Aua

According to my knowledge, people at the age of 40 should be screened if their family members are prone with cancer earlier. If not, may be its good idea at the age of 50. As, I had seen in many journals, most of them who had prostate cancer is at the age of above 50.

Keep in mind that about 50% of men over age 60 have prostate cancer on autopsy after death from other causes. I am not sure how screening accomplishes much in average risk men.

First, if you mean population-based PSA screening (like breast mammography) the answer is that it is now clear that the benefits (at population level) do not outweigh the harms, and it is certainly not going to be cost-effective. Further, for ad hoc or individual PSA testing, the ERSPC screening trial indeed claims a mortality reduction of about 30% in a scenario where non-attendants are eliminated. Nevertheless, there is a huge amount of overdiagnosis (at least 50%) and men who wish PSA testing should recognize that most (PSA-detected) prostate cancers are harmless as is also apparent from older and recent autopsy studies as the early knowledge of carrying a prostate cancer may otherwise may impact their quality of life . The EAU recommendation to measure a baseline PSA at young age (e.g. 40-45 yr) in order to determine whether men should be screened at all, and at which frequency if screening is "necessary" is unproven: This procedure would certainly not improve the already modest mortality reduction achieved by the stringent ERSPC screening, but on the plus side, it would likely reduce overdiagnosis. But again, its effectiveness has not been shown in reducing metastatic disease or mortality. I attach a few papers for further reading.

Hi there,

I suggest to have the PSA baseline recorded, maybe like3 times within a year in the age between 40-42.

DRE and TRUSI are exciting methods when performed by an experienced urologist. I recommend to undergo those tests at the age of 45 without symptoms or if you have symptoms as soon as possible. Biopsy is a risky procedure, and very painful. There are 2 new screenings tests in clinical trials:

1. PCA3

2. PSA total+PSA free+ kallikrein

Both tests are available in UK as a private treatment and should help to make the decision about the biopsy.

PET imaging with acetate is an excellent non-invasive method. To my knowledge is available in Italy.

There is no evidence in favor of prostate cancer screening , so all men should be discouraged. In no situation advantages overcome disadvantages for screening. PSA is at best a diagnostic procedure (symptomatic patients) invalidated for screening (use of a medical procedure on asymptomatic paient, based on non medical factors (sex, age for example) and was developed to follow up knonw prostate cancer..

please read my article ORPHAN PSA

The debate should be to avoid treatment of low risk (indolent) prostate cancers.

Since the start of use of PSA the mortality of prostate cancer is lower each year, and the diagnose of metastatic cancer is lower each year.

The use of PSA is defunded all over the world, we cannot go back in time, the PSA will be used (more and more each year). We have to learn not to treat indolent cancers more than not to screen patients.

If we STOP screening our patients we will see an increment up to 70% I metastatic prostate cancer (and legal demands), because we have a tool to prevent metastatic cancer, the PSA.

Follow the German S3 guideline on PCA indicating that men aged 40 to 69 should be informed on the options (risk and benefits) of PSA determination. In addition, not every patient with an increased PSA level will automatically lead to prostate biopsy and not any PCA diagnosis will result in RP/EBRT. In summary, we don´t do cohort screening here in Germany, which is reflected by the fact that over treatment (surgery/EBRT) defined along the different risk scores takes place in less than 20% of our patients.

Diego,

I think that you have a too simplistic view: It is not entirely correct to state that since PSA screening began, mortality rates started dropping. Age-standardized mortality rates in USA (SEER data) increased slowly from 1975, reaching a peak around 1990 and then started dropping slowly. This drop is too quick to be explained by screening, and a similar drop in mortality was seen in areas without PSA screening. Further, the mortality rate in USA is now back at the SAME level as in 1975.

There may also be other explanations such as improved treatment of prostate cancer pts.

Theodorus,

If we use PSA screening after a clearance of advanceds cancers we will detect all of prostate cancers on Stage T1 c.

Is very difficult to find patients withouth a PSA test maid (even in Argentina). We have to learn to use the PSA and observe patients with indolent cancers

Hi Theo,

you are correct for the moment and by now population screening should definitely not be recommended. Nevertheless, this could change with the time and updated results from ERSPC and there are serious considerations and calculations that the answwr may change in 15 years from now. All the best Bernd

Until a better and more specific test comes on the market, PSA screening from 50-70 yrs still makes some sense if one is guided by the results. For high risk (family history or Black race) 45 yrs should be start of screen. If results show very low values, (although still not totally exclusive of carcinoma) and rectal exam is normal, PSA can be done every three years. Rising values are more significant than a raised value.

I think that men aged 40 to 69 should be informed on the risk and benefits of PSA screen. Let them make the decision.

And it not only a scientific question. When we disscus a method of diagnosis or treatment, we must consider the economic conditions, educational level (or tradition), concept of life, and so on in a society or country.

For example, because of the concept of heath or poor economic conditions, especially in the countryside and remote border area, there are many many people don't attach importance to heath in China. PSA-screening is far to enough in China. So although I know the harms of population-based PSA screening, I'll make an effort do propaganda and agitation of the PSA-screening.

Another thing is the enviroment of practising one's profession. Doctor-patient relationship in China is not good. There are many violent attacks to coctor. And patients without necessary knowledge about the disease usually can't understand the result of every option. So some doctors make a choice which is safe; it is examination. If you give every people the advice of examination, to some extent, they became screening.

Thank you all for the comments. Unfortunately for us and our patients, there is no unisonous answer for this topic. All points of view are backed up by relevant literature, but still, there are substantial limitations, controversies, and room for improvements in prostate cancer screening and treatment.

There are some points that should be discussed with our patients:

1. Although recent improvements in prostate cancer mortality rates cannot be entirely attributed to prostate cancer screening, screening is at least partially responsible for it, as demonstrated by mathematical models that estimated that between 45% and 70% of mortality rates decrease are due to prostate cancer screening, together with improved treatments for localized and metastatic prostate cancer (ETZIONI et al., 2008).

2. Medical community has been disappointed with the number of men needed to be treated to prevent one death from prostate cancer. In the ERSPC, 1055 men would need to be invited for screening and 37 cancers would have to be treated. However, these numbers are similar to the results from breast cancer screening, and colorectal cancer screening. For breast cancer, 1224 women have to be screened through mammography to prevent on death (HUMPHREY et al., 2002), and 1173 people have to be screened by fecal occult blood test to prevent one death from colorectal cancer (TOWLER et al., 1998).

3. (If) prostate cancer screening reduces the rate of death from prostate cancer, (it does so) at the cost of considerable overdiagnosis and overtreatment, and the majority of patients with prostate cancer die from other causes (LU-YAO et al., 2009; WILT et al., 2012). However, prostate cancer continues to be the second leading cause of death from all non-cutaneous cancer in the world!

4. If we cannot state that prostate cancer screening reduces prostate cancer specific mortality, based especially on the PLCO study, we also cannot say that investigating prostate cancer only in the presence of signs or symptoms of cancer will save as many lives as with prostate cancer screening, based on the same study, since there was significant contamination of the control group.

5. Maybe overdiagnosis will not be much of a problem if we learn to treat only aggressive or progressive prostate cancers (by active surveillance), the ones with the most chances of reducing survival or impairing the quality of life of the patients. By doing this, we will be able to maintain the benefits of prostate cancer screening and to reduce the harms of overtreatment.

The data of the PLCO is contaminated with pre study PSA tests and intra study PSA tests in control groul.

If you take the data from the Gotemburg part of ERSPC you need near of 300 men screened to cure a prostate cancer.

The ERSPC and the PLCO were designed 20 YEARS ago with the indications of biopsy of 20 YEARS AGO.

Today we use the ratio of Free/total PSA, PSA density, PSA velocity, and PCA3 .

We don't biopsy a patient only if PSA is more than 3 or 4 (PLCO or ERSPC)

I think what Diego Barreiro said is right. The ratio of f/t PSA and PSA velocity are important. They help us avoid many biopsy.

Although different strategies - including PSA velocity, PSA density, free PSA, complexed PSA, [-2]proPSA, and PSA stratified by age and race - do improve the diagnostic performance of PSA, there is no consensus on using any of them in urological practice, because none has been shown in clinical trials to reduce the number of unnecessary biopsies or improve clinical outcomes (WOLF et al., 2010; HOFFMAN, 2013). If they cannot improve the diagnostic accuracy for aggressive tumors, they will occasionally miss prostate cancers that would be best candidates for radical therapy and benefit the most from prostate cancer screening. In my opinion, the best indications for prostate biopsy are still a PSA threshold of 4.0 ng/mL and the presence of a nodule on digital rectal examination, because they balance the tradeoff between missing important cancers at a curable stage and avoiding detection of clinically insignificant disease.

Sometimes the ratio of F/T PSA can give us some help when we make a decision, but the PSA and nodule on digital rectal are the "gold standard" for biospy. On this point, I agree with Frederico Romero.

What does everyone think about the nodule on TRUS? And PSA between 4 and 10ng/ml?

In published by CUA (Chinese Urological Association), the nodule on TRUS is one of indicators of biospy. And if PSA is between 4 and 10 ng/ml, F/T, PSAD and PSAV should be considered.

And in China, patient's economic conditions and individual idea and medical risks are very important considerations. Perhaps it sounded a little odd, but it's true.

Liang, very interesting the doctor-patient relationship in China, isn’t it? But although there is not much violence against doctors in Brazil, we do have a very similar picture to China in terms of economic conditions. There are recommendations in our public health system to use PSA density or free/total PSA to prompt biopsy for PSA values between 4 and 10 ng/mL to avoid expenses and to reduce the number of biopsies. But this should not be standard of care. As for TRUS, it is not recommended as a primary screening test for prostate cancer because of its low sensitivity and positive predictive value (HOFFMAN, 2013). Only 40% of hypoechoic lesions detected by TRUS are due to prostate cancer (NORBERG et al., 1993) and 20% of normal prostates on TRUS may have a biopsy positive for cancer (EL-GABRY et al., 2001).

Hi, Frederico, Romero, Thanks! I'm a surgeon in China.

As for TRUS, I never think it is an rigid indicator of biospy. The reason is similar to yours. And about the doctor-patient relationship in China, there are much violence against doctors. Perharps it is the side-effect of developing economy. There was a paper about this in .

Sorry for digressing from the main subject. In short, I have to comply with the Guidline strictly to avoid the dispute, although sometime I don't think it is always absolutely right.

The best detector for high risk prostate cáncer is a PSA velocity of 2 or higer.

If we don´t use the PSA we cannot detect high risk prostate cáncer and cure it.

If a patient with PSA of 1 or lower at 60 year will not have a significant prostate cáncer in the next 10 years.

We have to remember that PSA is an indicator of BPH progression, if PSA is greater then 1,5 this is a factor of progression of BPH.

The PSA have multiple uses rater tan screening and we have to know how to use it.

I follow the guidelines by the American Urological Association. Those guidelines in my judgement and experience strike the right balance on the contentious issue of screening for prostate cancer. I agree we need better biomarkers to identify with almost 100% certainty, newly detected prostate cancers that will run an aggressive course. I am sure with time, such biomarkers will be discovered.

I think that opportunistic PSA and DRE have contaminated the population studies of both PLCO and ERSPC. The Gothenburg study is the one closest to PSA screening vs no screening or DRE screening and there the results are more well defined than in the other populations studies. So I still advise for PSA screening on an informed basis and in the context of EAU.

It is quite fascinating to see that the discussion goes on when ALL officials committees are saying clearly that prostate cancer should not be screened for.

The prevalence of prostate cancer is nearly equal to age (60 years old = 60%; 80 years old = 80%). Only 3% of men die from prostate cancer. Much more men die WITH a prostate cancer than FROM prostate cancer. Further, to differentiate individual screening from population screening is not science, as they are just alike, unless thinking that it is possible to sharpen indications when they are only opinions. Then, we should wait for a way to differentiate active prostate cancer from quiescent cancer and stop doing more harm than good.

There are ways to differentiate active cáncer from quiescent cáncer. A PSA velocity greater tan 2 points a year. The clasification of D´Amico of prostate cáncer (using the PSA value).

Why we don´t look at the demography and still looking the por quality ERSPC and PLCO.

There are two different diseases: The indolent prostate cáncer, and the high risk prostate cáncer. The Frame and Carlson criteria for secrrening diseases does not fit for indolent prostate cáncer but HIGH RISK prostate cáncer does match ALL of the Frame and Carlson criteria for screening.

We have to learn to avoid active treatments for indolent prostate cáncer.

None of the PSA measures are effective to differentiate quiescent from developping prostate cancer. That's the "Graal" of prostate cancer screening the one who find it will get rich!). They are not even paid for in France because they are not validated. It is necessary to separate "trust" from "proof". Nothing is self evident with screening. It took years to get rid of themography to screen breast cancer. It could take longer to get rid of PSA for prostate cancer screening. The researcher who discovered PSA made the statement that he was regretting it because of the huge misuse of his test. It was developped for the follow up of clinical prostate cancer.

There is a method which can differentiate quiescent from developping prostate cancer? I think the answer is "No". In clinical test, PSA is the best indicator of prostate cancer. The key is how to use it. As I have said, it is not only a technique question and economic conditions, medical policy, and so on should be considered.

As a technique question or a medical question, I think in some special populations, we should push it. In other words, it should be restrict within special populations. Perhaps it is more valuable to discuss the question "what is the limit".

since the discover of PSA the metastatic rostate cancer decreased a 70%. In Argentina with the cost of one year of hormone treatment of one prostate cancer we can make a PSA test for 2100 patients.

The cost of the screening is not a problem.

Who loses with a decrease in 70% in metastatic prostate cancer ??

The ones who sell the treatment for prostate cancer for example??

The researcher who discovered PSA was not a clinician, and thus his comments about his view about the use of PSA are repeatedly taken out of context. PSA may have started life as one thing, but in 2013 it has a number of roles, as an indicator of prostatic activity, size and possible (I stress possible) indicator of cancer. However, dispensing with the good that PSA has brought is will send the management of prostate cancer back thirty years, with alkaline phosphatase being used as a marker for cancer, and patients presenting with paraplegia, obstructed ureters, intractable prostatic bleeding etc. Obviously more accuracy in diagnosis is required, but diagnosis at present is relatively safe (prostate biopsy is not the medieval torture that some detractors claim it is. Compare it's safety profile to colonoscopy). As proposed very well in the Melbourne Consensus Statment recently, the key is to uncouple cancer diagnosis from radical cancer treatment. Within the limitations that we have now, we need to work out who will benefit from treatment and who won't. Two final points: Firstly treatment options for prostate cancer are markedly different than the massively disfiguring operations or radiation treatments that press reports (and supposedly knowledgeble physicians) commonly refer to. With robotic surgery, for example, most patients go home the next day, and the vast majority are cancer free and continent in under 12 weeks or less (potency is more difficult to maintain, I will admit). Secondly, I never want to be in the position of telling a patient that we ignored your elevated PSA when you were 52, now you are 60, you have painful bony metastases, and I'm going to chemically castrate you, and you will be dead by 65-68. That is the exact opposite of why I became interested in the management and cure of prostate cancer, which was to cure men of their cancer, not ignore warning signs of it. I have yet to meet a man whose prostate I have removed who hasn't thanked me for curing their disease. Yes, we need to do better in choosing who to treat aggressively, but if we don't know who has cancer, we can't make that choice.

Frederico:

I would like to step back re your excellent question and take up the logically prior issue, that for the recommendations that are most authoritative in the U.S. at present and have generated the most controversy, namely those of the USPSTF, have the USPSTF authors in fact sufficiently motivated their conclusions as to materially challenge current screening practice, and as will be seen below, I answer decidedly in the negative, that they have not.

I have reviewed (internally commissioned review for evidence-based authorities) - and judged misguided - the USPSTF guideline in PSA-based prostate cancer screening and so I here provide a condensed version of my critical review on the PSA/PC (prostate cancer) issue both to conserve space (the full review occupies 20+ pages and 100+ references), and to provide a model of what undermines these recommendations.

First, it must be noted that the U.S. Preventive Services Task Force (USPSTF) represents an constitutive anomaly of "inexpertise": a panel that does not include (1) urologists, nor (2) uro-oncologists, and - as I will strongly document below - (3) appears to have a substandard understanding of the core principles of evidence-based medicine, including critical appraisal of RCTs.

FLAWS IN REASONING

The USPSTF review [1] concluded that that screening results only “in small or no reduction in prostate cancer–specific mortality" as found in the large prospective ERSPC (European Randomized study of Screening for Prostate Cancer) Trial [2], but the ERSPC Trial was still active and hence incomplete at time of USPSTF review: this is illicit since the ERSPC results were interim and necessarily equivocal, and the trial had not yet reported actual final results at its prespecified follow-up time. When it did so, it was found in the recent analysis of the ERSPC trial [3] that used two additional years of follow-up (11 years) this confirmed the previous finding that PSA screening does indeed significantly reduces prostate cancer mortality (relative risk, 0.79). In addition, a secondary analysis [25] of data from ERSPC Trial under tight methodological control, correcting for failure of participants to have protocol-prescribed screening procedures as well as contamination, showed that PSA screening reduced the risk for dying of prostate cancer by as much as 31%, and recent pending randomized data, after adjustment for nonattendance and contamination, suggest this may be as high as 51% [32].

If we instead consider the remaining trials that were at fair-quality according to USPSTF classification, two of these in fact found significant reductions in prostate cancer mortality: the original ERSPC trial [2] found a 20% reduction in prostate cancer mortality after 9 years of follow-up, while the Göteborg trial [11] found a 44% reduction in prostate cancer mortality after 14 years of follow-up.

The USPSTF report focused on all-cause mortality and on whether this is decreased by PSA-based screening, but it's a profound fundamental misunderstanding to believe that the screening trials such as ERSPC, PLCO, or PIVOT can address this question, given that the statistical noise of deaths from other causes entails that this question has much lower power than the more narrow question of effect on cancer-specific mortality.

The USPSTF put forth a false high ratio of treatment to each prostate cancer–specific death prevented, claiming that “48 men received treatment for every prostate cancer–specific death prevented”; indeed, they estimated a number needed to screen (NNS) of 1,410 and a number needed to treat (NNT) of 48 to prevent one prostate cancer death at 9 years [1], these estimates of NNS and NNT at a single time point during a survival study being known to be misleading given that because of the long natural history of prostate cancer, a follow-up time of more than 10 years is necessary to evaluate cancer-specific mortality [15]. This is in error since it was computed from the number of men diagnosed, not, as it should have been, the number of men treated, and furthermore the USPSTF authors failed to realize that this statistic is time-specific and depends necessarily on the length of follow-up. The Piecewise exponential (PWE) model, a robust and widely used approach to survival analysis particularly suited for situations involving nonproportional hazards - as such those in ERSPC where the relative hazards for prostate cancer specific death and, therefore, the absolute mortality differences, change over time, allowing flexibility in defining the shape of the hazard function over time needed in situations such as prostate cancer screening trials where the delayed emergence of a mortality benefit can be expected - can be used to estimate the number needed to diagnose for prostate cancer screening to in fact decrease to approximately 20 at 12 years of follow-up in the ERSPC [15] as a whole, and (using simulation-based competing risks model) to decrease to approximately nine at 25 years of follow-up [16].

The USPSTF authors attempt to buttress their wider claim of the lack of significant positive effect of PSA-based screening on prostate cancer-specific mortality, by citing two recent meta-analyses, the Djulbegovic meta-analysis [4] and the Cochrane systematic review [5], claiming “no pooled effect of screening”. But combining different types of screening trials in meta-analysis is improper. Furthermore, two of trials meta-analyzed -the Quebec RCT [6] and the Norrköping RCT [7] exhibited significant methodological flaws.

FLAWS IN SUPPORTING TRIALS: NORRKÖPING, QUEBEC, ERSPC, PLCO, PIVOT

PROBLEMS IN THE NORRKÖPING AND QUEBEC TRIALS

For example: in the Norrköping RCT [7], the trial protocol assures that some men may only have ever received one PSA test, and also assures that no one will ever have received more than two PSA tests. Based on these and other methodological flaws, lead study author Dr. Gabriel Sandblom (Karolinska Institute) himself acknowledged that "the study was initiated more than 20 years ago, when PSA [prostate specific antigen testing] was not available and the treatment of localized prostate cancer was not as effective as it is today. I would thus not categorically advise against PSA testing . . . " [8].

Similarly, in the Quebec RCT [6], the fatal methodological flaw was the extremely poor compliance with the screening intervention itself: screening occurred in only 23.6% of the group randomized to screening, compared to 7.3% of the group randomized to no screening, so that 76.4% of the screening population never actually received the intended interventio, and with screening occurring in only 16.3% more of the screened group than in the unscreened group. Based on the available formula to determine sample size accounting for non-compliance developed by the NHMRC Clinical Trials Centre (Sidney, AU) [9], based on the components of (1) trial power, (2) level of significance, (3) Underlying population event rate, and (4) size of treatment effect, the trial would have required over half a million subjects per arm to find a difference with the same power [10].

PROBLEMS IN THE ERSPC AND PLCO TRIALS

The results of these trials (ERSPC [2], and the PLCO trial [12]) should not have been pooled together in the meta-analysis: PLCO is US-based, where PSA was widespread (first year of the PLCO trial, 40% in the control arm underwent PSA testing, with contamination of 52% by year six.) while ERSPC is European-based where background rates of PSA testing were very low (with contamination no more than 15%) [13].

Although the PLCO (Prostate Lung Colorectal and Ovarian Cancer) screening trial [12] reported no benefit from PSA-based screening for prostate cancer, an estimated 85% of men in the planned ‘non-screened’ group actually had been screened, and that with this fatal flaw alone, that of a high rate of screening among controls, any differences between groups would be dramatically reduced, so we can safely conclude that the PLCO study lacks the statistical power to reach any valid conclusion [14,23]. Indeed, control arm screening only can explain the null result in the PLCO trial [30].

But there are still others grave flaws in the PLCO Trial: (1) greater than 50% “contamination” rate by non-protocol PSA measurements in the control group, (2) prescreening of 40% of study participants before enrollment in the trial, and (3) the fact that two thirds of patients with abnormal screening tests did not have prompt biopsy, collectively impairing any claim that the PLCO Trial is a legitimate screening trial [24].

A further limitation of both the PLCO the ERSPC trials was their restriction to a median follow-up of roughly 10 years, likely inadequate for an often slowly progressive malignancy like prostate cancer. For that reason it is odd that little weight was given by USPSTF to the longer Göteborg RCT [11], which exhibited better protocol compliance, having 3% contamination, 93% complying with biopsy recommendation, and 77% having 14-year follow-up. The Göteborg RCT showed a 41% decrease in advanced disease (66% in men actually screened) and a 44% decrease (risk ratio = 0.56) in prostate cancer mortality (56% in men actually screened), despite one-third being solely under with active surveillance management [16]. In this robust trial, the number needed to treat to save one life was 12; note that this compares quite favorably with breast cancer screening programs.

Furthermore, with regard to PLCO, as leading prostate cancer epidemiologist Ruth Etzioni has convincingly argued [26], the PLCO trial neither can be interpreted as a negative study, nor as supporting the claim that screening has no benefit since in fact, as we have noted above, considering only the healthy men in the trial, there was a significant 27% cancer-specific mortality benefit from PSA-based screening.

PROBLEMS IN THE PIVOT TRIAL

As to PIVOT (Prostate cancer Intervention Versus Observation Trial) [27], this trial that was included in the critical underlying USPSTF considerations, was manifestly statistically underpowered: with an enrollment target of 2,000 men, only 731 could be enrolled 731. In addition, there were other serious flaws: (1) patients were largely older VA (Veterans Administration) hospital patients, known to have more comorbidities [29]; (2) although the trial had an explicit enrollment criterion of a 10-year life expectancy, on the contrary by 10 years, fully half the patients had died. This assured that rather than healthy candidates for either surgery or observation being recruited, PIVOT in fact recruited men with limited life expectancy, who moreover were only candidates for observation, and then proceeded, against better wisdom, to randomized half of them to surgery.

USPSTF IGNORES THE ROBUST GÖTEBORG TRIAL

The USPSTF was wrong to give equal weight to ERSPC on one side and PLCO and PIVOT on the other, considering the extensive flaws of PLCO and PIVOT.

The USPSTF gave little weight to the independent, longer, and better-designed Göteborg population-based screening trial [11], having 3% contamination, 93% complying with biopsy recommendation, and 77% having 14-year follow-up. There was a 41% decrease in advanced disease (66% in men actually screened) and a 44% decrease in prostate cancer mortality (56% in men actually screened) despite one-third being managed with active surveillance. The number needed to treat to save one life was 12, comparing favorably with breast cancer screening programs. If we assume overdiagnosis and screening efficacy consistent with known U.S. incidence, then we can project that, after 25 years of follow-up, 186 to 220 men need to be screened, and only two to five additional men need to have screen-detected prostate cancer to prevent one prostate cancer death [16].

FALSE CLAIMS RE ANXIETY/PSYCHOLOGICAL HARM

As to harm, the USPSTF both overstates the potential psychological harms, and, worse, claims that there were no RCTs of PSA-based screening's potential psychological harm. This is completely false, and moreover was so at the time of the USPSTF review. Three different RCTs reported no detrimental effect on men's anxiety levels or generic health status [17-20]. Thus, although some anxiety associated with having a prostate biopsy certainly may occur, side effects are usually mild and short-term transient, as for example one recent RCT [21] reported that only 6% of patients had high anxiety while almost half (45%) reported no anxiety at all.

OTHER HARMS OVERESTIMATED

The USPSTF authors claim a 0.5% 30-day perioperative mortality rate after radical prostatectomy, but we note that this is based on a study of Medicare claims from 1991 to 1994, meaning older patients who were treated almost 20 years ago, but the more contemporary estimates of perioperative mortality in the recent population-based study for all men treated are one fifth of that, close to 0.1% [22].

USPSTF RECOMMENDATIONS ARE INAPPROPRIATELY AGE-INDEPENDENT

Somewhat bizarrely, the USPSTF recommendation opposes PSA testing regardless of age. But given that although the expected lifespan of a 75 year old man is about 10 years, for men at age 45 to 50 years the lifespan reaches 30 years. So although it may be plausible that many men >= 75 years will die of other causes before developing metastatic prostate cancer, the current USPSTF recommendation, in a claimed attempt to avoid adverse effects of screening we have already disputed above, is likely to result in delayed diagnosis of curable cancer in younger men presenting with advanced disease and thus significantly raise the numbers of those who will consequently die of prostate cancer. This appears secondary to the fact that the USPSTF recommendation relies exclusively on mortality data from the PLCO and the ERSPC trials and from the early data from the PIVOT (Prostate Cancer Intervention Versus Observation Trial) [27], but studies with only a 10-year median follow-up are arguably insufficient to dictate how, say 45 - to 60-year-old men with prostate cancer should be treated.

Taking an even odder stand, USPSTF authors strongly recommend against testing men older than 75 years of age, but this is against the evidence since although the >75 years age group represents only 26% of prostate cancer cases, it represents almost half (48%) of all metastatic prostate cancer cases and more than half (53%) of deaths from prostate cancer [28], making it clear that older men with aggressive disease may benefit significantly from early detection and treatment.

USPSTF IGNORES BENEFITS OF REDUCTION OF ADVANCED DISEASE

In addition, USPSTF overlooked the fact that diagnostic procedures and related complications are not solely the purview of screened populations, but that these also occur in unscreened populations, and - importantly -typically at later stages of cancer discovery. This can be seen from the ERSPC trial, where higher-grade cancer (with a Gleason score ≥7) was almost twice as common in the control group (45.2%) as in the screened group (27.8%), accompanied by a 40% greater incidence of locally advanced and metastatic cancer, so by focusing on mortality, the USPSTF overlooked the substantial morbidity and suffering associated with living with advanced cancer (painful bone metastases, pathologic fractures, and urinary tract obstruction, among others). Indeed, in all of the screening trials, we find a lower rate of advanced disease in the screening arm, and tellingly as Emil Scosyrev at the University of Rochester and colleagues elegantly demonstrated [28], if we applied the pre-PSA era metastases rates to today’s U.S. population, we would be three times as many metastatic cases (17,000 more) diagnosed each year, clearly a disastrous state of affairs, especially for the patients to say nothing of the total societal burden of such advanced disease.

SUMMARY

In conclusion, the best trials that are available to date, which are currently still in progress, have demonstrated that screening can reduce prostate cancer death by 20% to 44% (ERSPC [2,3], Göteborg [11], and the USPSTF recommendations against screening on the basis of “moderate or high certainty” of no benefit is founded as we have demonstrated on errors fact, interpretation, statistics, methodology and misunderstandings of core principles of evidence-based medicine. In addition, if we extrapolate the ERSPC results to the long-term US setting, PSA-based screening provides a five times greater absolute mortality reduction. Furthermore, screening plausibly explains 45% of the prostate cancer mortality decline in the US, while changes in primary treatment can explain 33% of this prostate cancer mortality decline [30]. Extrapolating the ERSPC results to the long-term US setting implies an absolute mortality reduction at least 5 times greater than that observed in the trial, and approximately 28% of screen-detected cases are overdiagnosed (US) versus the 58% of screen-detected cases suggested by the ERSPC results. And in general, estimates of the frequency of overdiagnosis in breast and prostate cancer screening vary greatly across studies [31].

Collectively, the above commentary and critiques demonstrate that (1) the USPSTF are not based on strong evidence-based foundations as they need to be, that (2) the trials used to support their conclusions are fatally tainted by severe methodological flaws, that (3) the USPSTF authors proffer numerous and critical factual errors, and that (4) their discussion exhibits several lines of significant misreasoning, which in the aggregate rob their recommendations of clinical relevance and reliability and as such should not inform current clinical practice in prostate cancer screening, diagnosis and consequent therapeutics.

METHODOLOGY OF THIS REVIEW

A search of the PUBMED, Cochrane Register of Controlled Trials, MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, (WoS) Web of Science, BIOSIS, LILACS and Scirus databases was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). A further "broad-spectrum" science search using Scirus (410+ million entry database) was then deployed for resources not otherwise included. Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.

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My advice is exactly what I, as a clinical pathologist have always maintained "Beware of numbers" and rely on clinical impression. This idea that PSA numbers can be useful in a universal sense is really the product of business concerns and not one based in medical science. Hoorah for the USA finally acknowledging that the use of PSA numbers for selection of therapy does far more harm than good. Maybe someday we can return to medicine and use numbers only in support of a clinical impression. And of course, we must still remember "Above all else, do no harm."

Because their is no perfect bio marker and PSA is still our best and economically esthetic we need to evaluate prostate adenocarcinoma aggressively for the many it affects. It can still be cost effectively reviewed in a large population and at a cost that we must still bear. Cost after our diagnosis at this point and time needs to be appreciated as the cost of doing business. Other options are a sieve that will cost lives in each generation and that should be our message to funding physicians and the like. Yes, so many negative biopsies will eventually be overcome with enhanced bio markers which to this day are not available but remain the hot topic of urological oncological research. Save and maintain the precious few life's were can affect to the better. The support of anything else is a detriment to society.

Just as a news. One of the proposals made to prepare the next French Cancer Plan (the 3rd one), is to stop paying for PSA testting for all men without urological symptoms. 1.3 million tests are being made annually for a cost of 150 million euro. Another goal being given is to decrease the number of prostatectomies by 20%.

It looks like that the evidence against screening are gaining weight in a country where PSA screening is intense when NO official institution (health ministry, High Committe on Health, Nationa lCancer Institute) is recommending it. Only the Urologist organization is advocating for PSA "individual" screening.

A well treated prostate adenocarcinoma if organ confined is well treated by any number of surgical procedures including the gamma knife, brachytherapy, da Vinci robot, laparoscopic and open. Yes, with the last twenty years of screening we are capturing many tumors which depending on Gleasons score and Stage may not need to be treated. However, the diversity of treatment invasiveness is now becoming so minute that if the patient fears CAP presence in their life the CAP should be treated. Early screening at 50 and at 40 for strong family history is a reasonable price to pay for ones Heath . We have learned so much about CAP these last twenty years because of aggressive screening and more research highlights are right around the corner.we must pull together as a community and advocate continued screening for this readily treated tumor.

If we will use the PSA only in sintomatic patientes the CAP that we will diagnose will be only local advanced cáncer.

The syntoms of BPH are different of prostate cáncer screening. We are going back 20 or 30 years if we diagnose the prostate cáncer in sintomatic patients.

Why is everyone determined to ignore prostate cancer and still believe that it is an innoccous disease? The only time to cure it is when it is only indicated by PSA. If you wait for symptoms of LUTS, then the cancer has gone from the periphery of the gland to the transitional zone, and is a much more advanced disease. LUTS are caused by BPH, not cancer. That fact is self evident. The French system is, I am afraid to say, deluding itself if it thinks that prostate cancer treated when it causes urinary obstruction is as curable as asymptomatic cancer. The devastation of this descision will be be borne by the castrate patients dying of prostate cancer (and their families) in 10-15 years.

No-one has explained to me how I am to diagnose early, curable prostate cancer in a population without some PSA testing. Also remember, diagnosis does not equal and should not equal radical treatment. Yes, there has been over treatment, but that realisation has come about over a period of time and is in part due to surgeons looking at removed prostate specimens and saying 'There's very little cancer in this gland, could we start delaying/avoiding treatment in some/many men?'. Now we can accurately (or more accurately) counsel men about their risks of dying from prostate cancer. You certainly cannot do that in someone if you don't know they have cancer at all! It's very simple. If you diagnose the cancer, you have choices and information. If you never diagnose prostate cancer, you have darkness and no choice. You will have fewer incontinent and impotent patients, but you will have a lot of dead patients also who can't respond to your quality of life surveys etc. Be careful what you wish for if you completely devalue and demonise PSA. Do the test, biopsy the appropriate patients and treat the ones that need treatment. Don't live in ignorance.

It has taken us a very long time to reach where we are since the advent of PSA, but the process has refined us in diagnosing PCa. The treatment modalities has increased exponentially, although not all are evidence driven, thus resulting in the "mess" that we are in now - overdiagnosed and more importantly, overtreated PCa. I think, the correct response is to adopt an evidence approach in distinguishing the clinically significant PCa from those which are not (yet), using a multimodal approach, including PSA, DRE, and even multiparametric MRI. However, to stop using PSA is like throwing the baby together with the bath water.

Excellent discussion so far on this rather confusing subject. Three important issues needs to be considered. 1. The biological potential of prostate cancer is variable ( Had prostate cancer uniformly fatal like bladder or cervical cancer) screening, early detection and early treatment would never become controversial; 2. Screen detected cancer and treatment has not led to a decrease in the mortality; 3. Screening has become controversial due its cost effectiveness and Urologist over enthusiatic approach towards invasive treatment including radical prostate surgery has put doubts in the mind of medical care adminstrators like American Task force.

To add to the conversation and on the side of not discarding PSA as a screening tool I would like to site a newly published article.

Prostate-specific Antigen-Based Prostate Cancer Screening: Reduction of Prostate Cancer Mortality After Correction for Nonattendance and Contamination in the Rotterdam Section of the European Randomized Study of Screening for Prostate Cancer.

Abstract

BACKGROUND:

Large randomized screening trials provide an estimation of the effect of screening at a population-based level. The effect of screening for individuals, however, is diluted by nonattendance and contamination in the trial arms.

OBJECTIVE:

To determine the prostate cancer (PCa) mortality reduction from screening after adjustment for nonattendance and contamination.

DESIGN, SETTING, AND PARTICIPANTS:

A total of 34 833 men in the core age group, 55-69 yr, were randomized to a screening or control arm in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC). Prostate-specific antigen (PSA) testing was offered to all men in the screening arm at 4-yr intervals. A prostate biopsy was offered to men with an elevated PSA. The primary end point was PCa-specific mortality.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

Nonattendance was defined as nonparticipation in the screening arm. Contamination in the control arm was defined as receiving asymptomatic PSA testing or a prostate biopsy in the absence of symptoms. Relative risks (RRs) were calculated with an intention to screen (ITS) analysis and after correction for nonattendance and contamination using a method that preserves the benefits obtained by randomization.

RESULTS AND LIMITATIONS:

The ITS analysis resulted in an RR of 0.68 (95% confidence interval [CI], 0.53-0.89) in favor of screening at a median follow-up of 13 yr. Correction for both nonattendance and contamination resulted in an RR of 0.49 (95% CI, 0.27-0.87) in favor of screening.

CONCLUSIONS:

PCa screening as conducted in the Rotterdam section of the ERSPC can reduce the risk of dying from PCa up to 51% for an individual man choosing to be screened repeatedly compared with a man who was not screened. This benefit of screening should be balanced against the harms of overdiagnosis and subsequent overtreatment.

http://www.ncbi.nlm.nih.gov/pubmed/23954085

Evangelos:

Yes, that is an important study; I did cover it in my review, posted above (reference #32 there), citing as you did also a PSA-driven 51% reduction in the risk for dying of prostate cancer after adjustment for nonattendance and contamination, but it is I think useful for the reader of these discussions to have the full abstract, so thanks for posting that!

And always glad to meet a fellow compatriot and professional.

Constantine

"Nothing is more terrible than active ignorance" Goethe.

Some bullet points in my mind:

-All the guidelines become more prudent about PCa screening.

-Screening only BPH symptomatic patients will discover indolent or unexpected adn asymptomatic tumors.

-PSA remains the only test for wide population evaluation.

-A lot of PCA can be observed and followed without significant impact on overall survival.

-The biopsy provides all the best prognostic variables and is a reliable tool to evaluate the aggressiveness and the survival-related issues

-The main problem to accept that "diagnosis does not equal and should not equal radical treatment" as David Bouchier-Hayes said.

Probably we need to be deeply persuaded about the terapeutic options we offer to the patients and increase our communication skills, sharing with the patients and theri relatives the true risks of a delayed treatment or an active surveillance.

"Ignorance is the root of all evils". Socrates

AMSTERDAM — To the ongoing debate over whether routine screening for prostate cancer reduces prostate cancer mortality comes a new analysis that suggests that it does more harm than good. http://www.medscape.com/viewarticle/811846?nlid=34823_1885&src=wnl_edit_dail&uac=207949SK

This is a very controversial issue as we all know. Attached is a letter to the editor of the Journal of Urology that I co-authored with Drs Walsh, Catalona and many others that summarizes one viewpoint in favor of continued use of the PSA test and especially for high risk individuals.

Those recommendations are sound and logical to me and are based upon many studies showing little or no benefit and considerable harm from PSA screening. Like any test, it should be used by a knowledgeable person who knows the risks and benefits and chooses a test or treatment knowing the reasons for it ans how to interpret the results. The days should be long over where urologists resect anyone who moves based on a slightly elevated PSA.

The recent Swedish study does show some long term benefit of survival (at 18 years) of surgically treated patients if these were young, and this goes along with the recommendations to screen younger patients for potential elevation.

I hope that the AUA returns to the concept of using a baseline PSA in young men (age 40-45) to risk-stratify for the future liklihood of prostate cancer. While some will call this "screening" others contend this is just prudent personalized medicine. Anyway, there is quite a good body of literature. In general, young men at 40-45 who have a PSA less than 1.0 are very low risk and do not have to be tested yearly and probably can wait 5 years to be tested again. For young men who have a PSa from 1.1 to 2.4; they would be considered grry zone and testing every year may be prudent. Young men who have a PSA of 2.5 or greater should consider referral to a urologist for expert exam and counselling. The article below provides more information.

I believe that screening for prostate cancer improves survival, particularly in men at high risk. I do not believe that serum psa is the best biomarker with which to screen. I think we will see a lot of movement in this field over the next few years with development of tests with better specificity for aggressive prostate cancer.

Msmb and kallikrein variants would seem to be front runners.

A four-kallikrein panel predicts prostate cancer in men with recent screening: data from the European Randomized Study of Screening for Prostate Cancer, Rotterdam.

AuthorsVickers AJ, et al. Show all Journal

Clin Cancer Res. 2010 Jun 15;16(12):3232-9. doi: 10.1158/1078-0432.CCR-10-0122. Epub 2010 Apr 16.

Affiliation

Abstract

PURPOSE: We have developed a statistical prediction model for prostate cancer based on four kallikrein markers in blood: total, free, and intact prostate-specific antigen (PSA), and kallikrein-related peptidase 2 (hK2). Although this model accurately predicts the result of biopsy in unscreened men, its properties for men with a history of PSA screening have not been fully characterized.

EXPERIMENTAL DESIGN: A total of 1,501 previously screened men with elevated PSA underwent initial biopsy during rounds 2 and 3 of the European Randomized Study of Screening for Prostate Cancer, Rotterdam, with 388 cancers diagnosed. Biomarker levels were measured in serum samples taken before biopsy. The prediction model developed on the unscreened cohort was then applied and predictions compared with biopsy outcome.

RESULTS: The previously developed four-kallikrein prediction model had much higher predictive accuracy than PSA and age alone (area under the curve of 0.711 versus 0.585, and 0.713 versus 0.557 with and without digital rectal exam, respectively; both P < 0.001). Similar statistically significant enhancements were seen for high-grade cancer. Applying the model with a cutoff of 20% cancer risk as the criterion for biopsy would reduce the biopsy rate by 362 for every 1,000 men with elevated PSA. Although diagnosis would be delayed for 47 cancers, these would be predominately low-stage and low-grade (83% Gleason 6 T(1c)).

CONCLUSIONS: A panel of four kallikreins can help predict the result of initial biopsy in previously screened men with elevated PSA. Use of a statistical model based on the panel would substantially decrease rates of unnecessary biopsy.

(c) 2010 AACR.

PMID 20400522 [PubMed - indexed for MEDLINE]

PMCID PMC2891337 Free Full Text

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