MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK; Department of Women's Cancer, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK.
Lancet Oncol. 2023 Sep;24(9):1018-1028. doi: 10.1016/S1470-2045(23)00335-2.
In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy.
UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50-74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to-screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032.
202 562 eligible women were recruited (50 625 multimodal screening; 50 623 ultrasound screening; 101 314 no screening). 259 (0·5%) of 50 625 participants in the multimodal screening group and 520 (0·5%) of 101 314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04-13·00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6·9% (95% CI 0·4-13·0; p=0·042) at 18 years (21% [95% CI 15·6-26·2] vs 14% [95% CI 10·5-17·4]).
To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer.
National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal.
在 UKCTOCS 研究中，与未筛查组相比，多模式筛查组诊断出晚期卵巢癌的比例降低，但死亡率并未降低。因此，我们对高级别浆液性卵巢癌患者进行了探索性分析，以了解差异的原因。
UKCTOCS 是一项针对绝经后妇女的 13 中心随机对照试验，研究对象为年龄在 50-74 岁、卵巢完整的一般人群。试验管理系统采用计算机生成的随机数以 32 人为一组进行随机分组（2:1:1），将符合条件的参与者（2001 年 4 月 17 日至 2005 年 9 月 29 日招募）随机分配到不筛查或每年筛查（多模式筛查或超声筛查）组，直到 2011 年 12 月 31 日。通过国家登记处进行随访，直到 2020 年 6 月 30 日。结局审查委员会对卵巢癌诊断、组织类型、分期和死亡原因进行了盲法裁决。在这项研究中，对 2014 年 12 月 31 日（截止日期）多模式筛查与不筛查的高级别浆液性癌症患者进行了意向筛查比较，使用描述性统计方法比较了分期和治疗终点，并使用通用检验法比较了随机分组后的生存情况。该试验在 ISRCTN 注册中心注册，编号为 22488978，在 ClinicalTrials.gov 注册，编号为 NCT00058032。
共招募了 202625 名符合条件的女性（50625 名多模式筛查；50623 名超声筛查；101314 名未筛查）。在 50625 名多模式筛查组和 101314 名未筛查组中，分别有 259 名（0.5%）和 520 名（0.5%）被诊断为高级别浆液性癌症。与未筛查组相比，多模式筛查组诊断为晚期疾病的患者较少（195[75%]例 vs 446[86%]例；p=0.0003），更多患者接受了原发性手术（158[61%]例 vs 219[42%]例；p<0.0001），更多患者接受了肿瘤细胞减灭术且无残留（119[46%]例 vs 157[30%]例；p<0.0001），更多患者接受了包括手术和化疗在内的治疗（192[74%]例 vs 331[64%]例；p=0.0032）。一线联合化疗率无差异（142[55%]例 vs 293[56%]例；p=0.69）。在多模式和未筛查组中，有 779 名高级别浆液性癌症患者进行了随机分组，中位随访时间为 9.51 年（IQR 6.04-13.00）。截止日期（2020 年 6 月 30 日）时，多模式筛查组的高级别浆液性癌症患者的生存时间长于未筛查组，生存绝对差异为 6.9%（95%CI 0.4-13.0；p=0.042），18 年时生存率为 21%（95%CI 15.6-26.2），14%（95%CI 10.5-17.4）。
据我们所知，这是第一个证据表明，与不筛查相比，筛查可以更早地发现高级别浆液性癌症，并改善短期治疗效果。高级别浆液性癌症患者的潜在生存获益较小，这很可能是由于早期检测和治疗改善的幅度较小，以及肿瘤生物学的原因。该试验的累积结果表明，目前不应该在卵巢癌筛查试验中使用疾病特异性死亡率的替代终点。
英国国家卫生研究院、医学研究理事会、英国癌症研究中心、伊芙呼吁。
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