Risk algorithm using serial biomarker measurements doubles the number of screen-detected cancers compared with a single-threshold rule in the United Kingdom collaborative trial of ovarian cancer screening

PURPOSE: Cancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates. PATIENTS AND METHODS: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,237 women, age 50 years or older underwent incidence screening by using the multimodal strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA). Women were triaged by the ROCA: normal risk, returned to annual screening; intermediate risk, repeat CA-125; and elevated risk, repeat CA-125 and transvaginal ultrasound. Women with persistently increased risk were clinically evaluated. All participants were followed through national cancer and/or death registries. Performance characteristics of a single-threshold rule and the ROCA were compared by using receiver operating characteristic curves. RESULTS: After 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs). In all, 22 interval iEOCs occurred within 1 year of screening, of which one was detected by ROCA but was managed conservatively after clinical assessment. The sensitivity and specificity of MMS for detection of iEOCs were 85.8% (95% CI, 79.3% to 90.9%) and 99.8% (95% CI, 99.8% to 99.8%), respectively, with 4.8 surgeries per iEOC. ROCA alone detected 87.1% (135 of 155) of the iEOCs. Using fixed CA-125 cutoffs at the last annual screen of more than 35, more than 30, and more than 22 U/mL would have identified 41.3% (64 of 155), 48.4% (75 of 155), and 66.5% (103 of 155), respectively. The area under the curve for ROCA (0.915) was significantly (P = .0027) higher than that for a single-threshold rule (0.869). CONCLUSION: Screening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff. In the context of cancer screening, reliance on predefined single-threshold rules may result in biomarkers of value being discarded

Tumour stage, treatment, and survival of women with high-grade serous tubo-ovarian cancer in UKCTOCS: an exploratory analysis of a randomised controlled trial

Background: 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.// Methods: 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.// Findings: 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]).// Interpretation: 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

Ovarian cancer symptoms, routes to diagnosis and survival – population cohort study in the ‘no screen’ arm of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Objective: There are widespread efforts to increase symptom awareness of ‘pelvic/abdominal pain, increased abdominal size/bloating, difficulty eating/feeling full and urinary frequency/urgency’ in an attempt to diagnose ovarian cancer earlier. Long-term survival of women with these symptoms adjusted for known prognostic factors is yet to be determined. This study explored the association of symptoms, routes and interval to diagnosis and long-term survival in a population-based cohort of postmenopausal women diagnosed with invasive epithelial tubo-ovarian cancer (iEOC) in the ‘no screen’ (control) UKCTOCS arm. Methods: Of 101,299 women in the control arm, 574 were confirmed on outcome review to have iEOC between randomisation (2001–2005) and 31 December 2014. Data was extracted from medical notes and electronic records. A multivariable model was fitted for individual symptoms, time interval from symptom onset to diagnosis, route to diagnosis, speciality, morphological Type, age at diagnosis, year of diagnosis (period effect), stage, primary treatment, and residual disease. Results: Women presenting with symptoms listed in the NICE guidelines (HR1.48, 95%CI1.16–1.89, p = 0.001) or the modified Goff Index (HR1·68, 95%CI1·32–2.13, p < 0.0001) had significantly worse survival than those who did not. Each additional presenting symptom decreased survival (HR1·20, 95%CI1·12–1·28, p < 0.0001). In multivariable analysis, in addition to advanced stage, increasing residual disease and inadequate primary treatment, abdominal pain and loss of appetite/feeling full were significantly associated with increased mortality. Conclusions: The ovarian cancer symptom indices identify postmenopausal women with a poorer prognosis. This study however cannot exclude the possibility of better outcomes in those who are aware and act on their symptoms

Tumour stage, treatment, and survival of women with high-grade serous tubo-ovarian cancer in UKCTOCS: an exploratory analysis of a randomised controlled trial

Background: 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. Methods: 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. Findings: 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]). Interpretation: 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. Funding: National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal

The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Background: To assess the within trial cost-effectiveness of an NHS ovarian cancer screening (OCS) programme using data from UKCTOCS and extrapolate results based on average life expectancy. Methods: Within trial economic evaluation of no screening (C) versus either (1) an annual OCS programme using transvaginal ultrasound (USS) or (2) an annual ovarian cancer multimodal screening programme with serum CA125 interpreted using a risk algorithm (ROCA) and transvaginal ultrasound as a second line test (MMS), plus comparison of lifetime extrapolation of the no screening arm and the MMS programme using both a predictive and a Markov model. Results: Using a CA125-ROCA cost of £20, the within trial results show USS to be strictly dominated by MMS, with the MMS versus C comparison returning an Incremental Cost-Effectiveness ratio (ICER) of £91,452 per life year gained (LYG). If the CA125-ROCA unit cost is reduced to £15 the ICER becomes £77,818 per LYG. Predictive extrapolation over the expected lifetime of the UKCTOCS women returns an ICER of £30,033 per LYG, while Markov modelling produces an ICER of £46,922 per QALY. Conclusions: Analysis suggests that, after accounting for the lead-time required to establish full mortality benefits, a national OCS programme based on the MMS strategy quickly approaches the current NICE thresholds for cost-effectiveness when extrapolated out to lifetime as compared to the within trial ICER estimates. Whether MMS could be recommended on economic grounds would depend on the confirmation and size of the mortality benefit at the end of an ongoing follow-up of the UKCTOCS cohort

UKCTOCS update: applying insights of delayed effects in cancer screening trials to the long-term follow-up mortality analysis

Background During trials that span decades, new evidence including progress in statistical methodology, may require revision of original assumptions. An example is the continued use of a constant-effect approach to analyse the mortality reduction which is often delayed in cancer-screening trials. The latter led us to re-examine our approach for the upcoming primary mortality analysis (2020) of long-term follow-up of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (LTFU UKCTOCS), having initially (2014) used the proportional hazards (PH) Cox model. Methods We wrote to 12 experts in statistics/epidemiology/screening trials, setting out current evidence, the importance of pre-specification, our previous mortality analysis (2014) and three possible choices for the follow-up analysis (2020) of the mortality outcome: (A) all data (2001–2020) using the Cox model (2014), (B) new data (2015–2020) only and (C) all data (2001–2020) using a test that allows for delayed effects. Results Of 11 respondents, eight supported changing the 2014 approach to allow for a potential delayed effect (option C), suggesting various tests while three favoured retaining the Cox model (option A). Consequently, we opted for the Versatile test introduced in 2016 which maintains good power for early, constant or delayed effects. We retained the Royston-Parmar model to estimate absolute differences in disease-specific mortality at 5, 10, 15 and 18 years. Conclusions The decision to alter the follow-up analysis for the primary outcome on the basis of new evidence and using new statistical methodology for long-term follow-up is novel and has implications beyond UKCTOCS. There is an urgent need for consensus building on how best to design, test, estimate and report mortality outcomes from long-term randomised cancer screening trials

Completeness and accuracy of national cancer and death registration for outcome ascertainment in trials-an ovarian cancer exemplar

Background There is a trend to increasing use of routinely collected health data to ascertain outcome measures in trials. We report on the completeness and accuracy of national ovarian cancer and death registration in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Methods Of the 202,638 participants, 202,632 were successfully linked and followed through national cancer and death registries of Northern Ireland, Wales and England. Women with registrations of any of 19 pre-defined ICD-10 codes suggestive of tubo-ovarian cancer or notification of ovarian/tubal/peritoneal cancer from hospital episode statistics or trial sites were identified. Copies of hospital and primary care notes were retrieved and reviewed by an independent outcomes review committee. National registration of site and cause of death as ovarian/tubal/peritoneal cancer (C56/C57/C48) obtained up to 3 months after trial censorship was compared to that assigned by outcomes review (reference standard). Results Outcome review was undertaken in 3110 women on whom notification was received between 2001 and 2014. Ovarian cancer was confirmed in 1324 of whom 1125 had a relevant cancer registration. Sensitivity and specificity of ovarian/tubal/peritoneal cancer registration were 85.0% (1125/1324; 95% CI 83.7–86.2%) and 94.0% (1679/1786; 95% CI 93.2–94.8%), respectively. Of 2041 death registrations reviewed, 681 were confirmed to have a tubo-ovarian cancer of whom 605 had relevant death registration. Sensitivity and specificity were 88.8% (605/681; 95% CI 86.4–91.2%) and 96.7% (1482/1533, 95% CI 95.8–97.6%), respectively. When multiple electronic health record sources were considered, sensitivity for cancer site increased to 91.1% (1206/1324, 95% CI 89.4–92.5%) and for cause of death 94.0% (640/681, 95% CI 91.9–95.5%). Of 1232 with cancer registration, 8.7% (107/1232) were wrongly designated as ovarian/tubal/peritoneal cancers by the registry and 4.0% (47/1172) of confirmed tubo-ovarian cancers were mis-registered. In 656 with death registrations, 7.8% (51/656) were wrongly assigned as due to ovarian/tubal/peritoneal cancers while 6.2% (40/645) of confirmed tubo-ovarian cancer deaths were mis-registered. Conclusion Follow-up of trial participants for tubo-ovarian cancer using national registry data will result in incomplete ascertainment, particularly of the site due in part to the latency of registration. This can be reduced by using other routinely collected data such as hospital episode statistics. Central adjudication by experts though resource intensive adds value by improving the accuracy of diagnoses. Trial registration ISRCTN: ISRCTN22488978. Registered on 6 April 200

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial

Background Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the eff ect of early detection by screening on ovarian cancer mortality. Methods 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 computergenerated 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. Findings 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 fl exible parametric model showed that in the MMS group, this mortality eff ect 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 diff erent 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. Interpretation Although the mortality reduction was not signifi cant in the primary analysis, we noted a signifi cant 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-eff ectiveness of ovarian cancer screening

Performance characteristics of the ultrasound strategy during incidence screening in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Randomised controlled trials of ovarian cancer (OC) screening have not yet demonstrated an impact on disease mortality. Meanwhile, the screening data from clinical trials represents a rich resource to understand the performance of modalities used. We report here on incidence screening in the ultrasound arm of UKCTOCS. 44,799 of the 50,639 women who were randomised to annual screening with transvaginal ultrasound attended annual incidence screening between 28 April 2002 and 31 December 2011. Transvaginal ultrasound was used both as the first and the second line test. Participants were followed up through electronic health record linkage and postal questionnaires. Out of 280,534 annual incidence screens, 960 women underwent screen-positive surgery. 113 had ovarian/tubal cancer (80 invasive epithelial). Of the screen-detected invasive epithelial cancers, 37.5% (95%CI: 26.9–49.0) were Stage I/II. An additional 52 (50 invasive epithelial) were diagnosed within one year of their last screen. Of the 50 interval epithelial cancers, 6.0% (95%CI: 1.3–16.5) were Stage I/II. For detection of all ovarian/tubal cancers diagnosed within one year of screen, the sensitivity, specificity, and positive predictive values were 68.5% (95%CI: 60.8–75.5), 99.7% (95%CI: 99.7–99.7), and 11.8% (95%CI: 9.8–14) respectively. When the analysis was restricted to invasive epithelial cancers, sensitivity, specificity and positive predictive values were 61.5% (95%CI: 52.6–69.9); 99.7% (95%CI: 99.7–99.7) and 8.3% (95%CI: 6.7–10.3), with 12 surgeries per screen positive. The low sensitivity coupled with the advanced stage of interval cancers suggests that ultrasound scanning as the first line test might not be suitable for population screening for ovarian cancer. Trial registration: ISRCTN22488978. Registered on 6 April 2000

Performance characteristics of the ultrasound strategy during incidence screening in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Randomised controlled trials of ovarian cancer (OC) screening have not yet demonstrated an impact on disease mortality. Meanwhile, the screening data from clinical trials represents a rich resource to understand the performance of modalities used. We report here on incidence screening in the ultrasound arm of UKCTOCS. 44,799 of the 50,639 women who were randomised to annual screening with transvaginal ultrasound attended annual incidence screening between 28 April 2002 and 31 December 2011. Transvaginal ultrasound was used both as the first and the second line test. Participants were followed up through electronic health record linkage and postal questionnaires. Out of 280,534 annual incidence screens, 960 women underwent screen-positive surgery. 113 had ovarian/tubal cancer (80 invasive epithelial). Of the screen-detected invasive epithelial cancers, 37.5% (95%CI: 26.9–49.0) were Stage I/II. An additional 52 (50 invasive epithelial) were diagnosed within one year of their last screen. Of the 50 interval epithelial cancers, 6.0% (95%CI: 1.3–16.5) were Stage I/II. For detection of all ovarian/tubal cancers diagnosed within one year of screen, the sensitivity, specificity, and positive predictive values were 68.5% (95%CI: 60.8–75.5), 99.7% (95%CI: 99.7–99.7), and 11.8% (95%CI: 9.8–14) respectively. When the analysis was restricted to invasive epithelial cancers, sensitivity, specificity and positive predictive values were 61.5% (95%CI: 52.6–69.9); 99.7% (95%CI: 99.7–99.7) and 8.3% (95%CI: 6.7–10.3), with 12 surgeries per screen positive. The low sensitivity coupled with the advanced stage of interval cancers suggests that ultrasound scanning as the first line test might not be suitable for population screening for ovarian cancer. Trial registration: ISRCTN22488978. Registered on 6 April 2000