Effect of Hepatocellular Carcinoma Surveillance Programmes on Overall Survival in a Mixed Cirrhotic UK Population: A Prospective, Longitudinal Cohort Study

Introduction: Surveillance for hepatocellular carcinoma (HCC) is recommended by national and international guidelines. However, there are no trial data on whether surveillance improves clinical outcomes in a UK cirrhosis population of mixed aetiology. Our aim was to determine the impact of, and adherence to, surveillance on overall survival. Methods: We prospectively collected data on consecutive patients diagnosed with HCC between January 2009 and December 2015 at two large UK centres. We assessed outcomes depending on whether they had been entered into an HCC surveillance programme, and if they had adhered to that. Results: Out of 985 patients diagnosed with HCC in this study, 40.0% had been enrolled in a surveillance programme. Of these, 76.6% were adherent with surveillance and 24.4% were not. Adherence to surveillance was significantly associated with improved overall survival, even when accounting for lead-time bias using different approaches (HR for 270 days lead-time adjustment 0.64, 0.53 to 0.76, p < 0.001). Conclusions: When adjusted for lead-time bias, HCC surveillance is associated with improved overall survival; however, the beneficial effect of surveillance on survival was lower than reported in studies that did not account fully for lead-time bias.

Considering lead-time bias in evaluating the effectiveness of lung cancer screening with real-world data

Low-dose computed tomography screening can be used to diagnose lung cancer at a younger age compared to no screening. Real-world studies observing mortality after lung cancer diagnosis are subject to lead-time bias. This study developed a method using a nationwide cancer registry and stage shift from trial for the adjustment of lead-time bias. 78,897 Taiwanese nationwide lung cancer patients aged 55–82 were matched with 788,820 referents randomly selected from the general population at a ratio of 1:10 by age, sex, calendar year, and comorbidities, to estimate the pathology- and stage-specific life expectancy (LE). Loss-of-LE is the difference between the LE of cancer patients and that of referents. By multiplying LE and loss-of-LE by the pathology and stage shift in the National Lung Screening Trial (NLST), we compared the effectiveness of cancer screening measured by LE gained and loss-of-LE saved. The mean LEs of stage IA and IV adenocarcinoma were 14.5 and 1.9 years, respectively, indicating a LE gain of 12.6 years. However, the mean loss-of-LEs of stage IA and IV adenocarcinoma were 3.7 and 15.1 years, respectively, with a saving of only 11.4 years, implying an adjustment of different distributions of age, sex, and calendar year of diagnosis from stage shift and a reduction in lead-time bias. Applying such estimations on the results of 10,000 participants with the same pathology and stage shift in the NLST, the benefit of screening using LE gained would be 410.3 (95% prediction interval: 328.4 to 503.3) years. It became 297.1 (95% prediction interval: 187.8 to 396.4) years when using loss-of-LE saved, indicating the former approach would overestimate the effectiveness by 38%. Our approach of multiplying loss-of-LE by pathology and stage shift to estimate loss-of-LE saved could adjust for different distributions of age, sex, and calendar year at early diagnosis and reduce lead-time bias.

Bedeutung von Komorbiditäten bei der idiopathischen Lungenfibrose

ZusammenfassungKomorbiditäten der idiopathischen Lungenfibrose (IPF) sind sehr häufig und zumeist mit einer verschlechterten Lebensqualität und Prognose der Patienten verbunden. Vor allem pulmonale Hypertonie, chronische obstruktive Lungenerkrankung/Lungenemphysem, Lungenkarzinom und die koronare Herzerkrankung sind prognostisch relevant. Während Mikroaspirationen zwar als möglicher Auslöser und Progressionsfaktor einer IPF diskutiert werden, ist die Refluxerkrankung jedoch mit einer besseren Prognose assoziiert. Die Ursachen hierfür sind noch unklar, möglicherweise handelt es sich um einen „lead time bias“ oder einen Therapieeffekt des Refluxes; allerdings spricht die aktuelle Datenlage gegen einen solchen Zusammenhang für antazide Medikamente. Das Risiko ein Lungenkarzinom zu entwickeln, ist bei IPF signifikant höher im Vergleich zur Normalbevölkerung und die zweithäufigste respiratorische Todesursache bei der IPF. Eine Therapie des nicht-kleinzelligen Bronchialkarzinoms (NSCLC) ist jedoch nur im frühen Stadium der IPF mit einem verbesserten Outcome assoziiert, in anderen Fällen allerdings mit einem sehr hohen periinterventionellen Risiko. Bisherige Daten suggerieren, dass ein Screening auf Komorbiditäten und deren konsequente Therapie zu einer verbesserten Lebensqualität und Prognose der chronisch erkrankten IPF-Patienten führen könnten.

Lead Time Bias as a Factor in Mammography Detected Invasive Breast Cancer Survival in an Institutional Cohort

Background: Lead time, the interval between screen detection and when a disease would have become clinically evident, has been cited to explain longer survival times in mammography detected breast cancer cases (BC). Methods: An institutional retrospective cohort study of BC outcomes related to detection method (mammography (MamD) vs. patient (PtD)). Cases were first primary invasive stage I-III BC, age 40-74 years (n = 6603), 1999-2016. Survival time was divided into 1) distant disease-free interval (DDFI) and 2) distant disease-specific survival (DDSS) as two separate time interval outcomes. We measured statistical association between detection method and diagnostic, treatment and outcome variables using bivariate comparisons, Cox proportional hazards analyses and mean comparisons. Outcomes were distant recurrence (n=422), DDFI and DDSS. Results: 39% of cases were PtD (n = 2566) and 61% were MamD (n = 4037). MamD cases had a higher percentage of Stage I tumors [MamD 69% stage I vs. PtD 31%, p<.001]. Rate of distant recurrence was 11% among PtD BC cases (n=289) vs. 3% of MamD (n=133) (p<.001). Order of factor entry into the distant recurrence time interval (DDFI) model was 1) TNM stage (p<.001), 2) HR/HER2 status (p<.001), 3) histologic grade (p=.005) and 4) detection method (p<.001). Unadjusted PtD DDFI mean time was 4.34 years and MamD 5.52 years (p<.001) however when stratified by stage, the most significant factor relative to distant recurrence, there was no significant difference between PtD and MamD BC. Distant disease specific survival time did not differ by detection method.Conclusion: We observed breast cancer survival differential lead time to be a function of stage at diagnosis and tumor characteristics with marginal contribution of detection method. Patient and mammography detected breast cancer time to distant recurrence did not differ stratified by stage indicating survival difference is more likely related to early diagnosis than lead time bias. Lead time bias associated with breast cancer detection method appears to have marginal influence on survival in the current diagnostic and treatment era.