Background and Objective
Due to relatively low incidence, bladder cancer screening might have a better ratio of benefits and harms if restricted to a high-risk population. We used data from the PLCO study and applied simple decision analytic techniques to compare different eligibility criteria for a screening trial.
For a variety of possible eligibility criteria, we calculated the percentage of the population aged 55 – 74 classified as being at high risk for developing invasive or high-grade carcinoma and therefore likely to benefit from screening. We used regression models to calculate a risk score based on age, sex, smoking history and family history of bladder cancer. We then calculated the reduction in cases given hypothetical risk reductions associated with screening. The trade-off between people screened and tumors avoided was calculated as a net benefit.
The five-year probability of being diagnosed with invasive bladder cancer was 0.24%. Using a risk score > 6 or >8 as the eligibility criterion for a trial was generally superior to including all older adults. In a typical scenario, a risk score > 6 would result in ~25% of the population being screened to prevent 57 invasive or high grade bladder cancers per 100,000; screening the entire population would prevent only an additional 38 cases.
Screening for bladder cancer can be optimized by restricting to a sub-group at elevated risk. Different eligibility criteria for a screening trial can be compared rationally using decision-analytic techniques.
The long-term risk of prostate cancer–specific mortality (PCSM) after radical prostatectomy is poorly defined for patients treated in the era of widespread prostate-specific antigen (PSA) screening. Models that predict the risk of PCSM are needed for patient counseling and clinical trial design.
A multi-institutional cohort of 12,677 patients treated with radical prostatectomy between 1987 and 2005 was analyzed for the risk of PCSM. Patient clinical information and treatment outcome was modeled using Fine and Gray competing risk regression analysis to predict PCSM.
Fifteen-year PCSM and all-cause mortality were 12% and 38%, respectively. The estimated PCSM ranged from 5% to 38% for patients in the lowest and highest quartiles of predicted risk of PSA-defined recurrence, based on a popular nomogram. Biopsy Gleason grade, PSA, and year of surgery were associated with PCSM. A nomogram predicting the 15-year risk of PCSM was developed, and the externally validated concordance index was 0.82. Neither preoperative PSA velocity nor body mass index improved the model's accuracy. Only 4% of contemporary patients had a predicted 15-year PCSM of greater than 5%.
Few patients will die from prostate cancer within 15 years of radical prostatectomy, despite the presence of adverse clinical features. This favorable prognosis may be related to the effectiveness of radical prostatectomy (with or without secondary therapy) or the low lethality of screen-detected cancers. Given the limited ability to identify contemporary patients at substantially elevated risk of PCSM on the basis of clinical features alone, the need for novel markers specifically associated with the biology of lethal prostate cancer is evident.
A preoperative nomogram is an effective tool for assessing the risk of disease progression following radical prostatectomy for localized prostate cancer. To better understand the performance of nomograms for patients with a low PSA, we examined whether patients with PSA < 2.5 had different outcomes versus that predicted by a validated preoperative nomogram.
A cohort of 6130 patients from two referral centers was analyzed. Kaplan-Meier methods were used to estimate the recurrence-free probabilities based on PSA grouping (< 2.5 vs ≥ 2.5 ng/mL). Cox proportional hazards regression was used to evaluate whether PSA grouping was associated with biochemical recurrence controlling for preoperative nomogram probability.
A total of 399/6130 (6.5%) patients had PSA < 2.5. Patients with PSA ≤ 0.5 had a high rate of non-organ confined disease (33% vs. 15% for PSA 0.6 – 2.5). The median follow-up for recurrence-free patients was 2.4 years, and 10 patients with PSA < 2.5 and 597 patients with PSA > 2.5 recurred (total 607/6130). With adjustment for the preoperative nomogram probability, there was no significant difference in recurrence by PSA grouping (hazard ratio 0.78 for PSA <2.5 vs ≥2.5; 95% C.I. 0.42, 1.48; p=0.5).
Patients with a low PSA comprise a small proportion of those treated, and the majority have palpable disease. Patients with especially low PSA values (≤ 0.5) have a high rate of non-organ confined disease. We saw no evidence that patients with low PSA have worse outcomes, after stage and grade were taken into account.
prostate cancer; PSA; nomogram
In September 2012, the Acupuncture Trialists' Collaboration published the results of an individual patient data meta-analysis of close to 18,000 patients in high quality-randomized trials. The results favored acupuncture. Although there was little argument about the findings in the scientific press, a controversy played out in blog posts and the lay press. This controversy was characterized by ad hominem remarks, anonymous criticism, phony expertise, and the use of opinion to contradict data, predominately by self-proclaimed skeptics. There was a near complete absence of substantive scientific critque. The lack of any reasoned debate about the main findings of the Acupuncture Trialists' Collaboration paper underlines that mainstream science has moved on from the intellectual sterility and ad hominem attacks that characterize the skeptics’ movement.
Pain; Skepticism; Headache; Acupuncture; Statistics and Research Design
Although acupuncture is widely used for chronic pain, there remains considerable controversy as to its value. We aimed to determine the effect size of acupuncture for four chronic pain conditions: back and neck pain, osteoarthritis, chronic headache, and shoulder pain.
We conducted a systematic review to identify randomized trials of acupuncture for chronic pain where allocation concealment was determined unambiguously to be adequate. Individual patient data meta-analyses were conducted using data from 29 of 31 eligible trials, with a total of 17,922 patients analyzed.
In the primary analysis including all eligible trials, acupuncture was superior to both sham and no acupuncture control for each pain condition (all p<0.001). After exclusion of an outlying set of trials that strongly favored acupuncture, the effect sizes were similar across pain conditions. Patients receiving acupuncture had less pain, with scores 0.23 (95% C.I. 0.13, 0.33), 0.16 (95% C.I. 0.07, 0.25) and 0.15 (95% C.I. 0.07, 0.24) standard deviations lower than sham controls for back and neck pain, osteoarthritis, and chronic headache respectively; the effect sizes in comparison to no acupuncture controls were 0.55 (95% C.I. 0.51, 0.58), 0.57 (95% C.I. 0.50, 0.64) and 0.42 (95% C.I. 0.37, 0.46). These results were robust to a variety of sensitivity analyses, including those related to publication bias.
Acupuncture is effective for the treatment of chronic pain and is therefore a reasonable referral option. Significant differences between true and sham acupuncture indicate that acupuncture is more than a placebo. However, these differences are relatively modest, suggesting that factors in addition to the specific effects of needling are important contributors to the therapeutic effects of acupuncture.
Due to the complexity and challenging nature of radical prostatectomy (RP), it seems reasonable to suppose that both short- and long-term outcomes strongly depend on the cumulative number of cases performed by the surgeon as well as within the hospital.
To review systematically the association between hospital and surgeon volume and perioperative, oncologic, and functional outcomes after RP.
A systematic review of the literature was performed, searching PubMed, Embase, and Scopus databases for original and review articles between January 1, 1995, and December 31, 2011. Inclusion and exclusion criteria comprised RP, hospital and/or surgeon volume reported as a predictor variable, a measurable end point, and a description of multiple hospitals or surgeons.
Overall 45 publications fulfilled the inclusion criteria, where most data originated from retrospective institutional or population-based cohorts. Studies generally focused on hospital or surgeon volume separately. Although most of these analyses corroborated the impact of increasing volume with better outcomes, some others failed to find any significant effect. Studies also differed with respect to the proposed volume cut-off for improved outcomes, as well as the statistical means of evaluating the volume–outcome relationship. Five studies simultaneously compared hospital and surgeon volume, where results appear to suggest that the importance of either hospital or surgeon volume largely depends on the end point of interest.
Undeniable evidence suggests that increasing volume improves outcomes. Although it would seem reasonable to refer RP patients to high-volume centers, such regionalization may not be entirely practical. As such, the implications of such a shift in practice have yet to be fully determined and warrant further exploration.
Prostatic neoplasms; Prostatectomy; Selective referral; Hospital volume; Surgeon volume; Regionalization
Cancer is a growth process and it is natural that we should be concerned with how the routinely used marker of prostate cancer tumour burden – PSA – changes over time. Such change is measured by PSA velocity or PSA doubling time, described in general as “PSA kinetics”. However, it turns out that calculation of PSA velocity and doubling time is far from straightforward. More than 20 different methods have been proposed, and many of these give quite divergent results. There is clear evidence that PSA kinetics are critical for understanding prognosis in advanced or relapsed prostate cancer. However, PSA kinetics have no value for men with an untreated prostate: neither PSA velocity nor doubling time have any role in diagnosing prostate cancer or providing a prognosis for men before treatment.
Prostatic neoplasms; prostate specific antigen
Patients with chronic renal failure show a greater incidence of malignancies. We evaluated whether moderately impaired renal function at baseline influenced risk of all cancers during long-term follow in young persons. Our cohort included 33,346 subjects, aged 26–61 years at baseline, in a representative, population-based study enrolling subjects from 1974 to 1992. Median follow-up time was 28 years. Plasma creatinine was analysed as a single measure at baseline. Incident cases of cancer were identified from the Swedish Cancer Registry. We studied 24,552 subjects from the cohort. To account for the unique sampling design, participants were divided by sex and age at baseline into 1,132 older men (age 60), 14,254 younger men (age 40–52), 7,498 older women (age 47–57) and 1,688 younger women (age 35–43). Glomerular filtration rate (GFR) was estimated using the CKD-EPI formula. Patients were classified as having either normal to mildly impaired kidney function (eGFR≥60 mL/min/1.73m2), or moderate kidney dysfunction (eGFR<60 mL/min/1.73m2). We calculated the risk of all cancers using competing risks regression. Overall, 6,595 participants were diagnosed with cancer, and 854 subjects (3.5%) had moderately impaired renal dysfunction at baseline. There was a significant association between moderately decreased GFR and subsequent risk of kidney cancer in younger men (hazard ratio, 3.38; 95% CI, 1.48 to 7.71; P=0.004). However, we found no association with overall long-term cancer risk. Our confirmation of an association between moderately impaired renal function and risk of kidney cancer in younger men requires further exploration of high-risk groups and biological mechanisms.
Cancer; chronic kidney disease; kidney cancer; renal function
Spiritual well-being and sense of meaning are important concerns for clinicians who care for patients with cancer. We developed Individual Meaning-Centered Psychotherapy (IMCP) to address the need for brief interventions targeting spiritual well-being and meaning for patients with advanced cancer.
Patients and Methods
Patients with stage III or IV cancer (N = 120) were randomly assigned to seven sessions of either IMCP or therapeutic massage (TM). Patients were assessed before and after completing the intervention and 2 months postintervention. Primary outcome measures assessed spiritual well-being and quality of life; secondary outcomes included anxiety, depression, hopelessness, symptom burden, and symptom-related distress.
Of the 120 participants randomly assigned, 78 (65%) completed the post-treatment assessment and 67 (56%) completed the 2-month follow-up. At the post-treatment assessment, IMCP participants demonstrated significantly greater improvement than the control condition for the primary outcomes of spiritual well-being (b = 0.39; P <.001, including both components of spiritual well-being (sense of meaning: b = 0.34; P = .003 and faith: b = 0.42; P = .03), and quality of life (b = 0.76; P = .013). Significantly greater improvements for IMCP patients were also observed for the secondary outcomes of symptom burden (b = −6.56; P < .001) and symptom-related distress (b = −0.47; P < .001) but not for anxiety, depression, or hopelessness. At the 2-month follow-up assessment, the improvements observed for the IMCP group were no longer significantly greater than those observed for the TM group.
IMCP has clear short-term benefits for spiritual suffering and quality of life in patients with advanced cancer. Clinicians working with patients who have advanced cancer should consider IMCP as an approach to enhance quality of life and spiritual well-being.
medical education; communication skills; faculty development; communication
Numerous predictive and prognostic tools have recently been developed for risk stratification of prostate cancer (PCa) patients who are candidates for or have been treated with radical prostatectomy (RP).
To critically review the currently available predictive and prognostic tools for RP patients and to describe the criteria that should be applied in selecting the most accurate and appropriate tool for a given clinical scenario.
A review of the literature was performed using the Medline, Scopus, and Web of Science databases. Relevant reports published between 1996 and January 2010 identified using the keywords prostate cancer, radical prostatectomy, predictive tools, predictive models, and nomograms were critically reviewed and summarised.
We identified 16 predictive and 22 prognostic validated tools that address a variety of end points related to RP. The majority of tools are prediction models, while a few consist of risk-stratification schemes. Regardless of their format, the tools can be distinguished as preoperative or postoperative. Preoperative tools focus on either predicting pathologic tumour characteristics or assessing the probability of biochemical recurrence (BCR) after RP. Postoperative tools focus on cancer control outcomes (BCR, metastatic progression, PCa-specific mortality [PCSM], overall mortality). Finally, a novel category of tools focuses on functional outcomes. Prediction tools have shown better performance in outcome prediction than the opinions of expert clinicians. The use of these tools in clinical decision-making provides more accurate and highly reproducible estimates of the outcome of interest. Efforts are still needed to improve the available tools’ accuracy and to provide more evidence to further justify their routine use in clinical practice. In addition, prediction tools should be externally validated in independent cohorts before they are applied to different patient populations.
Predictive and prognostic tools represent valuable aids that are meant to consistently and accurately provide most evidence-based estimates of the end points of interest. More accurate, flexible, and easily accessible tools are needed to simplify the practical task of prediction.
Prostate cancer; Radical prostatectomy; Prediction tools; Nomograms
Women with localized breast cancer face difficult decisions about adjuvant therapy. Several decision aids are available to help women choose between treatment options. Decision aids are known to affect treatment choices and may therefore affect patient survival. The authors aimed to model the effects of the Adjuvant! decision aid on expected survival in women with early stage breast cancer.
Patients and Methods
Data were obtained from a randomized trial of Adjuvant! (n =395). To calculate the effects of the decision aid on survival, the authors used the Adjuvant! survival predictions as a surrogate endpoint. Data from each arm were entered separately into statistical models to estimate change in survival associated with receiving the Adjuvant! decision aid.
Most women (~85%) chose a treatment option that maximized predicted survival. The effects of the decision aid on outcome could not be modeled because a small number of women (n =12, 3%) chose treatment options associated with a large (5%–14%) loss in survival. These women—most typically estrogen receptor positive but refusing hormonal therapy—were equally divided between Adjuvant! and control groups and were not distinguished by medical or demographic factors.
Expected benefit from treatment is a key variable in understanding patient behavior. A small number of women refuse adjuvant treatment associated with large increases in predicted survival, even when they are explicitly informed about the degree of benefit they would forgo. Investigation of the effects of decision aids on cancer survival is unlikely to be fruitful due to power considerations.
Adjuvant!; breast cancer; decision aids; women’s health; oncology; outcomes research
Public adherence to cancer screening guidelines is poor. Patient confusion over multiple recommendations and modalities for cancer screening has been found to be a major barrier to screening adherence. Such problems will only increase as screening guidelines and timetables become individualized.
We propose to increase compliance with cancer screening through two-way rich media mobile messaging based on personalized risk assessment.
We propose to develop and test a product that will store algorithms required to personalize cancer screening in a central database managed by a rule-based workflow engine, and implemented via messaging to the patient’s mobile phone. We will conduct a randomized controlled trial focusing on prostate cancer screening to study the hypothesis that mobile reminders improve adherence to screening guidelines. We will also explore a secondary hypothesis that patients who reply to the messaging reminders are more engaged and at lower risk of non-adherence. We will conduct a randomized controlled trial in a sample of males between 40 and 75 years (eligible for prostate cancer screening) who are willing to receive text messages, email, or automated voice messages. Participants will be recruited from a primary care clinic and asked to schedule prostate cancer screening at the clinic within the next 3 weeks. The intervention group will receive reminders and confirmation communications for making an appointment, keeping the appointment, and reporting the test results back to the investigators. Three outcomes will be evaluated: (1) the proportion of participants who make an appointment with a physician following a mobile message reminder, (2) the proportion of participants who keep the appointment, and (3) the proportion of participants who report the results of the screening (via text or Web).
This is an ongoing project, supported by by a small business commercialization grant from the National Center for Advancing Translational Sciences of the National Institutes of Health.
We believe that the use of centralized databases and text messaging could improve adherence with screening guidelines. Furthermore, we anticipate this method of increasing patient engagement could be applied to a broad range of health issues, both inside and outside of the context of cancer. This project will be an important first step in determining the feasibility of personalized text messaging to improve long-term adherence to screening recommendations.
Early Detection of Cancer; Text Messaging; Prostatic Neoplasms
For the evaluation and comparison of markers and risk prediction models, various novel measures have recently been introduced as alternatives to the commonly used difference in the area under the ROC curve (ΔAUC). The Net Reclassification Improvement (NRI) is increasingly popular to compare predictions with one or more risk thresholds, but decision-analytic approaches have also been proposed.
We aimed to identify the mathematical relationships between novel performance measures for the situation that a single risk threshold T is used to classify patients as having the outcome or not.
We considered the NRI and three utility-based measures that take misclassification costs into account: difference in Net Benefit (ΔNB), difference in Relative Utility (ΔRU), and weighted NRI (wNRI). We illustrate the behavior of these measures in 1938 women suspect of ovarian cancer (prevalence 28%).
The three utility-based measures appear transformations of each other, and hence always lead to consistent conclusions. On the other hand, conclusions may differ when using the standard NRI, depending on the adopted risk threshold T, prevalence P and the obtained differences in sensitivity and specificity of the two models that are compared. In the case study, adding the CA-125 tumor marker to a baseline set of covariates yielded a negative NRI yet a positive value for the utility-based measures.
The decision-analytic measures are each appropriate to indicate the clinical usefulness of an added marker or compare prediction models, since these measures each reflect misclassification costs. This is of practical importance as these measures may thus adjust conclusions based on purely statistical measures. A range of risk thresholds should be considered in applying these measures.
There is firm evidence that PSA velocity is statistically associated with many prostate cancer outcomes, including those related to early detection. But clinical use of a marker depends on clinical as well as statistical significance. Before using PSA velocity to inform decisions such as whether or not to biopsy a man, there should be clear evidence that doing so would improve clinical outcome. A systematic review on PSA velocity found that almost no studies had evaluated whether PSA velocity aids clinical decision-making. Since that time, several reports have indicated that including PSA in a statistical model alongside standard predictors (such as PSA and digital rectal exam) does not improve predictive accuracy. Specifically, biopsying men with high PSA velocity in the absence of other indications, as recommended by the NCCN guidelines, would lead to many millions of unnecessary biopsies, without a corresponding number of aggressive cancers being detected. Advocates of PSA velocity have been reduced to citing a single paper purporting to show that PSA velocity aids clinical decision-making. The paper involves selective reporting of an unusual subgroup analysis based on an extremely limited number of events. This is not to say that, in clinical practice, urologists should ignore prior PSA values: clinical judgment can be aided by careful longitudinal evaluation of PSA changes, interpreted in the context of symptoms and treatments. However, the literature clearly demonstrates that simplistic application of PSA velocity cut-offs is not of value for early detection of prostate cancer.
prostate cancer; detection; screening; PSA
One of the most basic biostatistical problems is the comparison of two binary diagnostic tests. Commonly, one test will have greater sensitivity and the other greater specificity. In this case, the choice of the optimal test generally requires a qualitative judgment as to whether gains in sensitivity are offset by losses in specificity. Here we propose a simple decision-analytic solution in which sensitivity and specificity are weighted by an intuitive parameter, the threshold probability of disease at which a patient will opt for treatment. This gives a net benefit that can be used to determine which of two diagnostic tests will give better clinical results at a given threshold probability, and whether either is superior to the strategy of assuming that all or no patients have disease. We derive a simple formula for the relative diagnostic value, which is the difference in sensitivities of two tests divided by the difference in the specificities. We show that multiplying relative diagnostic value by the odds at the prevalence gives the odds of the threshold probability below which the more sensitive test is preferable, and above which the more specific test should be chosen. The methodology is easily extended to incorporate combination of tests, and the risk or side-effects of a test.
diagnostic tests; decision analysis; combination tests; sequential testing; prostate cancer; molecular markers
Evidence of reduced prostate cancer mortality from randomized trials in Europe supports early detection of prostate cancer with prostate-specific antigen (PSA). Yet PSA screening has generated considerable controversy: it is far from clear that the benefits outweigh risks, in terms of overdiagnosis and overtreatment. One way to shift the ratio of benefits to harms is to focus on men at highest risk, who have more to benefit than average. Neither family history nor any of the currently identified genomic markers offer sufficient risk stratification for practical use. However, there is considerable evidence that the levels of PSA in blood are strongly prognostic of the long-term risk of aggressive prostate cancer. Specifically, it is difficult to justify continuing to screen men age 60 or older if they have a PSA less than 1 or 2 ng/ml; for men 45 – 60, intervals between PSA tests can be based on PSA levels, with 2 to 4 year re-testing interval for men with PSA of 1 ng/ml or higher, and tests every 6 to 8 years for men with PSA < 1 ng/ml. Men with the top 10% of PSAs at a young age (PSA ~1.5 ng / ml or higher below 50) are at particularly high risk and should be subject to intensive monitoring.
prostatic neoplasms; early detection of cancer; prostate-specific antigen
The National Comprehensive Cancer Network and American Urological Association guidelines on early detection of prostate cancer recommend biopsy on the basis of high prostate-specific antigen (PSA) velocity, even in the absence of other indications such as an elevated PSA or a positive digital rectal exam (DRE).
To evaluate the current guideline, we compared the area under the curve of a multivariable model for prostate cancer including age, PSA, DRE, family history, and prior biopsy, with and without PSA velocity, in 5519 men undergoing biopsy, regardless of clinical indication, in the control arm of the Prostate Cancer Prevention Trial. We also evaluated the clinical implications of using PSA velocity cut points to determine biopsy in men with low PSA and negative DRE in terms of additional cancers found and unnecessary biopsies conducted. All statistical tests were two-sided.
Incorporation of PSA velocity led to a very small increase in area under the curve from 0.702 to 0.709. Improvements in predictive accuracy were smaller for the endpoints of high-grade cancer (Gleason score of 7 or greater) and clinically significant cancer (Epstein criteria). Biopsying men with high PSA velocity but no other indication would lead to a large number of additional biopsies, with close to one in seven men being biopsied. PSA cut points with a comparable specificity to PSA velocity cut points had a higher sensitivity (23% vs 19%), particularly for high-grade (41% vs 25%) and clinically significant (32% vs 22%) disease. These findings were robust to the method of calculating PSA velocity.
We found no evidence to support the recommendation that men with high PSA velocity should be biopsied in the absence of other indications; this measure should not be included in practice guidelines.
In a recent individual patient data meta-analysis, acupuncture was found to be superior to both sham and non-sham controls in patients with chronic pain. In this paper we identify variations in types of sham and non-sham controls used and analyze their impact on the effect size of acupuncture.
Based on literature searches of acupuncture trials involving patients with headache and migraine, osteoarthritis, and back, neck and shoulder pain, 29 trials met inclusion criteria, 20 involving sham controls (n = 5,230) and 18 non-sham controls (n = 14,597). For sham controls, we analysed non-needle sham, penetrating sham needles and non-penetrating sham needles. For non-sham controls, we analysed non-specified routine care and protocol-guided care. Using meta-regression we explored impact of choice of control on effect of acupuncture.
Acupuncture was significantly superior to all categories of control group. For trials that used penetrating needles for sham control, acupuncture had smaller effect sizes than for trials with non-penetrating sham or sham control without needles. The difference in effect size was −0.45 (95% C.I. −0.78, −0.12; p = 0.007), or −0.19 (95% C.I. −0.39, 0.01; p = 0.058) after exclusion of outlying studies showing very large effects of acupuncture. In trials with non-sham controls, larger effect sizes associated with acupuncture vs. non-specified routine care than vs. protocol-guided care. Although the difference in effect size was large (0.26), it was not significant with a wide confidence interval (95% C.I. −0.05, 0.57, p = 0.1).
Acupuncture is significantly superior to control irrespective of the subtype of control. While the choice of control should be driven by the study question, our findings can help inform study design in acupuncture, particularly with respect to sample size. Penetrating needles appear to have important physiologic activity. We recommend that this type of sham be avoided.
Prediction model; validation; nomogram; discrimination; calibration; decision curve
The relationship between prostate specific antigen (PSA) level and prostate cancer risk remains subject to fundamental disagreements. We hypothesize that the risk of prostate cancer on biopsy for a given PSA level is affected by identifiable characteristics of the cohort under study.
We used data from 5 European and 3 US cohorts of men undergoing biopsy for prostate cancer; six were population-based studies and two were clinical cohorts. The association between PSA and prostate cancer was calculated separately for each cohort using locally-weighted scatterplot smoothing.
The final data set included 25,772 biopsies and 8,503 cancers. There were gross disparities between cohorts with respect to both the prostate cancer risk at a given PSA level and the shape of the risk curve. These disparities were associated with identifiable differences between cohorts: for a given PSA level, a greater number of biopsy cores increased risk of cancer (odds ratio for >6 vs. 6 core biopsy 1.35; 95% C.I. 1.18, 1.54; p<0.0005); recent screening led to a smaller increase in risk per unit change in PSA (p=0.001 for interaction term) and US cohorts had higher risk than the European cohorts (2.14; 95% C.I. 1.99, 2.30; p<0.0005).
Our results suggest that the relationship between PSA and risk of a positive prostate biopsy varies, both in terms of the probability of prostate cancer at a given PSA value and the shape of the risk curve. This poses challenges to the use of PSA-driven algorithms to determine whether biopsy is indicated.
prostate cancer; PSA; prediction; multicenter studies; screening
Prostate cancer screening depends on a careful balance of benefits, in terms of reduced prostate cancer mortality, and harms, in terms of overdiagnosis and overtreatment. We aimed to estimate the effect on overdiagnosis of restricting prostate specific antigen (PSA) testing by age and baseline PSA.
Estimates of the effects of age on overdiagnosis were based on population based incidence data from the US Surveillance, Epidemiology and End Results database. To investigate the relationship between PSA and overdiagnosis, we used two separate cohorts subject to PSA testing in clinical trials (n = 1,577 and n = 1,197) and a population-based cohort of Swedish men not subject to PSA-screening followed for 25 years (n = 1,162).
If PSA testing had been restricted to younger men, the number of excess cases associated with the introduction of PSA in the US would have been reduced by 85%, 68% and 42% for age cut-offs of 60, 65 and 70, respectively. The risk that a man with screen-detected cancer at age 60 would not subsequently lead to prostate cancer morbidity or mortality decreased exponentially as PSA approached conventional biopsy thresholds. For PSAs below 1 ng/ml, the risk of a positive biopsy is 65 (95% CI 18.2, 72.9) times greater than subsequent prostate cancer mortality.
Prostate cancer overdiagnosis has a strong relationship to age and PSA level. Restricting screening in men over 60 to those with PSA above median (>1 ng/ml) and screening men over 70 only in selected circumstances would importantly reduce overdiagnosis and change the ratio of benefits to harms of PSA-screening.
Prostate cancer; Early detection; Overdiagnosis; PSA; Screening