{'fraction_non_alphanumeric': 0.020278196748784984, 'fraction_numerical': 0.010390480978716274, 'mean_word_length': 5.26890756302521, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Ovarian Cancer Screening There May Be Light at the End of the Tunnel?

To the Editor: J et al1 and Menon et al2 recently reported results of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). The investigators are to be congratulated on successfully undertaking and completing such a large complex population-based randomized trial. The only other screening trial to report on mortality was the PLCO study,3 which found no mortality benefit and a significantly high 15% complication rate from surgical diagnostic evaluation. Several things stand out that differentiate UKCTOCS from previous PLCO and Japanese Shizuoka randomized studies.3,4 These include the concept of a longitudinal biomarker algorithm analysis for screening using ROCA (Risk of Ovarian Cancer Algorithm), a Webbased trial management and call-recall system as well as tight protocol-driven centralized coordination and management. It is the results of the ROCAdriven multimodal screening arm that appear particularly encouraging. The authors report a high sensitivity of 84% to 85.9%, specificity of 99.8%, and an extremely acceptable 2.7 operations per case of cancer detected, with a 3% complication rate.1,2 Although the Cox model showed a 15% nonsignificant mortality benefit, on post hoc analysis the authors found a potential statistically significant delayed effect on mortality of more than 7 years after randomization. Their finding of a statistically significant stage shift of 14% (40% vs 26%) stage 3A disease or less is noteworthy and adds biological plausibility to this. This would have resulted in a higher R0 resection rate (nil-residual disease) in the screened group. R0 resection is well documented as the critically important factor associated with higher survival rates following debulking surgery for advancedstage ovarian cancer.5,6 The philosophy of ovarian cancer debulking surgery has changed over the last few years, with far more complex ultraradical surgeries being undertaken in most major cancer centers, to achieve ‘‘nil-residual’’disease or R0 resection. If screening is associated with an increase in lower volume disease, this maywell lead to the need for proportionally fewer ultraradical surgical procedures with lower morbidity and potentially beneficial cost implications. At the same time, it remains unknown if screening also resulted in less bulky or lower-volume stage 3B/3C disease, which may be more amenable to achieving R0 resection and better outcomes. This is an important issue, and it would be helpful if this were further evaluated and reported by the research team. Maximizing translation of a screening strategy into patient benefit also requires increasing awareness and changing the mind set of gynecological oncologists and multidisciplinary teams to act/operate on a rising biomarker without any radiological confirmation of disease. This report also highlights for all investigators and trialists the importance of the critical issue of ‘‘prespecified’’ analysis and choice of statistical plan. Unlike some other large populationbased screening trials (PLCO3 and National Lung Cancer7 trials), the UKCTOCS prespecified analysis plan does not appear to have taken into account any statistical adjustment for a potential delayed effect on mortality. The time needed for the process of diagnosis, treatment, recurrence, and occurrence of death can result in a lag/delay between initiation of screening and observation of a mortality impact. This has been reported in other screening trials. In such situation, mortality rates for the screened group relative to those of the control group are not likely to be constant as a function of years from randomization, and thus the log-rank test for differences in mortality between the 2 randomized groups is not optimal.8,9 This leads to a loss in power, which may be recovered or adjusted for by using other tests that are more sensitive to nonproportional odds alternatives such as an adaptive weighted log-rank test8 or likelihood ratio test.9 The trial was underpowered to detect a less than 30% difference that may exist between the arms. The observed stage shift of 14% may well be associated with a lower than 30% mortality impact. However, even a lower level of mortality benefit could have significant impact on this poor prognostic disease at a population level. This possibility of lower-volume disease and higher complete cytoreduction rates translating into a less than 30% mortality benefit may be corroborated by the statistically significant results of the weighted logrank and Royston Palmer tests, which helps boost power of the study to enable identification of a smaller difference between screening and control arms that may exist. The authors have suggested further follow-up of the cohort to establish this. While many of us hope this will be positive, the possibility that the mortality impact will remain nonsignificant despite additional follow-up cannot be discounted. It is critically important for these results to be published, and benefits of OC screening well established to enable appropriate inferences before considering introduction into practice or a national program. The harms of false-positive surgery and complications from screening are not insignificant. A negative outcome would once again highlight the current limitations of early detection technologies and difficulties linked to disease biology. A successful strategy may need to detect tumors of 0.4 to 1.3 cm and surmount the signal-to-noise conundrum associated with this.10 Circulating DNA and multimarker algorithms used in a longitudinal analysis may hold promise, but new biomarkers that add significantly to CA-125 in the screening context remain to be validated. Novel/innovative functional imaging modalities also need to be developed and evaluated. We await with interest and hope the results from further follow-up and additional analysis of surgical outcomes.