of colon and rectum after polypectomy: implication for efficacy of colonoscopy. Br J Cancer 88 (12): 1866-73, 2003.[PUBMED Abstract]

13. Cho E, Smith-Warner SA, Ritz J, et al.: Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies. Ann Intern Med 140 (8): 603-13, 2004.[PUBMED Abstract]

14. Newcomb PA, Storer BE, Marcus PM: Cancer of the large bowel in women in relation to alcohol consumption: a case-control study in Wisconsin (United States). Cancer Causes Control 4 (5): 405-11, 1993.[PUBMED Abstract]

15. Meyer F, White E: Alcohol and nutrients in relation to colon cancer in middle-aged adults. Am J Epidemiol 138 (4): 225-36, 1993.[PUBMED Abstract]

16. Longnecker MP, Orza MJ, Adams ME, et al.: A meta-analysis of alcoholic beverage consumption in relation to risk of colorectal cancer. Cancer Causes Control 1 (1): 59-68, 1990.[PUBMED Abstract]

17. Boutron MC, Faivre J: Diet and the adenoma-carcinoma sequence. Eur J Cancer Prev 2 (Suppl 2): 95-8, 1993.[PUBMED Abstract]

18. Boutron MC, Faivre J: Alcohol, tobacco and the adenoma-carcinoma sequence: a case-control study in Burgundy, France. [Abstract] Gastroenterology 104 (Suppl 4): A-390, 1993.

19. Thun MJ, Peto R, Lopez AD, et al.: Alcohol consumption and mortality among middle-aged and elderly U.S. adults. N Engl J Med 337 (24): 1705-14, 1997.[PUBMED Abstract]

20. Neugut AI, Jacobson JS, DeVivo I: Epidemiology of colorectal adenomatous polyps. Cancer Epidemiol Biomarkers Prev 2 (2): 159-76, 1993 Mar-Apr.[PUBMED Abstract]

21. Giovannucci E, Colditz GA, Stampfer MJ, et al.: A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in U.S. women. J Natl Cancer Inst 86 (3): 192-9, 1994.[PUBMED Abstract]

22. Giovannucci E, Rimm EB, Stampfer MJ, et al.: A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in U.S. men. J Natl Cancer Inst 86 (3): 183-91, 1994.[PUBMED Abstract]

23. Chao A, Thun MJ, Jacobs EJ, et al.: Cigarette smoking and colorectal cancer mortality in the cancer prevention study II. J Natl Cancer Inst 92 (23): 1888-96, 2000.[PUBMED Abstract]

24. Terry P, Ekbom A, Lichtenstein P, et al.: Long-term tobacco smoking and colorectal cancer in a prospective cohort study. Int J Cancer 91 (4): 585-7, 2001.[PUBMED Abstract]

25. Slattery ML, Potter JD, Friedman GD, et al.: Tobacco use and colon cancer. Int J Cancer 70 (3): 259-64, 1997.[PUBMED Abstract]

26. Knekt P, Hakama M, Järvinen R, et al.: Smoking and risk of colorectal cancer. Br J Cancer 78 (1): 136-9, 1998.[PUBMED Abstract]

27. Baron JA, Sandler RS, Haile RW, et al.: Folate intake, alcohol consumption, cigarette smoking, and risk of colorectal adenomas. J Natl Cancer Inst 90 (1): 57-62, 1998.[PUBMED Abstract]

28. Botteri E, Iodice S, Bagnardi V, et al.: Smoking and colorectal cancer: a meta-analysis. JAMA 300 (23): 2765-78, 2008.[PUBMED Abstract]

29. Martínez ME, Giovannucci E, Spiegelman D, et al.: Leisure-time physical activity, body size, and colon cancer in women. Nurses' Health Study Research Group. J Natl Cancer Inst 89 (13): 948-55, 1997.[PUBMED Abstract]

30. Giovannucci E, Ascherio A, Rimm EB, et al.: Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med 122 (5): 327-34, 1995.[PUBMED Abstract]

31. Calle EE, Rodriguez C, Walker-Thurmond K, et al.: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348 (17): 1625-38, 2003.[PUBMED Abstract]

32. White E, Jacobs EJ, Daling JR: Physical activity in relation to colon cancer in middle-aged men and women. Am J Epidemiol 144 (1): 42-50, 1996.[PUBMED Abstract]

33. Slattery ML, Schumacher MC, Smith KR, et al.: Physical activity, diet, and risk of colon cancer in Utah. Am J Epidemiol 128 (5): 989-99, 1988.[PUBMED Abstract]

34. Kune GA, Kune S, Watson LF: Body weight and physical activity as predictors of colorectal cancer risk. Nutr Cancer 13 (1-2): 9-17, 1990.[PUBMED Abstract]

35. Friedenreich CM: Physical activity and cancer prevention: from observational to intervention research. Cancer Epidemiol Biomarkers Prev 10 (4): 287-301, 2001.[PUBMED Abstract]

36. Wolin KY, Yan Y, Colditz GA, et al.: Physical activity and colon cancer prevention: a meta-analysis. Br J Cancer 100 (4): 611-6, 2009.[PUBMED Abstract]

37. Ruder EH, Laiyemo AO, Graubard BI, et al.: Non-steroidal anti-inflammatory drugs and colorectal cancer risk in a large, prospective cohort. Am J Gastroenterol 106 (7): 1340-50, 2011.[PUBMED Abstract]

38. Hinz B, Brune K: Cyclooxygenase-2--10 years later. J Pharmacol Exp Ther 300 (2): 367-75, 2002.[PUBMED Abstract]

39. Kerr DJ, Dunn JA, Langman MJ, et al.: Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med 357 (4): 360-9, 2007.[PUBMED Abstract]

40. Graham DJ, Campen D, Hui R, et al.: Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 365 (9458): 475-81, 2005.[PUBMED Abstract]

41. Bresalier RS, Sandler RS, Quan H, et al.: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352 (11): 1092-102, 2005.[PUBMED Abstract]

42. Solomon SD, McMurray JJ, Pfeffer MA, et al.: Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352 (11): 1071-80, 2005.[PUBMED Abstract]

43. Trelle S, Reichenbach S, Wandel S, et al.: Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 342: c7086, 2011.[PUBMED Abstract]

44. Chan AT, Giovannucci EL, Meyerhardt JA, et al.: Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 294 (8): 914-23, 2005.[PUBMED Abstract]

45. Arber N, Eagle CJ, Spicak J, et al.: Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 355 (9): 885-95, 2006.[PUBMED Abstract]

46. Smalley W, Ray WA, Daugherty J, et al.: Use of nonsteroidal anti-inflammatory drugs and incidence of colorectal cancer: a population-based study. Arch Intern Med 159 (2): 161-6, 1999.[PUBMED Abstract]

47. Labayle D, Fischer D, Vielh P, et al.: Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 101 (3): 635-9, 1991.[PUBMED Abstract]

48. Giardiello FM, Hamilton SR, Krush AJ, et al.: Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 328 (18): 1313-6, 1993.[PUBMED Abstract]

49. Steinbach G, Lynch PM, Phillips RK, et al.: The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342 (26): 1946-52, 2000.[PUBMED Abstract]

50. Earnest DL, Hixson LJ, Fennerty MB, et al.: Inhibition of prostaglandin synthesis: potential for chemoprevention of human colon cancer. Cancer Bull 43(6): 561-568, 1991.

51. Vargas PA, Alberts DS: Colon cancer: the quest for prevention. Oncology (Huntingt) 7 (11 Suppl): 33-40, 1993.

52. Imperiale TF: Aspirin and the prevention of colorectal cancer. N Engl J Med 348 (10): 879-80, 2003.[PUBMED Abstract]

53. Thun MJ, Namboodiri MM, Heath CW Jr: Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 325 (23): 1593-6, 1991.[PUBMED Abstract]

54. Thun MJ, Namboodiri MM, Calle EE, et al.: Aspirin use and risk of fatal cancer. Cancer Res 53 (6): 1322-7, 1993.[PUBMED Abstract]

55. Giovannucci E, Rimm EB, Stampfer MJ, et al.: Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med 121 (4): 241-6, 1994.[PUBMED Abstract]

56. Cook NR, Lee IM, Gaziano JM, et al.: Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial. JAMA 294 (1): 47-55, 2005.[PUBMED Abstract]

57. Flossmann E, Rothwell PM; British Doctors Aspirin Trial and the UK-TIA Aspirin Trial.: Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 369 (9573): 1603-13, 2007.[PUBMED Abstract]

58. Gann PH, Manson JE, Glynn RJ, et al.: Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J Natl Cancer Inst 85 (15): 1220-4, 1993.[PUBMED Abstract]

59. Stürmer T, Glynn RJ, Lee IM, et al.: Aspirin use and colorectal cancer: post-trial follow-up data from the Physicians' Health Study. Ann Intern Med 128 (9): 713-20, 1998.[PUBMED Abstract]

60. Sandler RS, Halabi S, Baron JA, et al.: A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 348 (10): 883-90, 2003.[PUBMED Abstract]

61. Baron JA, Cole BF, Sandler RS, et al.: A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 348 (10): 891-9, 2003.[PUBMED Abstract]

62. Rothwell PM, Wilson M, Elwin CE, et al.: Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376 (9754): 1741-50, 2010.[PUBMED Abstract]

63. Rothwell PM, Fowkes FG, Belch JF, et al.: Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377 (9759): 31-41, 2011.[PUBMED Abstract]

64. Algra AM, Rothwell PM: Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol 13 (5): 518-27, 2012.[PUBMED Abstract]

65. Jacobs EJ, Newton CC, Gapstur SM, et al.: Daily aspirin use and cancer mortality in a large US cohort. J Natl Cancer Inst 104 (16): 1208-17, 2012.[PUBMED Abstract]

66. Cook NR, Lee IM, Zhang SM, et al.: Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial. Ann Intern Med 159 (2): 77-85, 2013.[PUBMED Abstract]

67. Calle EE, Miracle-McMahill HL, Thun MJ, et al.: Estrogen replacement therapy and risk of fatal colon cancer in a prospective cohort of postmenopausal women. J Natl Cancer Inst 87 (7): 517-23, 1995.[PUBMED Abstract]

68. Newcomb PA, Storer BE: Postmenopausal hormone use and risk of large-bowel cancer. J Natl Cancer Inst 87 (14): 1067-71, 1995.[PUBMED Abstract]

69. Grodstein F, Newcomb PA, Stampfer MJ: Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 106 (5): 574-82, 1999.[PUBMED Abstract]

70. Terry MB, Neugut AI, Bostick RM, et al.: Risk factors for advanced colorectal adenomas: a pooled analysis. Cancer Epidemiol Biomarkers Prev 11 (7): 622-9, 2002.[PUBMED Abstract]

71. Risch HA, Howe GR: Menopausal hormone use and colorectal cancer in Saskatchewan: a record linkage cohort study. Cancer Epidemiol Biomarkers Prev 4 (1): 21-8, 1995 Jan-Feb.[PUBMED Abstract]

72. Gerhardsson de Verdier M, London S: Reproductive factors, exogenous female hormones, and colorectal cancer by subsite. Cancer Causes Control 3 (4): 355-60, 1992.[PUBMED Abstract]

73. Prihartono N, Palmer JR, Louik C, et al.: A case-control study of use of postmenopausal female hormone supplements in relation to the risk of large bowel cancer. Cancer Epidemiol Biomarkers Prev 9 (4): 443-7, 2000.[PUBMED Abstract]

74. Simon MS, Chlebowski RT, Wactawski-Wende J, et al.: Estrogen plus progestin and colorectal cancer incidence and mortality. J Clin Oncol 30 (32): 3983-90, 2012.[PUBMED Abstract]

75. Ritenbaugh C, Stanford JL, Wu L, et al.: Conjugated equine estrogens and colorectal cancer incidence and survival: the Women's Health Initiative randomized clinical trial. Cancer Epidemiol Biomarkers Prev 17 (10): 2609-18, 2008.[PUBMED Abstract]

76. Winawer SJ, Zauber AG, Ho MN, et al.: Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 329 (27): 1977-81, 1993.[PUBMED Abstract]

77. Zauber AG, Winawer SJ, O'Brien MJ, et al.: Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 366 (8): 687-96, 2012.[PUBMED Abstract]

78. Atkin WS, Edwards R, Kralj-Hans I, et al.: Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 375 (9726): 1624-33, 2010.[PUBMED Abstract]

79. Stryker SJ, Wolff BG, Culp CE, et al.: Natural history of untreated colonic polyps. Gastroenterology 93 (5): 1009-13, 1987.[PUBMED Abstract]

80. Brenner H, Chang-Claude J, Seiler CM, et al.: Protection from colorectal cancer after colonoscopy: a population-based, case-control study. Ann Intern Med 154 (1): 22-30, 2011.[PUBMED Abstract]

81. Baxter NN, Goldwasser MA, Paszat LF, et al.: Association of colonoscopy and death from colorectal cancer. Ann Intern Med 150 (1): 1-8, 2009.[PUBMED Abstract]

82. Brenner H, Hoffmeister M, Arndt V, et al.: Protection from right- and left-sided colorectal neoplasms after colonoscopy: population-based study. J Natl Cancer Inst 102 (2): 89-95, 2010.[PUBMED Abstract]

83. Levin TR, Zhao W, Conell C, et al.: Complications of colonoscopy in an integrated health care delivery system. Ann Intern Med 145 (12): 880-6, 2006.[PUBMED Abstract]

84. Warren JL, Klabunde CN, Mariotto AB, et al.: Adverse events after outpatient colonoscopy in the Medicare population. Ann Intern Med 150 (12): 849-57, W152, 2009.[PUBMED Abstract]

85. Rose DP, Boyar AP, Wynder EL: International comparisons of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption. Cancer 58 (11): 2363-71, 1986.[PUBMED Abstract]

86. Reddy BS: Dietary fat and its relationship to large bowel cancer. Cancer Res 41 (9 Pt 2): 3700-5, 1981.[PUBMED Abstract]

87. Reddy BS, Narisawa T, Vukusich D, et al.: Effect of quality and quantity of dietary fat and dimethylhydrazine in colon carcinogenesis in rats. Proc Soc Exp Biol Med 151 (2): 237-9, 1976.[PUBMED Abstract]

88. Nauss KM, Locniskar M, Newberne PM: Effect of alterations in the quality and quantity of dietary fat on 1,2-dimethylhydrazine-induced colon tumorigenesis in rats. Cancer Res 43 (9): 4083-90, 1983.[PUBMED Abstract]

89. Potter JD, McMichael AJ: Diet and cancer of the colon and rectum: a case-control study. J Natl Cancer Inst 76 (4): 557-69, 1986.[PUBMED Abstract]

90. Bingham SA: Diet and large bowel cancer. J R Soc Med 83 (7): 420-2, 1990.[PUBMED Abstract]

91. Hirayama T, Tannenbaum SR, Reddy BS, et al.: A large-scale cohort study on the relationship between diet and selected cancers of the digestive organs. In: Bruce WR, Correa P, Lipkin M, et al., eds.: Gastrointestinal cancer: endogenous factors. [Cold Spring Harbor, NY]: Cold Spring Harbor Laboratory, 1981, Branbury Report 7, 409-429.

92. Bjelke E: Epidemiology of colorectal cancer, with emphasis on diet. Int Congr Ser 484: 158-174, 1980.

93. Goldbohm RA, van den Brandt PA, van 't Veer P, et al.: A prospective cohort study on the relation between meat consumption and the risk of colon cancer. Cancer Res 54 (3): 718-23, 1994.[PUBMED Abstract]

94. Phillips RL, Snowdon DA: Dietary relationships with fatal colorectal cancer among Seventh-Day Adventists. J Natl Cancer Inst 74 (2): 307-17, 1985.[PUBMED Abstract]

95. Willett WC, Stampfer MJ, Colditz GA, et al.: Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med 323 (24): 1664-72, 1990.[PUBMED Abstract]

96. Thun MJ, Calle EE, Namboodiri MM, et al.: Risk factors for fatal colon cancer in a large prospective study. J Natl Cancer Inst 84 (19): 1491-500, 1992.[PUBMED Abstract]

97. Bostick RM, Potter JD, Sellers TA, et al.: Relation of calcium, vitamin D, and dairy food intake to incidence of colon cancer among older women. The Iowa Women's Health Study. Am J Epidemiol 137 (12): 1302-17, 1993.[PUBMED Abstract]

98. Singh PN, Fraser GE: Dietary risk factors for colon cancer in a low-risk population. Am J Epidemiol 148 (8): 761-74, 1998.[PUBMED Abstract]

99. Augustsson K, Skog K, Jägerstad M, et al.: Dietary heterocyclic amines and cancer of the colon, rectum, bladder, and kidney: a population-based study. Lancet 353 (9154): 703-7, 1999.[PUBMED Abstract]

100. Forman D: Meat and cancer: a relation in search of a mechanism. Lancet 353 (9154): 686-7, 1999.[PUBMED Abstract]

101. Beresford SA, Johnson KC, Ritenbaugh C, et al.: Low-fat dietary pattern and risk of colorectal cancer: the Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 295 (6): 643-54, 2006.[PUBMED Abstract]

102. Howard BV, Van Horn L, Hsia J, et al.: Low-fat dietary pattern and risk of cardiovascular disease: the Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 295 (6): 655-66, 2006.[PUBMED Abstract]

103. Sugimura T: Carcinogenicity of mutagenic heterocyclic amines formed during the cooking process. Mutat Res 150 (1-2): 33-41, 1985 Jun-Jul.[PUBMED Abstract]

104. Lee HP, Gourley L, Duffy SW, et al.: Colorectal cancer and diet in an Asian population--a case-control study among Singapore Chinese. Int J Cancer 43 (6): 1007-16, 1989.[PUBMED Abstract]

105. Reddy BS, Hedges AR, Laakso K, et al.: Metabolic epidemiology of large bowel cancer: fecal bulk and constituents of high-risk North American and low-risk Finnish population. Cancer 42 (6): 2832-8, 1978.[PUBMED Abstract]

106. Kampman E, Giovannucci E, van 't Veer P, et al.: Calcium, vitamin D, dairy foods, and the occurrence of colorectal adenomas among men and women in two prospective studies. Am J Epidemiol 139 (1): 16-29, 1994.[PUBMED Abstract]

107. Neugut AI, Garbowski GC, Lee WC, et al.: Dietary risk factors for the incidence and recurrence of colorectal adenomatous polyps. A case-control study. Ann Intern Med 118 (2): 91-5, 1993.[PUBMED Abstract]

108. Schatzkin A, Lanza E, Corle D, et al.: Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. Polyp Prevention Trial Study Group. N Engl J Med 342 (16): 1149-55, 2000.[PUBMED Abstract]

109. Cheah PY: Hypotheses for the etiology of colorectal cancer--an overview. Nutr Cancer 14 (1): 5-13, 1990.[PUBMED Abstract]

110. Reddy BS, Engle A, Simi B, et al.: Effect of dietary fiber on colonic bacterial enzymes and bile acids in relation to colon cancer. Gastroenterology 102 (5): 1475-82, 1992.[PUBMED Abstract]

111. Morotomi M, Guillem JG, LoGerfo P, et al.: Production of diacylglycerol, an activator of protein kinase C, by human intestinal microflora. Cancer Res 50 (12): 3595-9, 1990.[PUBMED Abstract]

112. Steinmetz KA, Potter JD: Vegetables, fruit, and cancer. I. Epidemiology. Cancer Causes Control 2 (5): 325-57, 1991.[PUBMED Abstract]

113. Steinmetz KA, Potter JD: Vegetables, fruit, and cancer. II. Mechanisms. Cancer Causes Control 2 (6): 427-42, 1991.[PUBMED Abstract]

114. Jacobs LR: Fiber and colon cancer. Gastroenterol Clin North Am 17 (4): 747-60, 1988.[PUBMED Abstract]

115. Roediger WE: The effect of bacterial metabolites on nutrition and function of the colonic mucosa: symbiosis between man and bacteria. In: Kasper H, Goebell H, eds.: Colon and Nutrition. Lancaster, Pa: Lancaster Press. Falk Symposium 32, 1981, pp 11-25.

116. Jacobs LR: Relationship between dietary fiber and cancer: metabolic, physiologic, and cellular mechanisms. Proc Soc Exp Biol Med 183 (3): 299-310, 1986.[PUBMED Abstract]

117. Howe GR, Benito E, Castelleto R, et al.: Dietary intake of fiber and decreased risk of cancers of the colon and rectum: evidence from the combined analysis of 13 case-control studies. J Natl Cancer Inst 84 (24): 1887-96, 1992.[PUBMED Abstract]

118. Potter JD: Epidemiology of diet and cancer: evidence of human maladaptation. In: Micozzi MS, Moon TE, eds.: Macronutrients: Investigating their Role in Cancer. New York: Marcel Dekker, 1992, pp 55-84.

119. Kritchevsky D: Dietary guidelines. The rationale for intervention. Cancer 72 (3 Suppl): 1011-4, 1993.[PUBMED Abstract]

120. Fuchs CS, Giovannucci EL, Colditz GA, et al.: Dietary fiber and the risk of colorectal cancer and adenoma in women. N Engl J Med 340 (3): 169-76, 1999.[PUBMED Abstract]

121. World Cancer Research Fund., American Institute for Cancer Research.: Food, Nutrition and the Prevention of Cancer: A Global Perspective. Washington, DC: The Institute, 1997.

122. Michels KB, Edward Giovannucci, Joshipura KJ, et al.: Prospective study of fruit and vegetable consumption and incidence of colon and rectal cancers. J Natl Cancer Inst 92 (21): 1740-52, 2000.[PUBMED Abstract]

123. Terry P, Giovannucci E, Michels KB, et al.: Fruit, vegetables, dietary fiber, and risk of colorectal cancer. J Natl Cancer Inst 93 (7): 525-33, 2001.[PUBMED Abstract]

124. Alberts DS, Martínez ME, Roe DJ, et al.: Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. Phoenix Colon Cancer Prevention Physicians' Network. N Engl J Med 342 (16): 1156-62, 2000.[PUBMED Abstract]

125. Bostick RM, Potter JD, McKenzie DR, et al.: Reduced risk of colon cancer with high intake of vitamin E: the Iowa Women's Health Study. Cancer Res 53 (18): 4230-7, 1993.[PUBMED Abstract]

126. Lee IM, Cook NR, Gaziano JM, et al.: Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA 294 (1): 56-65, 2005.[PUBMED Abstract]

127. Bjelakovic G, Nikolova D, Simonetti RG, et al.: Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet 364 (9441): 1219-28, 2004.[PUBMED Abstract]

128. Gorham ED, Garland CF, Garland FC, et al.: Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol 97 (1-2): 179-94, 2005.[PUBMED Abstract]

129. Pritchard RS, Baron JA, Gerhardsson de Verdier M: Dietary calcium, vitamin D, and the risk of colorectal cancer in Stockholm, Sweden. Cancer Epidemiol Biomarkers Prev 5 (11): 897-900, 1996.[PUBMED Abstract]

130. Giovannucci E, Stampfer MJ, Colditz GA, et al.: Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med 129 (7): 517-24, 1998.[PUBMED Abstract]

131. Cole BF, Baron JA, Sandler RS, et al.: Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 297 (21): 2351-9, 2007.[PUBMED Abstract]

132. Wargovich MJ, Eng VW, Newmark HL, et al.: Calcium ameliorates the toxic effect of deoxycholic acid on colonic epithelium. Carcinogenesis 4 (9): 1205-7, 1983.[PUBMED Abstract]

133. Slattery ML, Sorenson AW, Ford MH: Dietary calcium intake as a mitigating factor in colon cancer. Am J Epidemiol 128 (3): 504-14, 1988.[PUBMED Abstract]

134. Kune S, Kune GA, Watson LF: Case-control study of dietary etiological factors: the Melbourne Colorectal Cancer Study. Nutr Cancer 9 (1): 21-42, 1987.[PUBMED Abstract]

135. Yang CY, Chiu HF: Calcium and magnesium in drinking water and risk of death from rectal cancer. Int J Cancer 77 (4): 528-32, 1998.[PUBMED Abstract]

136. Zheng W, Anderson KE, Kushi LH, et al.: A prospective cohort study of intake of calcium, vitamin D, and other micronutrients in relation to incidence of rectal cancer among postmenopausal women. Cancer Epidemiol Biomarkers Prev 7 (3): 221-5, 1998.[PUBMED Abstract]

137. Manousos O, Day NE, Trichopoulos D, et al.: Diet and colorectal cancer: a case-control study in Greece. Int J Cancer 32 (1): 1-5, 1983.[PUBMED Abstract]

138. Wargovich MJ, Baer AR: Basic and clinical investigations of dietary calcium in the prevention of colorectal cancer. Prev Med 18 (5): 672-9, 1989.[PUBMED Abstract]

139. Lipkin M, Newmark H: Effect of added dietary calcium on colonic epithelial-cell proliferation in subjects at high risk for familial colonic cancer. N Engl J Med 313 (22): 1381-4, 1985.[PUBMED Abstract]

140. Buset M, Lipkin M, Winawer S, et al.: Inhibition of human colonic epithelial cell proliferation in vivo and in vitro by calcium. Cancer Res 46 (10): 5426-30, 1986.[PUBMED Abstract]

141. Wargovich MJ, Isbell G, Shabot M, et al.: Calcium supplementation decreases rectal epithelial cell proliferation in subjects with sporadic adenoma. Gastroenterology 103 (1): 92-7, 1992.[PUBMED Abstract]

142. Bostick RM, Potter JD, Fosdick L, et al.: Calcium and colorectal epithelial cell proliferation: a preliminary randomized, double-blinded, placebo-controlled clinical trial. J Natl Cancer Inst 85 (2): 132-41, 1993.[PUBMED Abstract]

143. Konishi H, Steinbach G, Hittelman WN, et al.: Cell kinetic analysis of intact rat colonic crypts by confocal microscopy and immunofluorescence. Gastroenterology 111 (6): 1493-500, 1996.[PUBMED Abstract]

144. Baron JA, Beach M, Mandel JS, et al.: Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group. N Engl J Med 340 (2): 101-7, 1999.[PUBMED Abstract]

145. Grau MV, Baron JA, Sandler RS, et al.: Prolonged effect of calcium supplementation on risk of colorectal adenomas in a randomized trial. J Natl Cancer Inst 99 (2): 129-36, 2007.[PUBMED Abstract]

146. Wactawski-Wende J, Kotchen JM, Anderson GL, et al.: Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 354 (7): 684-96, 2006.[PUBMED Abstract]

147. Forman MR, Levin B: Calcium plus vitamin D3 supplementation and colorectal cancer in women. N Engl J Med 354 (7): 752-4, 2006.[PUBMED Abstract]

148. Jacobs EJ, Rodriguez C, Brady KA, et al.: Cholesterol-lowering drugs and colorectal cancer incidence in a large United States cohort. J Natl Cancer Inst 98 (1): 69-72, 2006.[PUBMED Abstract]

149. Dale KM, Coleman CI, Henyan NN, et al.: Statins and cancer risk: a meta-analysis. JAMA 295 (1): 74-80, 2006.[PUBMED Abstract]

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