The pros and cons of lung cancer screening.

Several trials have shown that low-dose computed tomography-based lung cancer screening (LCS) allows a substantial reduction in lung cancer-related mortality, carrying the potential for other clinical benefits. There are, however, some uncertainties to be clarified and several aspects to be implemented to optimize advantages and minimize the potential harms of LCS. This review summarizes current evidence on LCS, discussing some of the well-established and potential benefits, including lung cancer (LC)-related mortality reduction and opportunity for smoking cessation interventions, as well as the disadvantages of LCS, such as overdiagnosis and overtreatment. CLINICAL RELEVANCE STATEMENT: Different perspectives are provided on LCS based on the updated literature. KEY POINTS: Lung cancer is a leading cancer-related cause of death and screening should reduce associated mortality. This review summarizes current evidence related to LCS. Several aspects need to be implemented to optimize benefits and minimize potential drawbacks of LCS.

Neglected impacts of patient decision-making associated with genetic testing.

We highlight non-health-related impacts associated with genetic testing (GT) and knowing one's genetic status so that health technology assessment (HTA) analysts and HTA audiences may more appropriately consider the pros and cons of GT. Whereas health-related impacts of GT (e.g., increased healthy behaviors and avoidance of harms of unnecessary treatment) are frequently assessed in HTA, some non-health-related impacts are less often considered and are more difficult to measure. This presents a challenge for accurately assessing whether a genetic test should be funded. In health systems where HTA understandably places emphasis on measurable clinical outcomes, there is a risk of creating a GT culture that is pro-testing without sufficient recognition of the burdens of GT. There is also a risk of not funding a genetic test that provides little clinical benefit but nonetheless may be seen by some as autonomy enhancing. The recent development of expanded HTA frameworks that include ethics analyses helps to address this gap in the evidence and bring awareness to non-health-related impacts of GT. The HTA analyst should be aware of these impacts, choose appropriate frameworks for assessing genetic tests, and use methods for evaluating impacts. A new reporting tool presented here may assist in such evaluations.

Clinicians' perspectives on diagnosing polycystic ovary syndrome in Australia: a qualitative study.

STUDY QUESTION: What are clinicians' views about the diagnosis of polycystic ovary syndrome (PCOS), and how do they handle any complexities and uncertainties in practice? SUMMARY ANSWER: Clinicians have to navigate many areas of complexity and uncertainty regarding the diagnosis of PCOS, related to the diagnostic criteria, limitations in current evidence and misconceptions surrounding diagnosis, and expressed concern about the risk and consequences of both under- and overdiagnosis. WHAT IS KNOWN ALREADY: PCOS is a complex, heterogeneous condition with many areas of uncertainty, raising concerns about both underdiagnosis and overdiagnosis. Quantitative studies with clinicians have found considerable variation in diagnostic criteria used and care provided, as well as a lack of awareness around the breadth of PCOS features and poor uptake of recommended screening for metabolic complications. Clinicians' views about the uncertainties and complexities of diagnosing PCOS have not been explored. STUDY DESIGN, SIZE, DURATION: Semi-structured telephone interviews were conducted with clinicians from September 2017 to July 2018 to explore their perceptions about the diagnosis of PCOS, including how they handle any complexities and uncertainties in practice. PARTICIPANTS/MATERIALS, SETTING, METHODS: A group of 36 clinicians (15 general practitioners, 10 gynaecologists and 11 endocrinologists) currently practicing in Australia, were recruited through advertising via professional organisations, contacting a random sample of endocrine and gynaecology teams across Australia and snowballing. Transcribed audio-recordings were analysed thematically using Framework analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Clinicians expressed a range of uncertainties and complexities regarding the diagnosis of PCOS, which were organised into three areas: (i) establishing diagnosis (e.g. lack of standardisation regarding diagnostic cut-offs, risk of misdiagnosis), (ii) factors influencing the diagnostic process (e.g. awareness of limitations in evidence and consideration of the benefits and harms) and (iii) strategies for handling challenges and uncertainties (e.g. using caution and communication of uncertainties). Clinicians also varied in their concerns regarding under- and overdiagnosis. Overall, most felt the diagnosis was beneficial for women provided that it was the correct diagnosis and time was taken to assess patient expectations and dispel misconceptions, particularly concerning fertility. LIMITATIONS, REASONS FOR CAUTION: There is possible selection bias, as clinicians who are more knowledgeable about PCOS may have been more likely to participate. Clinicians' views may also differ in other countries. WIDER IMPLICATIONS OF THE FINDINGS: These findings underscore the vital need to first consider PCOS a diagnosis of exclusion and use caution before giving a diagnosis in order to reduce misdiagnosis, as suggested by clinicians in our study. Until there is greater standardisation of diagnostic criteria, more transparent conversations with women may help them understand the uncertainties surrounding the criteria and limitations in the evidence. Additionally, clinicians emphasised the importance of education and reassurance to minimise the potential harmful impact of the diagnosis and improve patient-centred outcomes. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the University of Sydney Lifespan Research Network and an NHMRC Program Grant (APP1113532). T.C. is supported by an Australian Government Research Training Program (RTP) Scholarship and a Sydney Medical School Foundation Scholarship, from the The University of Sydney, Australia. B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA and Guerbet. No further competing interests exist. TRIAL REGISTRATION NUMBER: N/A.

Women's Benefits and Harms Trade-Offs in Breast Cancer Screening: Results from a Discrete-Choice Experiment.

BACKGROUND: Over the past decade, the benefits and harms balance of breast cancer (BC) screening has been widely debated. OBJECTIVES: To elicit women's trade-offs between the benefits and harms of BC screening and to analyze the main determinants of these trade-offs. METHODS: A discrete-choice experiment with seven attributes depicting BC screening programs including varying levels of BC mortality, overdiagnosis, and false-positive result was used. Eight hundred twelve women aged 40 to 74 years with no personal history of BC recruited by a survey institute and representative of the French general population (age, socioeconomic level, and geographical location) completed the discrete-choice experiment. Preference heterogeneity was investigated using generalized multinomial logit models from which individual trade-offs were derived, and their main determinants were assessed using generalized linear models. Screening acceptance rates under various benefits and harms ratios were simulated on the basis of the distribution of individual preferences. RESULTS: The women would be willing to accept on average 14.1 overdiagnosis cases (median = 9.6) and 47.8 false-positive results (median = 27.2) to avoid one BC-related death. After accounting for preference heterogeneity, less than 50% of women would be willing to accept 10 overdiagnosis cases for one BC-related death avoided. Screening acceptance rates were higher among women with higher socioeconomic level and lower among women with poor health. CONCLUSIONS: Women are sensitive to both the benefits and the harms of BC screening and their preferences are highly heterogeneous. Our study provides useful results for public health authorities and clinicians willing to improve their recommendations of BC screening on the basis of women's preferences.

Benefits and harms of breast cancer screening with mammography in women aged 40-49 years: A systematic review.

Early detection of breast cancer through screening can lower breast cancer mortality rates and reduce the burden of this disease in the population. In most western countries, mammography screening starting from age 50 is recommended. However, there is debate about whether breast cancer screening should be extended to younger women. This systematic review provides an overview of the evidence from RCTs on the benefits and harms of breast cancer screening with mammography in women aged 40-49 years. The quality of the evidence for each outcome was appraised using the GRADE approach. Four articles reporting on two different trials-the Age trial and the Canadian National Breast Screening Study-I (CNBSS-I)-were included. The results showed no significant effect on breast cancer mortality (Age trial: RR 0.93 (95% CI 0.80-1.09); CNBSS-I: HR 1.10 (95% CI 0.86-1.40)) nor on all-cause mortality (RR 0.98, 95% CI 0.93-1.03) in women aged 40-49 years offered screening. Among regularly attending women, the cumulative risk of experiencing a false-positive recall was 20.5%. Over-diagnosis of invasive breast cancer at 5 years post-cessation of screening for women aged 40-49 years was estimated to be 32% and at 20 years post-cessation of screening to be 48%. Including ductal carcinoma in situ, these numbers were 41% and 55%. Based on the current evidence from randomised trials, extending mammography screening to younger age groups cannot be recommended. However, there were limitations including relatively low sensitivity of screening and screening attendance, insufficient power, and contamination, which may explain the nonsignificant results.

German law on circumcision and its debate: how an ethical and legal issue turned political.

The article aims to illuminate the recent debate in Germany about the legitimacy of circumcision for religious reasons. The aim is both to evaluate the new German law allowing religious circumcision, and to outline the resulting conflict between the surrounding ethical and legal issues. We first elucidate the diversity of legal and medical views on religious circumcision in Germany. Next we examine to what extent invasive and irreversible physical interventions on infant boys unable to given their consent should be carried out for non-medical reasons. To this end, the potential benefits and harms of circumcision for non-medical reasons are compared. We argue that circumcision does not provide any benefits for the 'child as a child' and poses only risks to boys. We then set out to clarify and analyse political (rather than ethical) justifications of the new circumcision law. We demonstrate through this analysis how the circumcision debate in Germany has been transformed from a legal and ethical problem into a political issue, due at least in part to Germany's unique historical context. Although such a particular political sensibility is entirely comprehensible, it raises particular problems when it comes to framing and responding to medical ethical issues - as in the case of religious circumcision.

Patient-Centered Practice Guidelines: GRADEing Evidence to Incorporate Certainty, Balance Between Benefits and Harms, Equity, Feasibility, and Cost-Effectiveness.

The practice of medicine in recent years has emphasized the use of evidence-based clinical guidelines to help inform treatment decisions. Since its development in 2004, the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach has offered a systematic process for reviewing and summarizing the certainty of evidence found in the medical literature regarding various treatment options. To develop truly patient-centered care guidelines, this appraisal of the certainty of evidence must be combined with an understanding of the balance between benefits and harms, patient preferences, equity, feasibility, cost-effectiveness, and policy implications. This review examines each of these domains in detail, exploring the process and benefits of developing relevant, patient-focused guidelines directly applicable to the practice of modern medicine.

When describing harms and benefits to potential trial participants, participant information leaflets are inadequate.

BACKGROUND: Providing informed consent for trials requires providing trial participants with comprehensive information about the trial, including information about potential risks and benefits. It is required by the ethical principle of respecting patient autonomy. Our study examines the variation in the way information about potential trial benefits and harms is shared in participant information leaflets (PILs). METHODS: A total of 214 PILs and informed consent forms from clinical trials units (CTUs) and Clinical Research Facilities (CRFs) in Ireland and the UK were assessed by two authors independently, to check the extent to which they adhered to seven recently developed principles. Discrepancies were resolved by a third. RESULTS: Usage of the seven principles varied widely between PILs regardless of the intended recipient or trial type. None of the PILs used more than four principles, and some (4%) used none. Twenty-seven per cent of PILs presented information about all known potential harms, whereas 45% presented information on all known potential benefits. Some PILs did not provide any potential harms or potential benefits (8%). There was variation in the information contained in adult and children PILs and across disease areas. CONCLUSION: Significant variation exists in how potential trial benefits and harms are described to potential trial participants in PILs in our sample. Usage of the seven principles of good practice will promote consistency, ensure informed ethical decision-making and invoke trust and transparency. In the long term, a standardised PIL template is needed.

Psychosocial consequences of a three-month follow-up after receiving an abnormal lung cancer CT-screening result: A longitudinal survey.

BACKGROUND: Participation in lung cancer CT-screening can be associated with a need for follow-up procedures. The screening and waiting for test results introduce the risk of experiencing psychosocial consequences. Therefore, the aims of this study were: 1) To investigate if the psychosocial consequences changed from before an annual screening round to before a three-month follow-up CT-scan in participants with a positive screening result. 2) To investigate potential differences in psychosocial consequences between false positives (FP) and true positives (TP). FP were defined as those where cancer was not confirmed in the follow-up CT-scan and TP where it was. MATERIALS AND METHODS: This longitudinal study was based on data from the Danish Lung Cancer Screening Trial (DLCST). The Consequences of Screening - Lung cancer (COS-LC) questionnaire was used to measure psychosocial consequences among 130 participants who all received an abnormal CT-screening result at their annual screening round. Eligible participants completed the COS-LC before their annual CT-screening and before the three-month follow-up. RESULTS: We found a statistically significant increase in negative psychosocial consequences between the annual lung cancer CT-screening and the three-month follow-up CT-scan in four of nine psychosocial scales; Sense of dejection, Self-blame, Focus on airway symptoms and Harm of smoking. Furthermore, an increase, however not statistically significant, was identified in all remaining scales, except for the scale Stigmatisation which was slightly decreased. We found no evidence of an association between psychosocial consequences and diagnostic groups, FP and TP. CONCLUSIONS: An increase in negative psychosocial consequences was observed between the annual lung cancer CT-screening and the three-month follow-up CT-scan. Since we found no statistically significant difference between the diagnostic groups, the increase in negative psychosocial consequences is interpreted as a nocebo effect of living three months in uncertainty not knowing if one's positive CT-screening result was true or false.

Fear of COVID-19 and its associations with perceived personal and family benefits and harms in Hong Kong.

Fear of COVID-19 is associated with public health compliance but also with negative well-being; however, no articles have reported associations of such fear with perceived benefits and harms. We assessed the level of fear of COVID-19 in Hong Kong adults and its associations with sociodemographic factors and perceived benefits and harms of COVID-19. In a 6-day population-based cross-sectional online survey in May 2020, 4,890 adults provided data on fear and perceived benefits and harms, personal happiness and family well-being, and sociodemographic characteristics. Linear regression was used to analyze associations. The level of fear was moderate (mean score 6.3/10). Fewer respondents reported perceived benefits (10.6%-21.7%) than harms (13.4%-43.5%). Females, younger age groups, and respondents with lower education or more cohabitants had greater fear. Fear was associated with perceived personal (increased knowledge of personal epidemic prevention) and family benefits (improved family hygiene), both with a very small effect size (Cohen's d = 0.03). Fear was also associated with lower personal happiness and perceived personal (increased negative emotions, feeling depressed and anxious, decreased income, and decreased work efficiency) and family harms (increased conflicts and negative emotions among family members), with small effect sizes (0.08-0.37). We have first shown sociodemographic differences in the fear of COVID-19 and such fear was associated with both perceived personal and family benefits and harms of COVID-19. Our findings may guide the management of fear to reduce sociodemographic differences, and maximize benefits and minimize harms.

[From the evidence to recommendations-how to skillfully justify guideline recommendations]. / Von der Evidenz zur Empfehlung ­ die Kunst, Leitlinienempfehlungen zu begründen.

To justify clinical guideline recommendations comprehensibly is challenging. It is a matter of presenting the quality of the published evidence concerning its certainty and patient relevance, but also additional reasons for the grade of recommendation, as the strength of the recommendation does not only reflect the strength of the evidence. To state this reasoning in a structured manner, an "Evidence to Decision Framework" was developed. In addition to an evaluation of benefits and harms as well as information on certainty of the evidence, the framework comprises further criteria as patient preferences, acceptance of professional stakeholders, feasibility, equity and resources and costs. The most important arguments to justify recommendations in exemplary analyzed urological guidelines are the balance of benefits and harms and the appraisal of the certainty of the underlying evidence; in some cases, patient preferences are addressed. Whether there is an added value in applying further decision criteria for the development and implementation of guidelines remains to be verified. An opportunity of S3 guidelines (evidence- and consensus-based, 6/17 urological guidelines) is that knowledge gaps can be systematically identified, which enables the formulation of relevant research questions, which may contribute to a better basis for future recommendations.

177Lu-PSMA Radioligand Therapy Is Favorable as Third-Line Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer. A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

In this systematic review and network meta-analysis (NMA), we aimed to assess the benefits and harms of third-line (L3) treatments in randomized controlled trials (RCTs) of patients with metastatic castration-resistant prostate cancer (mCRPC). Two reviewers searched for publications from 1 January 2006 to 30 June 2021. The review analyzed seven RCTs that included 3958 patients and eight treatments. Treatment with prostate-specific membrane antigen (PSMA)-based radioligand therapy (PRLT) resulted in a 1.3-times-higher rate of median PSA decline ≥50% than treatment with abiraterone, enzalutamide, mitoxantrone, or cabazitaxel (p = 0.00001). The likelihood was 97.6% for PRLT to bring about the best PSA response, out of the examined treatments. PRLT resulted in a 1.1-times-higher six-month rate of median radiographic progression-free survival. Treatment with PRLT in the VISION trial resulted in 1.05-times-higher twelve-month median overall survival than L3 treatment with cabazitaxel in other RCTs. PRLT more often resulted in severe thrombocytopenia and less often in severe leukopenia than did cabazitaxel. In conclusion, for patients with mCRPC, L3 treatment with PRLT is highly effective and safe.

Current controversies in breast cancer screening.

Multiple large-scale, randomized controlled trials throughout the world have demonstrated screening mammography significantly reduces a woman's risk of dying from breast cancer. Despite the known mortality reduction, the perceived harms of mammography are weighed against the known value. Multiple national guidelines have moved away from recommending all women have annual screening mammograms beginning at age 40. Instead, many now encourage women at average risk for developing breast cancer to engage in shared decision-making with their providers, carefully weighing the perceived harms against the known benefits of mammography. These factors should be incorporated into the decision about when to begin and how often to screen. This paradigm shift has been particularly controversial as it relates to women in the 40-49-year age group, considering their incidence of breast cancer and therefore derived benefit of screening is lower, yet the breast cancers that do occur tend to be more aggressive and often require intensive therapy. Thus, debates ensue over the appropriate age at which to begin screening for breast cancer, how often screening should occur, and when to stop.

How personalized are benefit and harm results of randomized trials? A systematic review.

OBJECTIVES: This study aimed to review the degree of personalization of benefit and harm in the reporting of recent high-profile randomized controlled trials (RCTs) involving pharmacological interventions. STUDY DESIGN AND SETTING: This study is a systematic review of RCTs published between 2012 and 2017 with at least one intervention evaluating drug therapy and meeting the "high-profile" threshold in a premier academic literature abstraction service. Our primary outcome was the proportion of trials reporting subgroup analyses of a combined benefit-harm outcome. Secondary outcomes included the proportion of trials reporting subgroup analyses or clinical prediction guide for benefits or harms. We assessed the quality of the subgroup analyses using a modified version of previously published credibility criteria. RESULTS: Of 296 eligible RCTs, nine studies (3%) reported a combined benefit-harm endpoint. We found subgroup analyses of a combined benefit-harm endpoint in three studies (1%), a benefit endpoint in 167 studies (56.4%), and a harm endpoint in 18 studies (6.1%). The overall quality of the subgroup analyses was poor. Only one study reported a clinical prediction guide for an outcome. CONCLUSION: Despite great interest in the personalization of therapies, it is rarely reported in high-profile trials. Lack of rigorous and widely accepted methods may be the major barrier.

Breast Cancer Screening: Beyond Mortality.

Traditionally, the effectiveness of breast cancer screening has been measured in terms of reducing the number of deaths attributable to breast cancer. Other metrics such as the number of life-years or quality-adjusted life-years gained through screening may be more relevant and certainly may better reflect the important burden of the disease on younger women, their families, and society. The effects of earlier detection of breast cancer in reducing morbidities associated with treatment have often also been neglected. In addition, the harms and limitations associated with cancer screening have been poorly quantified and are seldom put into perspective vis-à-vis the benefits. Here, these alternative measures will be discussed and quantified.