Lead-time Bias Research Articles

Evaluating mammography screening in observational cohort designs: the importance of avoiding lead time bias.

To investigate the potential lead time bias of the evaluation model (extended follow-up for women diagnosed with breast cancer) used to evaluate mammography screening in a recent Danish study. This model was compared with two traditional models. We retrieved data on women diagnosed with breast cancer in each county of Norway from 1986 to 2016. In a population-based open cohort study, the change in incidence-based mortality (IBM) was estimated by relative rate ratios comparing a screening period with a historical period for each of three age groups: women eligible for screening and younger and older ineligible women. We applied the evaluation model, and for comparison two traditional IBM models from a recent Norwegian study: one without extended follow-up and no possibility of lead time bias and one with extended follow-up irrespective of diagnosis, possibly diluting any screening effect. The evaluation model estimated an extra 11% reduction in breast cancer mortality among the screening eligible relative to ineligible women. However, this result could largely be ascribed to lead time bias inflated by overdiagnosis and a decreasing mortality from other causes among eligible women. A reduction in breast cancer mortality was observed for both eligible and younger and older ineligible women across models, and relative rate ratios close to 1 were obtained using the two traditional IBM models, indicating no effect of screening on breast cancer mortality. Two models without lead time bias found no reduction in breast cancer mortality, whereas the evaluation model estimated a reduction attributable to lead time bias.

Impact of colorectal cancer screening programme on survival and employment in Taiwan: A nationwide analysis of real-world data.

Colorectal cancer (CRC) leads to life loss and a significant economic burden, which could be reduced by CRC screening. We assessed the potential savings of lives and employment to evaluate the effectiveness of the Taiwan CRC Screening Programme. Through interlinkages among Taiwan Cancer Registry, National Mortality Registry, Taiwan CRC Screening Database, and National Health Insurance claim data, we enroled patients with colorectal adenocarcinoma, aged 50-74years and diagnosed during 2004-2017, and followed them up to 2018. Life expectancy (LE), lifetime employment duration (LED), loss-of-LE and loss-of-LED were calculated, compared with age-, sex- and calendar year-matched cohorts. Assuming no difference within a specific stage for screen-detected versus non-screen detected CRC and weighting them by different stage distributions, we compared the total loss-of-LE and loss-of-LED. The cohort enroled 77,169 patients with colorectal adenocarcinoma, which included 31,728 women (mean [SD] age, 62.5 [7.1] years) and 45,441 men (mean [SD] age, 62.8 [6.8] years). The mean loss-of-LE and loss-of-LED in women were 6.0 (95% confidence interval [CI] 5.7-6.3) and 1.0 (95% CI 0.8-1.1) year(s), whereas those in men were 5.1 (95% CI 4.9-5.4) and 1.1 (95% CI 1.0-1.2) years, respectively. Among the cohort, 53,678 cases had the screening information. On average, screening potentially saved 2.9 (95% CI 2.6-3.2) years of life expectancy plus 0.5 (95% CI 0.4-0.6) years of employment per case in women and 2.7 (95% CI 2.5-3.0) years plus 0.6 (95% CI 0.5-0.7) years in men, respectively. The Taiwan CRC Screening Programme is associated with the savings of lives and employment duration. Future studies are warranted to evaluate the cost-effectiveness of beginning screening at a younger age after accounting for saving employment loss and possibly adjusting lead time bias.

Impact of screening on mortality for patients diagnosed with hepatocellular carcinoma at a safety-net hospital: An opportunity for addressing disparities.

140 Background: Hepatocellular carcinoma (HCC) is a common and deadly cancer with a rising incidence in the US. HCC almost always develops on a background of chronic liver disease, which disproportionately affects individuals of lower socioeconomic status (SES), perpetuating existing disparities. Compounding these disparities, individuals of lower SES are less likely to participate in recommended cancer screening exams. Here, we describe the outcomes of patients diagnosed with HCC at a large urban safety-net hospital primarily serving the underserved. Methods: We identified patients diagnosed with HCC at John Peter Smith Hospital in Fort Worth, Texas from January 1, 2018, to March 31, 2021 to determine the impact of screening on survival. Patients were allocated to the screened cohort if they had undergone liver imaging within one year prior to HCC diagnosis. Kaplan-Meier methods and log-rank test were used to illustrate and compare 3-year survival curves from an index date of diagnosis until death. Cox proportional hazards model were used to calculate unadjusted and adjusted hazards ratios (HR) and 95% confidence intervals (CI). Lead time bias was adjusted in a sensitivity analysis using the Duffy adjustment and a sojourn time of 70 days and 140 days. Results: A total of 158 patients were included (n=53 screened, n=105 unscreened). The mean age was 62 years; 144 (91%) had cirrhosis, 78% were male, 34% were non-Hispanic white, and 8.2% had private insurance. Those in the unscreened cohort had more severe liver dysfunction (as measured by the ALBI grade) and produced higher levels of AFP, but were less likely to have cirrhosis than the screened cohort. The median overall survival (OS) for the screened cohort was 19.0 months (95% CI: 9.9-NA) and 5.4 months (95% CI: 3.7-8.5) in the unscreened cohort (HR death (unscreened v screened) = 2.4, 95% CI: 1.6-3.6; log rank P <0.0001). After adjusting for ALBI grade, AFP, hepatitis C, insurance status and initial treatment, there was a statistical difference in hazard of death in the three years (HR: 2.3; 95% CI: 1.5-3.6), favoring the screened cohort. The benefit for screening remained after adjusting for lead-time bias. With a mean sojourn time of 70 days, the HR death was 2.19 (95% CI 1.4-3.3, P =0.0002) and was 2.09 (1.4-3.2, P =0.0005) with a 140-day sojourn time. Conclusions: In an urban safety-net population, screening for HCC was associated with improved outcomes compared to patients with incidentally-diagnosed HCC. Altogether, this implies that earlier diagnosis and institution of treatment can positively improve survival for patients with newly diagnosed HCC in a population of patients evaluated at a safety-net hospital. Development of screening programs in accordance with accepted guidelines with outreach to high-risk individuals represents an area of high value care for safety-net hospitals.

Prostate-specific Membrane Antigen Positron Emission Tomography Before Reaching the Phoenix Criteria for Biochemical Recurrence of Prostate Cancer After Radiotherapy: Earlier Detection of Recurrences

Background and objectiveBiochemical recurrence (BCR) of prostate cancer (PCa) after curative radiotherapy (RT) is defined according to the Phoenix criteria, which is a prostate-specific antigen (PSA) rise of ≥2.0 ng/ml above the PSA nadir. Prostate-specific membrane antigen (PSMA)-based positron emission tomography/computed tomography (PET/CT) can identify PCa recurrences at very low PSA values. Our aim was to investigate the detection rate and extent of PCa recurrences using PSMA PET/CT after curative RT among patients with a PSA rise of ≥2.0 ng/ml above the nadir (Phoenix positive, Ph+) and patients not reaching this threshold (Phoenix negative, Ph−) and to compare therapeutic management and clinical outcomes in terms of time to androgen deprivation therapy (ADT) and castration-resistance PCa (CRPC), as well as overall survival. MethodsWe conducted a retrospective analysis of the Prostate Cancer Network Amsterdam (2015–2023) cohort of 568 patients who received curative-intent RT for PCa. Data on PSMA PET/CT outcomes, therapeutic management, and clinical follow-up were collected, including (re)initiation of ADT, progression to CRPC, and survival. Results were compared between groups using logistic regression and survival analyses. Key findings and limitationsThe study cohort comprised 222 patients (39.1%) classified as Ph− and 346 (60.9%) classified as Ph+. PSMA-avid lesions were detected in 170 Ph− patients (76.6%) and 322 (93.1%) Ph+ patients. In these groups, 75.9% of Ph− patients and 45.0% of Ph+ patients were eligible for local salvage therapy (odds ratio [OR 3.84]; p < 0.001). Distant metastases were less frequent in the Ph− group (n = 37, 21.8%) than in the Ph+ group (n = 157, 48.8%; OR 0.29; p < 0.001). Survival analyses revealed longer times to ADT (re)initiation and progression to CRPC, as well as lower overall mortality, in the Ph− group (log-rank p < 0.001). The retrospective study design is the main limitation. Conclusions and clinical implicationsFor patients with PCa recurrence, PSMA PET/CT can detect this recurrence in the majority of cases not meeting the Phoenix criteria for BCR. Early imaging detects recurrences at a less advanced disease stage, allowing potential salvage treatments. In addition, early PSMA PET/CT is associated with longer times to ADT (re)initiation and progression to CRPC, as well as longer overall survival. These positive clinical implications warrant confirmation of our results in prospective studies to reduce potential leadtime bias. Patient summaryWe investigated early use of a special type of scan called PSMA PET (prostate-specific membrane antigen positron emission tomography) in patients with suspicion of recurrence of their prostate cancer after radiotherapy. Early scans can detect recurrence before the cancer progresses to a more advanced stage.

470. INTENSIVE EARLY SURVEILLANCE FOLLOWING ESOPHAGECTOMY IDENTIFIES DISTINCT PATTERNS OF RECURRENCE

Abstract Background There remains a lack of consensus about the protocol for follow-up following esophagectomy. Some centers will utilize a purely radiological approach to follow-up, while others will include routine endoscopy and blood markers. Furthermore, the frequency of follow-up is debated, though many centers will follow-up every 3 months due to the high recurrence rate in the first year. We follow patients every 3 months for the first year, every 6 months for the next year, then yearly to 5 years, solely with CT scans unless symptoms indicate endoscopy. We sought to examine our recurrence rate and survival using this follow-up protocol. Methods We reviewed our prospectively collected database for recurrence following esophagectomy in patients operated from March 2018 to May 2022. Consenting patients &amp;gt;18 years of age who underwent esophagectomy were included. Demographics including age, sex, and BMI, tumor factors including pathologic stage, tumor regression grade, and neoadjuvant therapy and post-recurrence treatment data were collected. Results We identified 190 patients who underwent esophagectomy and 69 patients had a recurrence. Patients with recurrence were younger (61.3 +/- 10.2 vs 66.4 +/- 10.1, p=0.001), were more likely pT3 (59.4% vs 36.4%, p=0.013) and have a tumor regression grade of 3 (27.5% vs 7.4%, p=0.002). There was no difference between patients with R1 resections vs R0 (5.8% vs 6.6%, p=0.824). Most recurrences were identified on CT scan (95.8%). For patients who recurred within 3 months, the mean time from operation to death was 9.11 months. Patients who recurred between 3-6mo, 6-9mo, and 9-12mo died at 17.1mo, 15.7mo, and 17.5mo following surgery, respectively. Patients who recurred in the next year died around 40 months from surgery. Conclusion As with other reports in the literature, recurrence is highest in the first year after esophagectomy. Patients recurring in the first 3 months had a short survival following esophagectomy and may represent missed micrometastatic disease at staging. Interestingly, patients who recurred between 3-12 months all had a similar time to death from the date of operation, suggesting lead-time bias for those detected at 3-6months. Early and later recurrence appear to have distinct biological behaviours. With improved and tailored adjuvant therapies, earlier detection may yet be beneficial and will require further study.

Clinical and Imaging Follow-Up for High-Risk Cutaneous Melanoma: Current Evidence and Guidelines.

The most recent (eighth) edition of the American Joint Committee on Cancer (AJCC) staging system divides invasive cutaneous melanoma into two broad groups: "low-risk" (stage IA-IIA) and "high-risk" (stage IIB-IV). While surveillance imaging for high-risk melanoma patients makes intuitive sense, supporting data are limited in that they are mostly respective and used varying methods, schedules, and endpoints. As a result, there is a lack of uniformity across different dermatologic and oncologic organizations regarding recommendations for follow-up, especially regarding imaging. That said, the bulk of retrospective and prospective data support imaging follow-up for high-risk patients. Currently, it seems that either positron emission tomography (PET) or whole-body computerized tomography (CT) are reasonable options for follow-up, with brain magnetic resonance imaging (MRI) preferred for the detection of brain metastases in patients who can undergo it. The current era of effective systemic therapies (ESTs), which can improve disease-free survival (DFS) and overall survival (OS) beyond lead-time bias, has emphasized the role of imaging in detecting various patterns of EST response and treatment relapse, as well as the importance of radiologic tumor burden.

Pancreatic Cancer Surveillance and Survival of High-Risk Individuals

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence. The majority of PDACs are incurable at presentation, but population-based screening is not recommended. Surveillance of high-risk individuals for PDAC may lead to early detection, but the survival benefit is unproven. To compare the survival of patients with surveillance-detected PDAC with US national data. This comparative cohort study was conducted in multiple US academic medical centers participating in the Cancer of the Pancreas Screening program, which screens high-risk individuals with a familial or genetic predisposition for PDAC. The comparison cohort comprised patients with PDAC matched for age, sex, and year of diagnosis from the Surveillance, Epidemiology, and End Results (SEER) program. The Cancer of the Pancreas Screening program originated in 1998, and data collection was done through 2021. The data analysis was performed from April 29, 2022, through April 10, 2023. Endoscopic ultrasonography or magnetic resonance imaging performed annually and standard-of-care surgical and/or oncologic treatment. Stage of PDAC at diagnosis, overall survival (OS), and PDAC mortality were compared using descriptive statistics and conditional logistic regression, Cox proportional hazards regression, and competing risk regression models. Sensitivity analyses and adjustment for lead-time bias were also conducted. A total of 26 high-risk individuals (mean [SD] age at diagnosis, 65.8 [9.5] years; 15 female [57.7%]) with PDAC were compared with 1504 SEER control patients with PDAC (mean [SD] age at diagnosis, 66.8 [7.9] years; 771 female [51.3%]). The median primary tumor diameter of the 26 high-risk individuals was smaller than in the control patients (2.5 [range, 0.6-5.0] vs 3.6 [range, 0.2-8.0] cm, respectively; P < .001). The high-risk individuals were more likely to be diagnosed with a lower stage (stage I, 10 [38.5%]; stage II, 8 [30.8%]) than matched control patients (stage I, 155 [10.3%]; stage II, 377 [25.1%]; P < .001). The PDAC mortality rate at 5 years was lower for high-risk individuals than control patients (43% vs 86%; hazard ratio, 3.58; 95% CI, 2.01-6.39; P < .001), and high-risk individuals lived longer than matched control patients (median OS, 61.7 [range, 1.9-147.3] vs 8.0 [range, 1.0-131.0] months; 5-year OS rate, 50% [95% CI, 32%-80%] vs 9% [95% CI, 7%-11%]). These findings suggest that surveillance of high-risk individuals may lead to detection of smaller, lower-stage PDACs and improved survival.

MDB-81. THE ROLE OF SURVEILLANCE IMAGING IN DETECTING RECURRENCE OF MEDULLOBLASTOMA

Abstract BACKGROUND In patients with medulloblastoma, imaging with magnetic resonance imaging (MRI) of the brain and spine plays an integral role in surveillance following treatment completion. The primary objective of imaging surveillance is to detect early recurrences, possibly leading to better salvage treatment. However, there is a lack of data to demonstrate the utility of imaging with possible demerits associated with increased resource utilization, scan-related anxiety, and lead or length time bias. METHODS Patients with histopathological confirmation of medulloblastoma treated in our institute between 2005 and 2022 were screened to identify patients with image-detected recurrences and corresponding documentation of symptoms and imaging intent (surveillance or directed by symptoms). RESULTS From a cohort of 545 patients treated during the period, 212 had disease recurrence, of which 153 had known symptomatology during the first recurrence. A total of 114 patients (75%) were having recurrence detected prompted by symptoms. Group 4 medulloblastomas were commonly seen to have recurrence detected on surveillance imaging (35%) compared to the SHH subgroup (25%) and group 3 (12%). During the final analysis, 141 of 153 patients had died. The median survival of patients detected to have asymptomatic relapse was 14 months compared to 5 months for symptomatic recurrences (p=0.03). The overall survival (calculated from index diagnosis) was not statistically significant between the two groups, with a 3-year survival of 53% (asymptomatic) vs 46% (symptomatic) (p=0.51). CONCLUSION In most patients, recurrences were detected by unplanned imaging ahead of scheduled surveillance imaging prompted by symptoms. Although the survival after recurrence is better in patients diagnosed on surveillance imaging, the overall survival was not different between the two groups, suggesting the possibility of lead time bias. Prospective studies are warranted to determine the role and appropriate frequency of surveillance imaging in patients with medulloblastoma.

Impact of lung cancer screening on stage migration and mortality among the national Veterans Health Administration population with lung cancer.

Despite randomized trials demonstrating a mortality benefit to low-dose computed tomography screening to detect lung cancer, uptake of lung cancer screening (LCS) has been slow, and the benefits of screening remain unclear in clinical practice. This study aimed to assess the impact of screening among patients in the Veterans Health Administration (VA) health care system diagnosed with lung cancer between 2011 and 2018. Lung cancer stage at diagnosis, lung cancer-specific survival, and overall survival between patients with cancer who did and did not receive screening before diagnosis were evaluated. We used Cox regression modeling and inverse propensity weighting analyses with lead time bias adjustment to correlate LCS exposure with patient outcomes. Of 57,919 individuals diagnosed with lung cancer in the VA system between 2011 and 2018, 2167 (3.9%) underwent screening before diagnosis. Patients with screening had higher rates of stage I diagnoses (52% vs. 27%; p ≤ .0001) compared to those who had no screening. Screened patients had improved 5-year overall survival rates (50.2% vs. 27.9%) and 5-year lung cancer-specific survival (59.0% vs. 29.7%) compared to unscreened patients. Among screening-eligible patients who underwent National Comprehensive Cancer Network guideline-concordant treatment, screening resulted in substantial reductions in all-cause mortality (adjusted hazard ratio [aHR], 0.79; 95% confidence interval [CI], 0.67-0.92; p=.003) and lung-specific mortality (aHR, 0.61; 95% CI, 0.50-0.74; p<.001). While LCS uptake remains limited, screening was associated with earlier stage diagnoses and improved survival. This large national study corroborates the value of LCS in clinical practice; efforts to widely adopt this vital intervention are needed.

Appropriate definition of non-metastatic castration-resistant prostate cancer (nmCRPC) and optimal timing of androgen receptor signaling inhibitor (ARSI)

BackgroundDefined by rising PSA levels under androgen deprivation therapy (ADT) despite no visible metastases on conventional imaging, non-metastatic castration-resistant prostate cancer (nmCRPC) represents a complex clinical challenge. A significant subset of these patients rapidly develops metastatic disease, negatively impacting survival. We examined the difference in prognosis of nmCRPC patients according to the timing of therapeutic interventions with androgen receptor signaling inhibitor (ARSI).MethodsWe examined 102 nmCRPC patients treated with ARSI. We divided patients according to their PSA levels when ARSI was administered: Cohort A (PSA 0.5–2.0 ng/mL), Cohort B (PSA 2.0–4.0 ng/mL), and Cohort C (PSA > 4.0 ng/mL). Utilizing the Kaplan–Meier method for survival analysis, our analytical starting point was the moment when PSA levels exceeded 0.5 ng/mL post-ADT nadir, ensuring a fair comparison and minimizing lead-time bias.ResultsAfter excluding 5 patients whose PSA nadir after ADT > 0.5 ng/mL, patient distribution across Cohort A, Cohort B, and Cohort C was 32, 24, and 41 patients, respectively. Kaplan–Meier survival analysis highlighted a 2-year metastasis-free survival rate of 97% for Cohort A, 87% for Cohort B, and 73% for Cohort C. A marked statistical difference emerged when comparing Cohort A with Cohorts B and C, with a p-value of 0.043.ConclusionThe timely initiation of ARSI is paramount in nmCRPC management. Our findings strongly advocate for consideration of ARSI administration in nmCRPC patients before their PSA levels exceed 2.0 ng/mL. Our results indicated a PSA threshold of 1.0 ng/mL for nmCRPC definition which is more reasonable to administer ARSI without delay.

Impact of artificial intelligence (AI) decision support on clinical trial participation: A before-after implementation study on a nationwide molecular tumor board.

1557 Background: Molecular Tumor Boards (MTB) have become the standard for deriving consensus therapy (Rx) recommendations (rec) for patients (pts) with advanced cancer undergoing comprehensive genomic profiling (CGP). However, finding matched Rx and trial options remains laborious, needing informatics strategies. Methods: We examined the outcomes before and after implementation of a decision support system (DSS) at the MTB of the Australian Molecular Screening &amp; Therapeutics program (MoST, ACTRN12616000908437), enrolling pts with refractory solid tumors and linking CGP results to Rx and trials through rec on clinical reports. The DSS comprises a variant interpretation pipeline, a symbolic AI system integrating the TOPOGRAPH database and an annotated trials registry, and a web platform used by the MTB for producing reports shortlisting matching Rx and therapeutic trials. The primary endpoint is the cumulative participation rate (CPR) in genomic matched trials (excluding MoST-related trials) in pts who received Rx after CGP. The secondary endpoints are the CPR in any trial, and overall survival (OS) from MTB. The Fine-Gray model was used to estimate the subdistribution hazard ratios (sHR) for between-group differences in participation. Kaplan-Meier and Cox regression were used for OS analysis. The time-to-event analyses were adjusted for age, ECOG, cancer type, lines of prior rx, and lead-time bias (OS only). Results: In 2203 of 5186 pts (42.5%) received ≥ 1 Rx after CGP, 971 pts were reviewed at MTB before and 1272 after DSS implementation in Sep 2020. At 3, 6 and 12 months (m) after enrolment, CPR in matched trials were 3.2%, 5.0%, and 6.8% before implementation and 3.6%, 5.8%, and 8.9% afterwards (sHR 1.19, 95% CI 0.90–1.57, p=0.23). Pts who received an MTB rec were more likely to participate in a matched trial (sHR 4.75, 3.13–7.23, p&lt;0.001). Notably, DSS specifically increased the likelihood of trial participation following MTB rec (interaction sHR 2.69, 1.02–7.07, p=0.045), with 12m CPR increasing from 10.0% to 12.2% after implementation of the DSS in pts with a MTB rec, whilst for pts without a MTB rec, the CPR fell from 3.1% to 1.6% after implementation. No association was seen between participation in any trials and MTB recs (sHR 1.12, 0.95–1.32) or implementation (sHR 0.95, 0.81–1.11; CPR pre 21.6% v post 23.7% at 12m). No OS difference was seen comparing before with after implementation of the DSS (median 16.7 v 15.3m, adjusted HR 0.97, 0.87–1.08). However, pts receiving genomic matched Rx had a longer OS (median 20.1 v 15.0m unmatched, HR 0.76, p=0.002). Conclusions: The observed interaction between the implementation of DSS and MTB rec suggests there is effect modification in participation rates of pts in genomic matched trials, warranting exploration into how AI might enhance trial participation among pts with incurable cancers undergoing CGP.

Real-world use of a CSF circulating tumor cell assay in the diagnosis and management of leptomeningeal metastasis.

2029 Background: The diagnosis of leptomeningeal metastasis (LM) can be challenging due to variability in clinical symptoms, radiographic, and cerebrospinal fluid (CSF) findings. The National Comprehensive Cancer Network (NCCN) guidelines recommend assessment of circulating tumor DNA (ctDNA) to increase sensitivity of tumor cell detection and assess the response to treatment. We hypothesize that the real-world use of an assay for the direct detection and enumeration of circulating tumor cells (CTCs) in the CSF is clinically useful for accurate diagnosis of LM, particularly in an early stage of disease. Methods: We report a series of 55 patients treated at our institution with a cancer diagnosis and either neurological symptoms or radiographic findings that suggested LM. All patients underwent a lumbar puncture, assessment for CSF CTCs, and conventional hospital-based cytology testing between 6/1/2020 and 8/1/2023. Survival data cutoff was 12/31/2023. Patient outcomes are reported. Results: 55 patients were tested, and 30 patients were found to be positive for CTCs and diagnosed with LM. Only 10 patients were concurrently positive for CTCs and cytology at our institution, whereas 20 patients with positive CTCs had a negative or ambiguous cytology. No patients with a negative CTC result (25 patients) were subsequently diagnosed with LM, whereas 4 patients with a positive CTC result remained without progressive neurological symptoms. 5 patients diagnosed with LM were alive at the time of data cutoff. The histologic breakdown for LM was: breast (11), non-small cell lung cancer (NSCLC) (16), gastrointestinal (GI) (3). Median overall survival (OS) was longer in patients with a positive CTC and negative cytology result compared to patients with concurrent positive CTC and cytology (172 vs. 63 days, p = 0.06). Median OS was also longer in breast cancer LM compared to NSCLC LM (235 vs. 63 days, p = 0.008). Most patients diagnosed with LM received therapies including Ommaya reservoir placement, intrathecal chemotherapy, and/or radiation. Conclusions: The use of a CSF circulating tumor cell assay aided the diagnosis of LM and led to timely initiation of treatment. A negative result of the CTC assay was associated with ruling out LM. Diagnosis of LM with the CTC assay and negative cytology was associated with longer survival, possibly due to earlier treatment initiation, and not solely a lead time bias. Breast cancer LM patients had improved survival compared to NSCLC and GI cancer patients, possibly due to more effective treatment options.

Breast cancer patients enrolled in the Swiss mammography screening program "donna" demonstrate prolonged survival.

We compared the survival rates of women with breast cancer (BC) detected within versus outside the mammography screening program (MSP) "donna". We merged data from the MSP with the data from corresponding cancer registries to categorize BC cases as within MSP (screen-detected and interval carcinomas) and outside the MSP. We analyzed the tumor stage distribution, tumor characteristics and the survival of the women. We further estimated hazard ratios using Cox-regressions to account for different characteristics between groups and corrected the survival rates for lead-time bias. We identified 1057 invasive (ICD-10: C50) and in-situ (D05) BC cases within the MSP and 1501 outside the MSP between 2010 and 2019 in the Swiss cantons of St. Gallen and Grisons. BC within the MSP had a higher share of stage I carcinoma (46.5% vs. 33.0%; p < 0.01), a smaller (mean) tumor size (19.1mm vs. 24.9mm, p < 0.01), and fewer recurrences and metastases in the follow-up period (6.7% vs. 15.6%, p < 0.01). The 10-year survival rates were 91.4% for women within and 72.1% for women outside the MSP (p < 0.05). Survival difference persisted but decreased when women within the same tumor stage were compared. Lead-time corrected hazard ratios for the MSP accounted for age, tumor size and Ki-67 proliferation index were 0.550 (95% CI 0.389, 0.778; p < 0.01) for overall survival and 0.469 (95% CI 0.294, 0.749; p < 0.01) for BC related survival. Women participating in the "donna" MSP had a significantly higher overall and BC related survival rate than women outside the program. Detection of BC at an earlier tumor stage only partially explains the observed differences.

#2576 Effect of dialysis versus conservative care on all-cause mortality in older patients with advanced CKD: nationwide Swedish cohort study

Abstract Background and Aims Conservative care is emerging as an alternative to dialysis in older patients with advanced chronic kidney disease (CKD). However, high-quality evidence comparing the effect of dialysis versus conservative care on patient survival is lacking. Previous observational studies suffered from avoidable biases, such as immortal time bias and lead time bias, and adjusted for limited confounders. This study aimed to assess the effects of dialysis versus conservative care on mortality in older patients with advanced CKD. Method The target trial emulation framework was used to design and analyze this observational study. We conducted a nationwide observational cohort study using data from the Swedish Renal Registry between 2007-2021. We included all nephrologist-referred patients with eGFR &amp;lt; 20 ml/min/1.73 m2 who had a registered decision for dialysis or conservative care. Eligible patients were required to be ≥ 65 years with a Davies Comorbidity Score ≥ 2 or ≥ 80 years. The primary endpoint was 5-year all-cause mortality. Inverse probability of treatment weighting was used to adjust for 50 baseline confounders, including demographics, comorbidities, medication use, blood pressure, laboratory measurements, hospitalizations, and calendar year. Patients in the non-overlapping region of the propensity score distribution were excluded since they had an absolute indication for dialysis or conservative care. Cox proportional hazards regression was used to estimate intention-to-treat hazard ratios (HRs) with 95% confidence intervals (CIs), and the Kaplan-Meier estimator was used to estimate absolute risks. Additionally, we calculated the 5-year restricted mean survival times (RMST) and the 5-year RMST difference between dialysis and conservative care arms. To test the robustness and consistency of our main results, we performed a subgroup analysis in patients aged ≥80. Results Of 2834 eligible patients, 1903 had a registered choice for dialysis and 931 for conservative care. The median age was 81 years, 36.1% were female and median eGFR was 13.1 ml/min/1.73 m2. During the 5-year follow-up period, 29 conservative care patients started dialysis and 430 patients died before starting dialysis. After weighting, all confounders were balanced (standardized mean difference &amp;lt; 0.10). Compared to dialysis, conservative care was associated with a higher absolute 5-year risk of death (91.8% vs. 74.1%), corresponding with an absolute risk difference of 17.6% (95% CI 13.3%-21.9%) (Fig. 1). The adjusted hazard ratio for conservative care vs. dialysis was 2.3 (95% CI 2.0-2.6). The 5-year restricted mean survival times were 34.8 (95% CI 33.2-37.3) months for dialysis and 21.5 (95% CI 19.4-23.6) months for conservative care groups. The 5-year RMST difference was 13.3 months (95% CI 10.8-16.6), meaning that dialysis patients would live on average 13.3 months longer over a 5-year follow-up period than conservative care patients (Table 1). The results were consistent among people ≥ 80 years (adjusted HR 2.2, 95% CI 1.9-2.5; 5-year RMST difference 9.4 months, 95% CI 7.2-13.9). Conclusion In older patients with advanced CKD under nephrologist care, conservative care was associated with a higher risk of mortality than dialysis. These findings could improve the shared decision-making process with patients on the choice of kidney failure treatment.

Lead Time and Immortal Time Biases Impact the Calculation of Post-colonoscopy Colorectal Cancer Survival

The World Endoscopy Organization (WEO) standardized the reporting of post-colonoscopy colorectal cancers (PCCRCs), which account for 7% to 10% of colorectal cancers (CRCs).1 PCCRCs are diagnosed 6 to 36 months after a false negative colonoscopy. Detected CRCs (dCRCs) are diagnosed ≤6 months after an index true positive colonoscopy.2 PCCRC prognosis is unclear, with outcomes reported as comparable,3 superior,4 or inferior5,6 to those of dCRC. Because WEO terminology defines cases relative to the index colonoscopy, conventional survival analyses of PCCRC are susceptible to lead time and immortal time biases. We evaluated the influence of these biases on mortality in a population-based retrospective cohort of 10,938 dCRCs (93.8%) and 717 PCCRCs (6.2%). This study was set within Kaiser Permanente Northern California (KPNC), a large integrated health system, whose members are similar in demographic and socioeconomic characteristics to the Northern California region.7.

Hepatocellular Carcinoma Screening in a Contemporary Cohort of At-Risk Patients

Cohort studies demonstrating an association of hepatocellular carcinoma (HCC) screening with reduced mortality are prone to lead-time and length-time biases. To characterize the clinical benefits of HCC screening, adjusting for lead-time and length-time biases, in a diverse, contemporary cohort of at-risk patients. This retrospective cohort study of patients with HCC was conducted between January 2008 and December 2022 at 2 large US health systems. Data analysis was performed from September to November 2023. The primary outcome was screen-detected HCC, defined by abnormal screening-intent abdominal imaging or α-fetoprotein level within 6 months before diagnosis. Cox regression analysis was used to characterize differences in overall survival between patients with screen-detected and non-screen-detected HCC; lead-time and length-time adjustments were calculated using the Duffy parametric formula. Among 1313 patients with HCC (mean [SD] age, 61.7 [9.6] years; 993 male [75.6%]; 739 [56.3%] with Barcelona Clinic Liver Cancer stage 0/A disease), HCC was screen-detected in 556 (42.3%) and non-screen detected in 757 (57.7%). Patients with screen-detected HCC had higher proportions of early-stage HCC (393 patients [70.7%] vs 346 patients [45.7%]; risk ratio [RR], 1.54; 95% CI, 1.41-1.70) and curative treatment receipt (283 patients [51.1%] vs 252 patients [33.5%]; RR, 1.52; 95% CI, 1.34-1.74) compared with patients with non-screen-detected HCC. The screen-detected group had significantly lower mortality, which persisted after correcting for lead-time bias (hazard ratio, 0.75; 95% CI, 0.65-0.87) in fully adjusted models. Both groups had similar tumor doubling times (median [IQR], 3.8 [2.2-10.7] vs 5.6 [1.7-11.4] months) and proportions of indolent tumors (28 patients [35.4%] vs 24 patients [38.1%]; RR, 0.93; 95% CI, 0.60-1.43). Adjustment for length-time bias decreased survival estimates, although 3-year and 5-year survival for patients with screen-detected HCC remained longer than that for patients with non-screen-detected HCC. The findings of this cohort study suggest that HCC screening is associated with reduced mortality even after accounting for lead-time and length-time biases. However, these biases should be considered in future studies.

Endocrine immune-related adverse event is a prognostic biomarker independent of lead-time bias

ObjectivesImmune-related adverse events (irAEs) are known to be associated with clinical efficacy and better prognoses in patients receiving immune checkpoint inhibitors. In particular, endocrine irAE (e-irAE) is related to better prognoses. Since the incidence of irAEs increase as treatment duration becomes longer, we should consider lead-time bias not to overvalue the result. We evaluated the impact of e-irAE on the outcome before and after 6-, 9-, and 12-week landmark analyses. Materials and MethodsWe evaluated 222 patients with advanced or recurrent non-small cell lung cancer who received anti-PD-1 antibodies such as nivolumab or pembrolizumab from January 2016 to April 2021. Treatment efficacy and outcomes of patients with or without e-irAE (e-irAE group or no e-irAE group) were retrospectively evaluated. In addition, we performed 6-, 9-, and 12-week landmark analyses to exclude the effect of lead-time bias. ResultsMedian progression free survival (PFS) was significantly longer in the e-irAE group than in the no e-irAE group (overall: 15.3 vs 3.9 months, p < 0.0001; 6-week: 15.3 vs 4.9 months, p < 0.0002; 9-week: 19.8 vs 6.1 months, p = 0.0012, 12-week: 19.8 vs 8.4 months, p = 0.017). Overall survival (OS) was significantly longer in the e-irAE group (overall: not reached (NR) vs 15.4 months, p = 0.0003; 6-week: NR vs 19.1 months, p = 0.0049, 9-week: NR vs 22.2 months, p = 0.006; 12-week: NR vs 23.3 months, p = 0.04). We used the multivariate cox proportional hazard model to adjust for confounding factors and found that e-irAE had better impact on both PFS and OS (PFS: overall: hazard ratio 0.37 [95% confidence interval 0.23–0.56], 6-week: 0.41 [0.26–0.63], 9-week: 0.43 [0.24–0.63], 12-week: 0.52 [0.31–0.84]; OS: overall: 0.40 [0.22–0.68], 6-week: 0.46 [0.25–0.79], 9-week: 0.47 [0.24–0.84], 12-week: 0.58 [0.29–1.08]). ConclusionThe occurrence of endocrine irAE was associated with better efficacy and prognoses regardless of the lead-time bias.

Lead-Time Corrected Effect on Breast Cancer Survival in Germany by Mode of Detection.

(1) Background: Screen-detected breast cancer patients tend to have better survival than patients diagnosed with symptomatic cancer. The main driver of improved survival in screen-detected cancer is detection at earlier stage. An important bias is introduced by lead time, i.e., the time span by which the diagnosis has been advanced by screening. We examine whether there is a remaining survival difference that could be attributable to mode of detection, for example, because of higher quality of care. (2) Methods: Women with a breast cancer (BC) diagnosis in 2000-2022 were included from a population-based cancer registry from Schleswig-Holstein, Germany, which also registers the mode of cancer detection. Mammography screening was available from 2005 onwards. We compared the survival for BC detected by screening with symptomatic BC detection using Kaplan-Meier, unadjusted Cox regressions, and Cox regressions adjusted for age, grading, and UICC stage. Correction for lead time bias was carried out by assuming an exponential distribution of the period during which the tumor is asymptomatic but screen-detectable (sojourn time). We used a common estimate and two recently published estimates of sojourn times. (3) Results: The analysis included 32,169 women. Survival for symptomatic BC was lower than for screen-detected BC (hazard ratio (HR): 0.23, 95% confidence interval (CI): 0.21-0.25). Adjustment for prognostic factors and lead time bias with the commonly used sojourn time resulted in an HR of 0.84 (CI: 0.75-0.94). Using different sojourn times resulted in an HR of 0.73 to 0.90. (4) Conclusions: Survival for symptomatic BC was only one quarter of screen-detected tumors, which is obviously biased. After adjustment for lead-time bias and prognostic variables, including UICC stage, survival was 27% to 10% better for screen-detected BC, which might be attributed to BC screening. Although this result fits quite well with published results for other countries with BC screening, further sources for residual confounding (e.g., self-selection) cannot be ruled out.

Association of immune-related adverse events with durvalumab efficacy after chemoradiotherapy in patients with unresectable Stage III non-small cell lung cancer.

Immune-related adverse events (irAEs) have been found to predict PD-L1 inhibitor efficacy in metastatic NSCLC. However, the relation of irAEs to clinical outcome for nonmetastatic NSCLC has remained unknown. In this multicenter prospective study of Stage III NSCLC treated with PACIFIC regimen, the relation of irAEs to PFS was evaluated by 8-week landmark analysis to minimise lead-time bias as well as by multivariable analysis adjusted for baseline factors. irAEs were categorised as mild or nonmild according to whether they were treated with systemic steroid. Median PFS was 16.0 months, not reached, and 9.7 months for patients without (85 cases) or with mild (21 cases) or nonmild (21 cases) irAEs, respectively. Multivariable analysis indicated that nonmild irAEs were associated with poor PFS, with HRs of 3.86 (95% CI, 1.31-11.38) compared with no irAEs and 11.58 (95% CI, 2.11-63.63) compared with mild irAEs. This pattern was consistent after irAE grade, the number of durvalumab doses and immune profiles (PD-L1 score, CD8+ tumour-infiltrating lymphocyte density, and tumour mutation burden) were taken into consideration. The development of mild irAEs might predict a better survival outcome, whereas immunosuppressive steroid-treated irAEs were associated with a worse outcome, regardless of baseline clinical and immune profiles.

The factors impacting on Gleason score upgrading in prostate cancer with initial low Gleason scores

BackgroundThis study aims to investigate the factors contributing to the discrepancy in between biopsy Gleason score (GS) and radical prostatectomy GS in patients diagnosed with prostate cancer. Methods341 patients who underwent radical prostatectomy from 2011/04 to 2020/12 were identified. 102 Patients with initial GS of six after biopsy were enrolled. Preoperative clinical variables and pathological variables were also obtained and assessed. The optimal cut-off points for significant continuous variables were identified by the area under the receiver operating characteristic curve. ResultsUpgrading was observed in 63 patients and non-upgrading in 39 patients. In the multiple variables assessed, smaller prostate volume (PV) (p value = 0.0007), prostate specific antigen density (PSAD) (p value = 0.0055), positive surgical margins (p value = 0.0062) and pathological perineural invasion (p value = 0.0038) were significant predictors of GS upgrading. To further explore preclinical variables, a cut-off value for PV (≤ 38 ml, p value = 0.0017) and PSAD (≥ 0.26 ng/ml2, p value = 0.0013) were identified to be associated with GS upgrading. ConclusionsSmaller PV and elevated PSAD are associated with increased risk of GS upgrading, whereas lead-time bias is not. A cut-off value of PV < 38 ml and PSAD > 0.26 ng/ml2 were further identified to be associated with pathological GS upgrading.