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Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M24-0887.

Competing Interests: Competing interests: None declared.

Background: In the past, patients were only diagnosed with cancer because they had symptoms. Now, because of screening and incidental detection, some patients are diagnosed with cancer when they are asymptomatic. While this shift is typically viewed as desirable, it has produced an unfortunate side-effect: it is now possible to be diagnosed with a cancer not destined to cause symptoms or death-a phenomenon labeled as overdiagnosis., Content: We begin with a brief introduction to the heterogeneity of cancer progression: at one extreme, some cancers are already systemic by the time they are detectable; at the other, some grow extremely slowly or even regress. The ensuing sections describe the evidence that the pursuit of earlier detection has led to overdiagnosis. Although rarely confirmed in an individual, overdiagnosis is readily identifiable in a long-term follow-up of a randomized trial of screening. Furthermore, 2 population signatures for overdiagnosis exist: (a) rising incidence coupled with stable mortality and (b) rising early-stage incidence coupled with stable late-stage incidence. Finally, we review the misleading feedback produced by overdiagnosis-such as rising 5-year survival rates and more cancer survivors. This feedback is erroneously interpreted as reinforcing the value of early detection, encourages more screening/incidental detection and, ironically, promotes more overdiagnosis., Summary: Overdiagnosis is an unintended consequence of the desire to detect cancer early. Given the evolving understanding that tumor biology and host response are more relevant to prognosis than early vs late diagnosis, it is time to challenge the assertion that early diagnosis is always the best approach to curing cancer., (© Association for Diagnostics & Laboratory Medicine 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Cancer screening is often promoted as a means to save lives. The question of whether cancer screening truly saves lives is becoming increasingly relevant given the growing enthusiasm for multicancer detection blood tests (ie, liquid biopsies). It is possible in randomized clinical trials for screening to reduce deaths due to the targeted cancer without reducing deaths due to all causes. To explore the feasibility of powering studies for cancer-specific vs all-cause mortality, a series of sample size calculations was performed for selected cancers (breast, colorectal, liver, pancreas, and prostate) and for all cancers combined., Observations: Randomized clinical trials of screening for an individual cancer typically require 100 000 or more participants to test its effect on cancer-specific mortality. Testing all-cause mortality requires trials of more than a million participants. However, the sample size requirements change markedly when considering a randomized clinical trial of screening for all cancers, as is envisioned when using multicancer detection blood tests. In this setting, the question of whether cancer screening reduces all-cause mortality can be reasonably addressed in a trial of fewer than 100 000 participants., Conclusions and Relevance: It is not feasible to test all-cause mortality when screening for an individual cancer. However, it is feasible to test all-cause mortality for multicancer screening because cancer deaths are such a large component of deaths in general. Observational data on the effects of cancer screening are misleading. Multicancer screening would entail tremendous costs and potentially substantial harms. For these reasons, a randomized clinical trial is mandatory not only to learn if multicancer screening saves lives, but also to learn how frequently it causes harm.

Importance: There has been great enthusiasm for the emerging technology of molecular-based tests to detect and quantify tumor DNA circulating in the bloodstream, colloquially known as a liquid biopsy. However, less attention has been given to how their clinical utility depends on the indication for testing, which includes a range of clinical situations, each presenting unique challenges., Observations: Five indications for circulating tumor DNA (ctDNA) blood testing were considered. (1) For therapy selection, ctDNA tests can identify genetic alterations in patients with cancer amenable to targeted therapy, but most patients do not have a targetable alteration. (2) For response to therapy, the absence of residual tumor DNA following cancer surgery could reduce the use of adjuvant chemotherapy, but it is unclear that this will happen in practice. (3) For disease surveillance following cancer treatment, ctDNA tests may well detect cancer recurrence before symptoms appear, yet earlier intervention may have no effect on mortality. (4) For diagnosis of suspected cancer, ctDNA tests are able to identify some symptomatic cancers, but how they add to the conventional diagnostic evaluation is unknown. (5) For screening for cancer, multicancer tests can detect many types of cancer, but their low sensitivity for early-stage tumors raises questions as to whether screening can help patients live longer or live better., Conclusions and Relevance: Circulating tumor DNA tests are being promoted for multiple indications. Numerous studies are ongoing, but randomized clinical trials of their effect on patient-centered outcomes are rare. While these tests have the potential to improve care in selected indications, this must be proven, as they will add cost, complexity, and unintended adverse effects for patients.

The NHS Long Term Plan for cancer aims to increase early-stage diagnoses from 50% to 75% and to have 55,000 more people each year survive their cancer for at least 5 years following diagnosis. The targets measures are flawed and could be met without improving outcomes that really matter to patients. The proportion of early-stage diagnoses could increase, while the number of patients presenting at a late-stage remains the same. More patients could survive their cancer for longer, but lead time and overdiagnosis bias make it impossible to know whether anyone had their life prolonged. The target measures should switch from biased case-based measures to unbiased population-based measures that reflect the key objectives in cancer care: reducing late-stage incidence and mortality., (© 2023. The Author(s).)

Importance: Although UV radiation exposure is the conventionally reported risk factor for cutaneous melanoma, an alternative exposure is diagnostic scrutiny: the more physicians look for and biopsy moles, the more melanoma they find., Objective: To assess the association of proxies for UV radiation exposure and diagnostic scrutiny with geographical patterns of melanoma incidence., Design, Setting, and Participants: This was a cross-sectional ecological analysis of the 727 continental US counties reporting to the Surveillance, Epidemiology, and End Results (SEER) Program (among a total of 3108 counties). Environmental data relevant to UV radiation exposure (from a variety of sources), Health Resources and Services Administration data relevant to diagnostic scrutiny, and SEER data on melanoma incidence among the non-Hispanic White population diagnosed with melanoma from 2012 through 2016 were combined. Data analysis was performed between January 2020 and July 2022., Exposures: Three UV radiation proxies (UV daily dose, cloud variability, and temperature variability) and 3 diagnostic scrutiny proxies (median household income, dermatologists, and primary care physician supply)., Main Outcomes and Measures: Melanoma incidence (in situ and invasive cancers)., Results: In total, 235 333 melanomas were diagnosed. Proxies for UV radiation exposure changed gradually across geography, while melanoma incidence and proxies for diagnostic scrutiny changed abruptly across contiguous counties. The UV daily dose, a variable the National Cancer Institute specifically developed for melanoma analyses, was uncorrelated with incidence (r = 0.03; P = .42). For context, smoking prevalence was highly correlated with lung cancer incidence in the same counties (r = 0.81; P < .001). Melanoma incidence was correlated with median household income (r = 0.43; P < .001). Counties with no dermatologists and shortages of primary care physicians had the lowest incidence, while counties amply supplied with both had the highest, despite having lower mean UV daily dose. There was little association between melanoma incidence and melanoma mortality (r = 0.09; P = .05), while the analogous association in lung cancer was strong (r = 0.96; P < .001)., Conclusions and Relevance: In this cross-sectional ecological study, the current geographical pattern of melanoma incidence across US counties was less associated with proxies for UV radiation exposure and more so with proxies for diagnostic scrutiny. Incidence-the fundamental epidemiologic measure of disease frequency-now had little association with the feared outcome of melanoma: death.

Importance: The incidence of cutaneous melanoma has been rising rapidly among White patients in the US; however, a commensurate increase in mortality due to melanoma has not been observed. These trends suggest overdiagnosis is occurring., Objective: To quantify melanoma overdiagnosis among White patients compared with Black patients in the US., Design, Setting, and Participants: This cohort study used joinpoint regression of Surveillance, Epidemiology, and End Results data from 1975 to 2014 to determine melanoma incidence and mortality trends among Black and White patients in the US. Using trends in mortality due to melanoma in Black patients as a marker for improvements in medical care, the expected mortality trends in White patients if medical care had not improved were estimated. This served as a marker for the change in true cancer occurrence. Overdiagnosis was calculated as the difference between observed incidence and estimated true cancer occurrence. Analyses were stratified by sex. Data were analyzed from September to December 2017., Main Outcomes and Measures: Proportion of melanoma cases overdiagnosed among White patients in 2014., Results: From 1975 to 2014, melanoma incidence increased approximately 4-fold in White women (incidence rate ratio [IRR], 4.01 [95% CI, 3.65-4.41]) and 6-fold in White men (IRR, 5.97 [95% CI, 5.47-6.52]), whereas it increased less than 25% in Black women (IRR, 1.21 [95% CI, 0.97-1.49]) and men (IRR, 1.17; [95% CI, 0.77-1.78]). Mortality due to melanoma decreased approximately 25% in Black women (morality rate ratio [MRR], 0.76 [95% CI, 0.63-0.90]) and men (MRR, 0.72 [95% CI, 0.62-0.84]), was stable in White women (MRR, 1.02 [95% CI, 0.96-1.09]), and increased almost 50% in White men (MRR, 1.49 [95% CI, 1.25-1.77]). Had medical care not improved, estimated mortality would have increased 60% in White women and more than doubled in White men. Based on these trends, an estimated 59% (95% CI, 45%-70%) of White women and 60% (95% CI, 32%-75%) of White men with melanoma were overdiagnosed in 2014., Conclusions and Relevance: The discrepancies in incidence and mortality trends found in this cohort study suggest considerable overdiagnosis of melanoma occurring among White patients in the US.

Importance: As smoking continues to decline in many developed countries, the proportion of lung cancers in nonsmokers will rise. This shift may create substantial pressure to further expand lung cancer screening to lower-risk groups., Objective: To determine the association of lung cancer incidence with the promotion of screening in a largely nonsmoking population., Design, Setting, and Participants: This population-based ecological cohort study of stage-specific lung cancer incidence used the Taiwan Cancer Registry to identify women diagnosed with lung cancer from January 1, 2004, to December 31, 2018. Smoking prevalence among Taiwanese women has been less than 5% since 1980. Data were analyzed from February 13, 2020, to November 10, 2021., Exposures: Low-dose computed tomography (LDCT) screening for lung cancer, initiated during the early 2000s., Main Outcomes and Measures: Change in stage-specific lung cancer incidence. An effective cancer screening program will not only increase the incidence of early-stage cancer but also decrease the incidence of cancer presenting at a late stage., Results: A total of 57 898 women were diagnosed with lung cancer in a population of approximately 12 million Taiwanese women. After the introduction of LDCT screening, the incidence of early-stage (stages 0-I) lung cancer in women increased more than 6-fold, from 2.3 to 14.4 per 100 000 population (absolute difference, 12.1 [95% CI, 11.3-12.8]) from 2004 to 2018. There was no change, however, in the incidence of late-stage (stages II-IV) lung cancer, from 18.7 to 19.3 per 100 000 (absolute difference, 0.6 [95% CI, -0.5 to 1.7]). Because the additional 12.1 per 100 000 early-stage cancers were not accompanied by a concomitant decline in late-stage cancers, virtually all the additional cancers detected represent overdiagnosis. Despite stable mortality, 5-year survival more than doubled from 2004 to 2013, from 18% to 40%, which is arguably the highest lung cancer survival rate in the world., Conclusions and Relevance: This population-based ecological cohort study found that low-dose computed tomographic screening of mostly nonsmoking Asian women was associated with considerable lung cancer overdiagnosis. Five-year survival is biased by the increased LDCT detection of indolent early-stage lung cancers. Unless randomized trials can demonstrate some value to low-risk groups, LDCT screening should remain targeted only to heavy smokers.

A randomized trial of the GRAIL Galleri TM multi-cancer screening test is being planned for the National Health Service in England, and will have 140,000 healthy participants aged 50-79: 70,000 exposed to screening and 70,000 unexposed. The test reportedly detects 50 different cancers and is expected to reduce all-cancer mortality by approximately 25%. Given this effect size-and that cancer deaths constitute a large fraction of all deaths-the trial is sufficiently large to test the effect on all-cause mortality. Because most patients believe cancer screening "saves lives", the GRAIL/National Health Service collaboration could set the evaluation standard for multi-cancer screening.

Background: During the height of the coronavirus disease 2019 (COVID-19) pandemic, elective surgeries, including oncologic surgeries, were delayed. Little prospective data existed to guide practice, and professional surgical societies issued recommendations grounded mainly in common sense and expert consensus, such as medical therapy for early-stage breast and prostate cancer patients. To understand the patient experience of delay in cancer surgery during the pandemic, we interviewed breast and prostate cancer patients whose surgeries were delayed due to the pandemic., Patients and Methods: Patients with early-stage breast or prostate cancer who suffered surgical postponement at Brigham and Women's Hospital (BWH) were invited to participate. Semi-structured telephone interviews were conducted with 21 breast and prostate cancer patients. Interviews were transcribed, and qualitative analysis using ground-theory approach was performed., Results: Most patients reported significant distress due to cancer and COVID. Key themes that emerged included the lack of surprise and acceptance of the surgical delays but endorsed persistent cancer- and delay-related worries. Satisfaction with patient-physician communication and the availability of a delay strategy were key factors in patients' acceptance of the situation; perceived lack of communication prompted a few patients to seek care elsewhere., Discussion: The clinical effect of delay in cancer surgery will take years to fully understand, but there are immediate steps that can be taken to improve the patient experience of delays in care, including elicitation of individual patient perspectives and ongoing communication. More work is needed to understand the wider experiences of patients, especially minority, socioeconomically disadvantaged, and uninsured patients, who encounter delays in oncologic care., (© 2021. Society of Surgical Oncology.)

Background: Individuals with carotid stenosis enter surveillance or are considered for surgery on the basis of disease severity assessed by ultrasound. However, there is variation in the ultrasound diagnostic thresholds used to determine disease severity. Our objective was to describe this variation and its potential impact on patients., Methods: To describe the variation in carotid ultrasound diagnostic thresholds, we examined testing protocols from 338 accredited vascular testing centers in the United States. To determine the potential impact of this variation, we applied the range of thresholds to carotid ultrasound parameters from 2 groups: a population-based sample ≥65 years of age in the Cardiovascular Health Study (n=4791), and a cohort of patients who underwent surgery for asymptomatic carotid stenosis in the Vascular Quality Initiative registry (n=28 483)., Results: Internal carotid artery peak systolic velocity was used by all centers to assess disease severity, with 60 distinct thresholds in use. The peak systolic velocity threshold for moderate (≥50%) stenosis ranged from 110 to 245 cm/s (median, 125; 5th and 95th percentile, 125 and 150), and the threshold for severe (≥70%) stenosis ranged from 175 to 340 cm/s (median, 230; 5th and 95th percentile, 230 and 275). In the population-based sample, the 5th percentile threshold would assign a diagnosis of moderate carotid stenosis to twice as many individuals as the 95th percentile threshold (7.9% versus 3.9%; relative risk, 2.01 [CI, 1.70-2.38]). In the surgical cohort, 1 in 10 (9.8%) patients had peak systolic velocity values that warranted the diagnosis of severe carotid stenosis at centers in the 5th percentile, but not in the 95th., Conclusions: The diagnostic threshold for carotid stenosis varies considerably. Whether or not a person is said to have moderate stenosis and enters surveillance, and whether or not they have severe stenosis and are candidates for surgery, can depend on which center performs their ultrasound.

Importance: While computed tomography (CT) represents a tremendous advance in diagnostic imaging, it also creates the problem of incidental detection-the identification of tumors unrelated to the clinical symptoms that initiate the test., Objective: To determine the geographic variation in the United States in CT imaging and the corresponding association with one of the most consequential sequelae of incidental detection: nephrectomy., Design, Setting, and Participants: This study is a cross-sectional analysis of age-, sex-, and race-adjusted Medicare data (January 2010-December 2014) from 306 hospital referral regions (HRRs) in the United States and includes information from 15 million fee-for-service Medicare beneficiaries age 65 to 85 years., Exposures: Regional CT risk (ie, the proportion of the population receiving either a chest or abdominal CT over 5 years)., Main Outcomes and Measures: Five-year risk of nephrectomy (partial or total)., Results: Data from 15 million fee-for-service Medicare beneficiaries age 65 to 85 years were gathered and illustrate that 43% of Medicare beneficiaries age 65 to 85 years received either a chest or abdominal CT from January 2010 to December 2014. This risk varied across the HRRs, ranging from 31% in Santa Cruz, California, to 52% in Sun City, Arizona. Increased regional CT risk was associated with a higher nephrectomy risk (r = 0.38; 95% CI, 0.28-0.47), particularly among HRRs with more than 50 000 beneficiaries (r = 0.47; 95% CI, 0.31-0.61). After controlling for HRR adult smoking rates, imaging an additional 1000 beneficiaries was associated with 4 additional nephrectomies (95% CI, 3-5). Case-fatality rates for those who underwent nephrectomy were 2.1% at 30 days and 4.3% at 90 days., Conclusions and Relevance: Fee-for-service Medicare beneficiaries are commonly exposed to CT imaging. Those residing in high-scanning regions face a higher risk of nephrectomy, presumably reflecting the incidental detection of renal masses. Additional surgery should be considered one of the risks of excessive CT imaging.

Competing Interests: Contributors and sources: HGW has studied and reported extensively on overdiagnosis. BH has scrutinised the role of technology in healthcare. Both authors have contributed to the design of the study, data collection, data analysis, revision of the manuscript and both have approved the final manuscript. BH is the guarantor for this study. Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following: BH has received funding from the Commonwealth Fund through the Harkness Fellowship at the Dartmouth Institute of Health Policy and Clinical Practice for part of this work. The views presented here are those of the author and not necessarily those of the Commonwealth Fund, their directors, officers, or staff or of the Dartmouth Institute. Neither BH or HGW have any relationships with any companies that might have an interest in the submitted work in the previous three years; their spouses, partners, or children have any financial relationships that may be relevant to the submitted work; and BH and HGW have no non-financial interests that may be relevant to the submitted work.

Background: The goal of screening mammography is to detect small malignant tumors before they grow large enough to cause symptoms. Effective screening should therefore lead to the detection of a greater number of small tumors, followed by fewer large tumors over time., Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER) program, 1975 through 2012, to calculate the tumor-size distribution and size-specific incidence of breast cancer among women 40 years of age or older. We then calculated the size-specific cancer case fatality rate for two time periods: a baseline period before the implementation of widespread screening mammography (1975 through 1979) and a period encompassing the most recent years for which 10 years of follow-up data were available (2000 through 2002)., Results: After the advent of screening mammography, the proportion of detected breast tumors that were small (invasive tumors measuring <2 cm or in situ carcinomas) increased from 36% to 68%; the proportion of detected tumors that were large (invasive tumors measuring ≥2 cm) decreased from 64% to 32%. However, this trend was less the result of a substantial decrease in the incidence of large tumors (with 30 fewer cases of cancer observed per 100,000 women in the period after the advent of screening than in the period before screening) and more the result of a substantial increase in the detection of small tumors (with 162 more cases of cancer observed per 100,000 women). Assuming that the underlying disease burden was stable, only 30 of the 162 additional small tumors per 100,000 women that were diagnosed were expected to progress to become large, which implied that the remaining 132 cases of cancer per 100,000 women were overdiagnosed (i.e., cases of cancer were detected on screening that never would have led to clinical symptoms). The potential of screening to lower breast cancer mortality is reflected in the declining incidence of larger tumors. However, with respect to only these large tumors, the decline in the size-specific case fatality rate suggests that improved treatment was responsible for at least two thirds of the reduction in breast cancer mortality., Conclusions: Although the rate of detection of large tumors fell after the introduction of screening mammography, the more favorable size distribution was primarily the result of the additional detection of small tumors. Women were more likely to have breast cancer that was overdiagnosed than to have earlier detection of a tumor that was destined to become large. The reduction in breast cancer mortality after the implementation of screening mammography was predominantly the result of improved systemic therapy.