Jacobs Ian J, Menon Usha, Ryan Andy, Gentry-Maharaj Aleksandra, Burnell Matthew, Kalsi Jatinderpal K, Amso Nazar N, Apostolidou Sophia, Benjamin Elizabeth, Cruickshank Derek, Crump Danielle N, Davies Susan K, Dawnay Anne, Dobbs Stephen, Fletcher Gwendolen, Ford Jeremy, Godfrey Keith, Gunu Richard, Habib Mariam, Hallett Rachel, Herod Jonathan, Jenkins Howard, Karpinskyj Chloe, Leeson Simon, Lewis Sara J, Liston William R, Lopes Alberto, Mould Tim, Murdoch John, Oram David, Rabideau Dustin J, Reynolds Karina, Scott Ian, Seif Mourad W, Sharma Aarti, Singh Naveena, Taylor Julie, Warburton Fiona, Widschwendter Martin, Williamson Karin, Woolas Robert, Fallowfield Lesley, McGuire Alistair J, Campbell Stuart, Parmar Mahesh, Skates Steven J
Department of Women's Cancer, Institute for Women's Health, University College London, London, UK; University of New South Wales, Sydney, NSW, Australia; Centre for Women's Health, Institute of Human Development, University of Manchester, Manchester, UK.
Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
Lancet. 2016 Mar 5;387(10022):945-956. doi: 10.1016/S0140-6736(15)01224-6. Epub 2015 Dec 17.
Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality.
In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032.
Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202,638 women: 50,640 (25·0%) to MMS, 50,639 (25·0%) to USS, and 101,359 (50·0%) to no screening. 202,546 (>99·9%) women were eligible for analysis: 50,624 (>99·9%) women in the MMS group, 50,623 (>99·9%) in the USS group, and 101,299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345,570 MMS and 327,775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0-12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI -3 to 30; p=0·10) with MMS and 11% (-7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favour of MMS.
Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7-14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening.
Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.
卵巢癌预后较差，仅有40%的患者能存活5年。我们开展了这项试验以确定通过筛查进行早期检测对卵巢癌死亡率的影响。
在这项随机对照试验中，我们从英格兰、威尔士和北爱尔兰国民健康服务信托基金的13个中心招募了50 - 74岁的绝经后女性。排除标准为既往双侧卵巢切除术或卵巢恶性肿瘤、家族性卵巢癌风险增加以及活动性非卵巢恶性肿瘤。试验管理系统确认入选资格，并使用计算机生成的随机数将参与者按32人一组进行随机分组，以1:1:2的比例分配至每年进行多模式筛查（MMS）并使用卵巢癌风险算法解读血清CA125、每年进行经阴道超声筛查（USS）或不进行筛查。主要结局是截至2014年12月31日因卵巢癌死亡，将MMS组和USS组分别与不筛查组进行比较，由对随机分组情况不知情的结局委员会确定。所有分析均采用改良意向性筛查，排除随机分组后发现已进行双侧卵巢切除术、患有卵巢癌或在招募前已退出登记的少数女性。研究者和参与者知晓筛查类型。本试验已在ClinicalTrials.gov注册，编号为NCT00058032。
在2001年6月1日至2005年10月21日期间，我们随机分配了202,638名女性：50,640名（25.0%）接受MMS，50,639名（25.0%）接受USS，101,359名（50.0%）不进行筛查。202,546名（>99.9%）女性符合分析条件：MMS组中有50,624名（>99.9%）女性，USS组中有50,623名（>99.9%）女性，不筛查组中有101,299名（>99.9%）女性。筛查于2011年12月31日结束，包括345,570次MMS年度筛查和327,775次USS年度筛查。在中位随访11.1年（四分位间距10.0 - 12.0年）时，我们诊断出1282名（0.6%）女性患有卵巢癌：MMS组中有338名（0.7%），USS组中有314名（0.6%），不筛查组中有630名（0.6%）。在这些女性中，MMS组有148名（0.29%）女性、USS组有154名（0.30%）女性、不筛查组有347名（0.34%）女性死于卵巢癌。使用Cox比例风险模型进行的主要分析显示，MMS组在0至14年期间死亡率降低了15%（95%置信区间 -3至30；p = 0.10），USS组降低了11%（-7至27；p = 0.21）。Royston - Parmar灵活参数模型显示，在MMS组中，这种死亡率降低效应在0至7年为8%（-20至31），在7至14年为23%（1至46）；在USS组中，0至7年为2%（-27至26），7至14年为21%（-2至42）。一项预先设定的排除现患病例后对MMS与不筛查的卵巢癌死亡情况分析显示，死亡率有显著差异（p = 0.021），总体平均死亡率降低20%（-2至40），0至7年降低8%（-27至43），7至14年降低28%（-3至49），支持MMS。
尽管在主要分析中死亡率降低不显著，但我们注意到排除现患病例后MMS组死亡率有显著降低。我们注意到在7至14年期间有令人鼓舞的死亡率降低证据，但在就卵巢癌筛查的疗效和成本效益得出确切结论之前，还需要进一步随访。
医学研究理事会、英国癌症研究中心、卫生部、伊芙呼吁组织。
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