Cancer screening in China: a steep road from evidence to implementation.

Cancer screening has the potential to decrease mortality from several common cancer types. The first cancer screening programme in China was initiated in 1958 and the Cancer High Incidence Fields established in the 1970s have provided an extensive source of information for national cancer screening programmes. From 2012 onwards, four ongoing national cancer screening programmes have targeted eight cancer types: cervical, breast, colorectal, lung, oesophageal, stomach, liver, and nasopharyngeal cancers. By synthesising evidence from pilot screening programmes and population-based studies for various screening tests, China has developed a series of cancer screening guidelines. Nevertheless, challenges remain for the implementation of a fully successful population-based programme. The aim of this Review is to highlight the key milestones and the current status of cancer screening in China, describe what has been achieved to date, and identify the barriers in transitioning from evidence to implementation. We also make a set of implementation recommendations on the basis of the Chinese experience, which might be useful in the establishment of cancer screening programmes in other countries.

Cancer overdiagnosis: a challenge in the era of screening.

"Screening" is a search for preclinical, asymptomatic disease, including cancer. Widespread cancer screening has led to large increases in early-stage cancers and pre-cancers. Ubiquitous public messages emphasize the potential benefits to screening for these lesions based on the underlying assumption that treating cancer at early stages before spread to other organs should make it easier to treat and cure, using more tolerable interventions. The intuition is so strong that public campaigns are sometimes launched without conducting definitive trials directly comparing screening to usual care. An effective cancer screening test should not only increase the incidence of early-stage preclinical disease but should also decrease the incidence of advanced and metastatic cancer, as well as a subsequent decrease in cancer-related mortality. Otherwise, screening efforts may be uncovering a reservoir of non-progressive and very slowly progressive lesions that were not destined to cause symptoms or suffering during the person's remaining natural lifespan: a phenomenon known as "overdiagnosis." We provide here a qualitative review of cancer overdiagnosis and discuss specific examples due to extensive population-based screening, including neuroblastoma, prostate cancer, thyroid cancer, lung cancer, melanoma, and breast cancer. The harms of unnecessary diagnosis and cancer therapy call for a balanced presentation to people considering undergoing screening, even with a test of accepted benefit, with a goal of informed decision-making. We also discuss proposed strategies to mitigate the adverse sequelae of overdiagnosis.

Delivery of Financial Navigation Services Within National Cancer Institute-Designated Cancer Centers.

Background: Cancer centers have a responsibility to help patients manage the costs of their cancer treatment. This article describes the availability of financial navigation services within the National Cancer Institute (NCI)-designated cancer centers. Methods: Data were obtained from the NCI Survey of Financial Navigation Services and Research, an online survey administered to NCI-designated cancer centers from July to September 2019. Of the 62 eligible centers, 57 completed all or most of the survey, for a response rate of 90.5%. Results: Nearly all cancer centers reported providing help with applications for pharmaceutical assistance programs and medical discounts (96.5%), health insurance coverage (91.2%), assistance with nonmedical costs (96.5%), and help understanding medical bills and out-of-pocket costs (85.9%). Although other services were common, in some cases they were only available to certain patients. These services included direct financial assistance with medical and nonmedical costs and referrals to outside organizations for financial assistance. The least common services included medical debt management (63.2%), detailed discussions about the cost of treatment (54.4%), and guidance about legal protections (50.1%). Providing treatment cost transparency to patients was reported as a common challenge: 71.9% of centers agreed or strongly agreed that it is difficult to determine how much a cancer patient's treatment will cost, and 70.2% of oncologists are reluctant to discuss financial issues with patients. Conclusions: Cancer centers provide many financial services and resources. However, there remains a need to build additional capacity to deliver comprehensive financial navigation services and to understand the extent to which patients are referred and helped by these services.

DeImplementing Ineffective and Low-Value Clinical Practices: Research and Practice Opportunities in Community Oncology Settings.

Patients, practitioners, and policy makers are increasingly concerned about the delivery of ineffective or low-value clinical practices in cancer care settings. Research is needed on how to effectively deimplement these types of practices from cancer care. In this commentary, we spotlight the National Cancer Institute Community Oncology Research Program (NCORP), a national network of community oncology practices, and elaborate on how it is an ideal infrastructure for conducting rigorous, real-world research on deimplementation. We describe key multilevel issues that affect deimplementation and also serve as a guidepost for developing strategies to drive deimplementation. We describe optimal study designs for testing deimplementation strategies and elaborate on how and why the NCORP network is uniquely positioned to conduct rigorous and impactful deimplementation trials. The number and diversity of affiliated community oncology care sites, coupled with the overall objective of improving cancer care delivery, make the NCORP an opportune infrastructure for advancing deimplementation research while simultaneously improving the care of millions of cancer patients nationwide.

Simple Methods for Evaluating 4 Types of Biomarkers: Surrogate Endpoint, Prognostic, Predictive, and Cancer Screening.

We review simple methods for evaluating 4 types of biomarkers. First, we discuss the evaluation of surrogate endpoint biomarkers (to shorten a randomized trial) using 2 statistical and 3 biological criteria. Second, we discuss the evaluation of prognostic biomarkers (to predict the risk of disease) by comparing data collection costs with the anticipated net benefit of risk prediction. Third, we discuss the evaluation of predictive markers (to search for a promising subgroup in a randomized trial) using a multivariate subpopulation treatment effect pattern plot involving a risk difference or responders-only benefit function. Fourth, we discuss the evaluation of cancer screening biomarkers (to predict cancer in asymptomatic persons) using methodology to substantially reduce the sample size with stored specimens.

Thyroid Incidentalomas in Association With Low-Dose Computed Tomography in the National Lung Screening Trial.

Advances in cancer screening methods have opened avenues for incidental findings and cancer overdiagnosis. We performed a secondary analysis of the National Lung Screening Trial (enrollment from 2002-2004), a randomized controlled trial comparing low-dose computed tomography (LDCT; n = 26,722) with chest radiography (CXR; n = 26,732) for lung cancer detection, to examine incidental findings related to thyroid cancer (ThCa). Three screening rounds were included, and median follow-up was 6.6 years for LDCT and 6.5 years for CXR. Radiologists reported lung and non-lung-related abnormalities. In the LDCT arm, 5.7%, 4.7%, and 4.5% of participants had abnormalities above the diaphragm (AADs) detected at baseline, year 1, and year 2, respectively, compared with 2.3%, 1.5%, and 1.3% in the CXR arm. In the LDCT arm, 205 AADs (7.0%) were thyroid-related. Overall, 60 ThCas were reported, 35 in the LDCT arm and 25 in the CXR arm (P = 0.2). In the LDCT arm, participants with a prior AAD had a 7.8-fold increased risk (95% confidence interval: 4.0, 15.1) of ThCa compared with those who did not have an AAD. Early and persistent excess of ThCas diagnosed earlier in the LDCT arm suggests overdiagnosis. The use of sensitive screening modalities for early detection of lung cancer might result in the discovery of thyroid incidentalomas.

Cancer overdiagnosis: a biological challenge and clinical dilemma.

For cancer screening to be successful, it should primarily detect cancers with lethal potential or their precursors early, leading to therapy that reduces mortality and morbidity. Screening programmes have been successful for colon and cervical cancers, where subsequent surgical removal of precursor lesions has resulted in a reduction in cancer incidence and mortality. However, many types of cancer exhibit a range of heterogeneous behaviours and variable likelihoods of progression and death. Consequently, screening for some cancers may have minimal impact on mortality and may do more harm than good. Since the implementation of screening tests for certain cancers (for example, breast and prostate cancers), a spike in incidence of in situ and early-stage cancers has been observed, but a link to reduction in cancer-specific mortality has not been as clear. It is difficult to determine how many of these mortality reductions are due to screening and how many are due to improved treatments of tumours. In cancers with lower incidence but high mortality (for example, pancreatic cancer), screening has focused on high-risk populations, but challenges similar to those for general population screening remain, particularly with regard to finding lesions with difficult-to-characterize malignant potential (for example, intraductal papillary mucinous neoplasms). More sensitive screening methods are detecting smaller and smaller lesions, but this has not been accompanied by a comparable reduction in the incidence of invasive cancers. In this Opinion article, we focus on the contribution of screening in general and high-risk populations to overdiagnosis, the effects of overdiagnosis on patients and emerging strategies to reduce overdiagnosis of indolent cancers through an understanding of tumour heterogeneity, the biology of how cancers evolve and progress, the molecular and cellular features of early neoplasia and the dynamics of the interactions of early lesions with their surrounding tissue microenvironment.

AACR White Paper: Shaping the Future of Cancer Prevention - A Roadmap for Advancing Science and Public Health.

The recent pace, extent, and impact of paradigm-changing cancer prevention science has been remarkable. The American Association for Cancer Research (AACR) convened a 3-day summit, aligned with five research priorities: (i) Precancer Atlas (PCA). (ii) Cancer interception. (iii) Obesity-cancer linkage, a global epidemic of chronic low-grade inflammation. (iv) Implementation science. (v) Cancer disparities. Aligned with these priorities, AACR co-led the Lancet Commission to formally endorse and accelerate the NCI Cancer Moonshot program, facilitating new global collaborative efforts in cancer control. The expanding scope of creative impact is perhaps most startling-from NCI-funded built environments to AACR Team Science Awarded studies of Asian cancer genomes informing global primary prevention policies; cell-free epigenetic marks identifying incipient neoplastic site; practice-changing genomic subclasses in myeloproliferative neoplasia (including germline variant tightly linked to JAK2 V617F haplotype); universal germline genetic testing for pancreatic cancer; and repurposing drugs targeting immune- and stem-cell signals (e.g., IL-1ß, PD-1, RANK-L) to cancer interception. Microbiota-driven IL-17 can induce stemness and transformation in pancreatic precursors (identifying another repurposing opportunity). Notable progress also includes hosting an obesity special conference (connecting epidemiologic and molecular perspectives to inform cancer research and prevention strategies), co-leading concerted national implementation efforts in HPV vaccination, and charting the future elimination of cancer disparities by integrating new science tools, discoveries and perspectives into community-engaged research, including targeted counter attacks on e-cigarette ad exploitation of children, Hispanics and Blacks. Following this summit, two unprecedented funding initiatives were catalyzed to drive cancer prevention research: the NCI Cancer Moonshot (e.g., PCA and disparities); and the AACR-Stand Up To Cancer bold "Cancer Interception" initiative.

Overall and Multiphasic Findings of the Prostate, Lung, Colorectal and Ovarian (PLCO) Randomized Cancer Screening Trial.

BACKGROUND: Screening tests are typically evaluated for a single disease, but multiple tests for multiple diseases are performed in practice. The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial assessed testing for four cancers simultaneously and can be viewed as a multiphasic cancer intervention. This paper presents overall and multiphasic findings of this trial. METHODS: The PLCO trial was a randomized multi-center trial conducted at ten screening centers in the US. Participants were 76,682 men and 78,215 women ages 55 - 74 and free of the target cancers at trial entry. Screening tests were PSA and digital rectal examination for prostate cancer, chest x-ray for lung cancer, flexible sigmoidoscopy for colorectal cancer, CA125 and transvaginal ultrasound for ovarian cancer. Outcomes and harms of screening were assessed including compliance, test results, incidence, mortality, false positives and overdiagnosis. RESULTS: Screening compliance was 82%, 72,820 (8%) of 906,064 exams were positive, the overall PPV was 4.2% and the cancer detection rate was 3.38/1000. A mortality reduction was observed only for colorectal cancer (RR 0.72, 95% CI 0.61 - 0.85) with no effect on all-cause mortality. Ninety-six percent of positive exams were falsely positive and there was a suggestion of overdiagnosis of prostate and possibly ovarian cancers. Multiphasic testing resulted in 7374 men and 2748 women experiencing multiple false positive results from multiple types of tests. CONCLUSION: Multiphasic cancer screening led to reduced mortality for one target cancer and imposed a burden on the health care system that included substantial false positives and likely overdiagnosis.

Validation: a critical step in bringing biomarkers to clinical fruition.

Screening is vital to reducing morbidity and mortality due to cancer. A primary cause of poor survival is that many cancers are detected late and often after they have metastasized to distant sites. Therapies, therefore, become challenging for late-stage disease and are not successful for nearly all cancer types. The mortality rates from cancers where screening tools are available are lower than from cancers for which no viable screening tools exist. Even for cancers where screening tools currently exist, there is room for improvement, either in the accuracy of the tests or in increasing widespread use of screening by making the tests less invasive. For instance, despite widely available screening methods that can detect early-stage colon cancer or its precursors, only approximately 40% of newly diagnosed colon cancers are localized. It is a challenge to develop screening tests that are not only highly sensitive but also highly specific, to avoid putting patients through unnecessary biopsies and treatment. Biomarkers have great potential to improve the existing diagnostic accuracies of screening modalities and substitute invasive screening methods with noninvasive methodologies using bodily fluids such as plasma, serum, saliva, urine, etc. Biomarkers are defined by the National Institutes of Health as "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention." In this commentary, we discuss important measures that could be taken to increase the chances of bringing biomarkers to clinical fruition.

Incidental renal tumours on low-dose CT lung cancer screening exams.

Introduction Renal cancer incidence has increased markedly in the United States in recent decades, largely due to incidentally detected tumours from computed tomography imaging. Here, we analyze the potential for low-dose computed tomography lung cancer screening to detect renal cancer. Methods The National Lung Screening Trial randomized subjects to three annual screens with either low-dose computed tomography or chest X-ray. Eligibility criteria included 30 + pack-years, current smoking or quit within 15 years, and age 55-74. Subjects were followed for seven years. Low-dose computed tomography screening forms collected information on lung cancer and non-lung cancer abnormalities, including abnormalities below the diaphragm. A reader study was performed on a sample of National Lung Screening Trial low-dose computed tomography images assessing presence of abnormalities below the diaphragms and abnormalities suspicious for renal cancer. Results There were 26,722 and 26,732 subjects enrolled in the low-dose computed tomography and chest X-ray arms, respectively, and there were 104 and 85 renal cancer cases diagnosed, respectively (relative risk = 1.22, 95% CI: 0.9-1.5). From 75,126 low-dose computed tomography screens, there were 46 renal cancer diagnoses within one year. Abnormalities below the diaphragm rates were 39.1% in screens with renal cancer versus 4.1% in screens without (P < 0.001). Cases with abnormalities below the diaphragms had shorter median time to diagnosis than those without (71 vs. 160 days, P = 0.004). In the reader study, 64% of renal cancer cases versus 13% of non-cases had abnormalities below the diaphragms; 55% of cases and 0.8% of non-cases had a finding suspicious for renal cancer (P < 0.001). Conclusion Low-dose computed tomography screens can potentially detect renal cancers. The benefits to harms tradeoff of incidental detection of renal tumours on low-dose computed tomography is unknown.