Department of Pathology, VU University Medical Centre, Amsterdam, Netherlands.
Lancet Oncol. 2012 Jan;13(1):78-88. doi: 10.1016/S1470-2045(11)70296-0. Epub 2011 Dec 14.
BACKGROUND: Human papillomavirus (HPV) testing is more sensitive for the detection of high-grade cervical lesions than is cytology, but detection of HPV by DNA screening in two screening rounds 5 years apart has not been assessed. The aim of this study was to assess whether HPV DNA testing in the first screen decreases detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse, CIN grade 2 or worse, and cervical cancer in the second screening. METHODS: In this randomised trial, women aged 29-56 years participating in the cervical screening programme in the Netherlands were randomly assigned to receive HPV DNA (GP5+/6+-PCR method) and cytology co-testing or cytology testing alone, from January, 1999, to September, 2002. Randomisation (in a 1:1 ratio) was done with computer-generated random numbers after the cervical specimen had been taken. At the second screening 5 years later, HPV DNA and cytology co-testing was done in both groups; researchers were masked to the patient's assignment. The primary endpoint was the number of CIN grade 3 or worse detected. Analysis was done by intention to screen. The trial is now finished and is registered, number ISRCTN20781131. FINDINGS: 22,420 women were randomly assigned to the intervention group and 22 518 to the control group; 19 999 in the intervention group and 20,106 in the control group were eligible for analysis at the first screen. At the second screen, 19 579 women in the intervention group and 19,731 in the control group were eligible, of whom 16,750 and 16,743, respectively, attended the second screen. In the second round, CIN grade 3 or worse was less common in the intervention group than in the control group (88 of 19 579 in the intervention group vs 122 of 19,731 in the control group; relative risk 0·73, 95% CI 0·55-0·96; p=0·023). Cervical cancer was also less common in the intervention group than in the control group (four of 19 579 in the intervention group vs 14 of 19,731; 0·29, 0·10-0·87; p=0·031). In the baseline round, detection of CIN grade 3 or worse did not differ significantly between groups (171 of 19 999 vs 150 of 20,106; 1·15, 0·92-1·43; p=0·239) but was significantly more common in women with normal cytology (34 of 19,286 vs 12 of 19,373; 2·85, 1·47-5·49; p=0·001). Furthermore, significantly more cases of CIN grade 2 or worse were detected in the intervention group than in the control group (267 of 19 999 vs 215 of 20,106; 1·25, 1·05-1·50; p=0·015). In the second screen, fewer HPV16-positive CIN grade 3 or worse were detected in the intervention group than in the control group (17 of 9481 vs 35 of 9354; 0·48, 0·27-0·85; p=0·012); detection of non-HPV16-positive CIN grade 3 or worse did not differ between groups (25 of 9481 vs 25 of 9354; 0·99, 0·57-1·72; p=1·00). The cumulative detection of CIN grade 3 or worse and CIN grade 2 or worse did not differ significantly between study arms, neither for the whole study group (CIN grade 3 or worse: 259 of 19 999 vs 272 of 20,106; 0·96, 0·81-1·14, p=0·631; CIN grade 2 or worse: 427 of 19 999 vs 399 of 20,106; 1·08, 0·94-1·24; p=0·292), nor for subgroups of women invited for the first time (CIN grade 3 or worse in women aged 29-33 years: 102 of 3139 vs 105 of 3128; 0·97, 0·74-1·27; CIN grade 2 or worse in women aged 29-33 years: 153 of 3139 vs 151 of 3128; 1·01, 0·81-1·26; CIN grade 3 or worse in women aged 34-56 years: 157 of 16,860 vs 167 of 16 978; 0·95, 0·76-1·18; CIN grade 2 or worse in women aged 34-56 years: 274 of 16,860 vs 248 of 16 978; 1·11, 0·94-1·32). INTERPRETATION: Implementation of HPV DNA testing in cervical screening leads to earlier detection of clinically relevant CIN grade 2 or worse, which when adequately treated, improves protection against CIN grade 3 or worse and cervical cancer. Early detection of high-grade cervical legions caused by HPV16 was a major component of this benefit. Our results lend support to the use of HPV DNA testing for all women aged 29 years and older. FUNDING: Zorg Onderzoek Nederland (Netherlands Organisation for Health Research and Development).
背景：与细胞学相比，人乳头瘤病毒（HPV）检测对高级别宫颈病变的检测更敏感，但相隔 5 年进行两次 HPV DNA 筛查检测并未得到评估。本研究的目的是评估初次筛查时进行 HPV DNA 检测是否会降低第二次筛查时宫颈上皮内瘤变（CIN）3 级或更高级别、CIN 2 级或更高级别和宫颈癌的检出率。
方法：本随机试验纳入了正在荷兰参加宫颈癌筛查项目的年龄为 29-56 岁的女性，她们被随机分配接受 HPV DNA（GP5+/6+-PCR 法）和细胞学联合检测或细胞学单独检测，随机分配于 1999 年 1 月至 2002 年 9 月进行。在取得宫颈标本后，通过计算机生成的随机数进行随机分组（1:1 比例）。5 年后的第二次筛查中，两组均行 HPV DNA 和细胞学联合检测；研究者对患者的分组情况设盲。主要终点是检测到的 CIN 3 级或更高级别病变的数量。分析采用意向性筛查。本试验现已完成，登记号为 ISRCTN20781131。
发现：22420 名女性被随机分配到干预组，22518 名女性被分配到对照组；在第一次筛查中，1999 名女性中的 19106 名符合分析条件。在第二次筛查中，干预组的 19579 名女性中有 19731 名符合条件，分别有 16750 名和 16743 名女性参加了第二次筛查。第二轮中，干预组的 CIN 3 级或更高级别病变比对照组更常见（干预组 19579 名女性中有 88 例，对照组 19731 名女性中有 122 例；相对风险 0.73，95%CI 0.55-0.96；p=0.023）。干预组宫颈癌的检出率也低于对照组（干预组 19579 名女性中有 4 例，对照组 19731 名女性中有 14 例；0.29，0.10-0.87；p=0.031）。在基线轮次中，两组的 CIN 3 级或更高级别病变检出率无显著差异（1999 名女性中有 171 例，20106 名女性中有 150 例；1.15，0.92-1.43；p=0.239），但细胞学正常的女性中病变更常见（19286 名女性中有 34 例，19373 名女性中有 12 例；2.85，1.47-5.49；p=0.001）。此外，干预组 CIN 2 级或更高级别病变的检出率显著高于对照组（1999 名女性中有 267 例，20106 名女性中有 215 例；1.25，1.05-1.50；p=0.015）。第二次筛查时，干预组中 HPV16 阳性的 CIN 3 级或更高级别病变的检出率低于对照组（9481 名女性中有 17 例，9354 名女性中有 35 例；0.48，0.27-0.85；p=0.012），而非 HPV16 阳性的 CIN 3 级或更高级别病变的检出率两组间无差异（9481 名女性中有 25 例，9354 名女性中有 25 例；0.99，0.57-1.72；p=1.00）。两组的 CIN 3 级或更高级别病变和 CIN 2 级或更高级别病变的累积检出率无显著差异，无论对于整个研究组（CIN 3 级或更高级别病变：1999 名女性中有 259 例，20106 名女性中有 272 例；0.96，0.81-1.14，p=0.631；CIN 2 级或更高级别病变：1999 名女性中有 427 例，20106 名女性中有 399 例；1.08，0.94-1.24；p=0.292），还是首次受邀的女性亚组（29-33 岁年龄组中 CIN 3 级或更高级别病变：3139 名女性中有 102 例，3128 名女性中有 105 例；0.97，0.74-1.27；CIN 2 级或更高级别病变：3139 名女性中有 153 例，3128 名女性中有 151 例；1.01，0.81-1.26；29-33 岁年龄组中 CIN 3 级或更高级别病变：16860 名女性中有 157 例，16978 名女性中有 167 例；0.95，0.76-1.18；CIN 2 级或更高级别病变：16860 名女性中有 274 例，16978 名女性中有 248 例；1.11，0.94-1.32）。
解释：在宫颈癌筛查中实施 HPV DNA 检测可更早地发现具有临床意义的 CIN 2 级或更高级别病变，当充分治疗时，可降低 CIN 3 级或更高级别病变和宫颈癌的发生风险。HPV16 引起的高级别宫颈病变的早期发现是这一获益的主要组成部分。我们的研究结果支持对 29 岁及以上的所有女性使用 HPV DNA 检测。
资助：荷兰卫生研究与发展组织（Zorg Onderzoek Nederland）。
J Natl Cancer Inst. 2009-12-2
Diagnostics (Basel). 2024-9-30
Cent Eur J Public Health. 2024-9
Zotero 插件