Do men with lower urinary tract symptoms have an increased risk of advanced prostate cancer?
BMJ 2018; 361 doi: https://doi.org/10.1136/bmj.k1202 (Published 03 May 2018) Cite this as: BMJ 2018;361:k1202
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There is no mention of the relatively new PHI (prostatic health index) which is a mathematical formulation incorporating PSA, free PSA and (-2)proPSA as a screening option. What is your opinion of this?
Competing interests: No competing interests
Dear Dr. David J Jones
Thank you for your interest and the organizing of an algorithm. We agree that your algorithm quite accurately summons up our advised approach. Of course, algorithms in general have limitations but are also helpful in gaining an overview - thank you for your thorough and clear input.
Dear Brian D Nicholson and Dr Samuel W D Merriel
Thank you for your comments. You argue that men attending primary care with LUTS are at higher risk of prostate cancer than men from screening populations or from the general population. The studies you refer to, like you mention, do not differentiate clinically significant from non-significant cancers. We therefore do not know to what degree the diagnosed prostate cancers are advanced or potentially fatal. The higher risk of prostate cancer in men attending primary care might also be due to increased PSA testing among these men and a diagnosis of indolent or not harmful prostate cancer. A Danish study in general practice found that in practices with the highest PSA test rate, men were at increased risk of getting a prostate cancer diagnosis, but more men were diagnosed with local stage disease with no difference regarding regional or distant stage. Furthermore, prostate cancer and overall mortality did not differ between practices with different PSA test rates. (1) Another American cohort study found that a possible cause of the association between LUTS and PCa is increased diagnostic intensity among men whose LUTS come to the attention of physicians. (2) We therefore tend to think that the reason for the higher risk of prostate cancer in men attending primary care is more due to the PSA testing by physicians than patient differences.
References
1. Hjertholm P, Fenger-Gron M, Vestergaard M, Christensen MB, Borre M, Moller H, et al. Variation in general practice prostate-specific antigen testing and prostate cancer outcomes: an ecological study. International journal of cancer. 2015;136(2):435-42.
2. Weight CJ, Kim SP, Jacobson DJ, McGree ME, Boorjian SA, Thompson RH, et al. The effect of benign lower urinary tract symptoms on subsequent prostate cancer testing and diagnosis. European urology. 2013;63(6):1021-7.
Dear Dr. Christopher Booth
Thank you for your comments. Below you will find our responses to your points:
* LUTS are not a risk factor for PCa but PCa may present with LUTS, therefore a PSA should be performed. A result >1.4ng/ml but within the age-related normal range suggests a likely diagnosis of BPH. If above the upper limit of the range, UTI etc should be ruled out, the PSA repeated and if still abnormal, referral to a urologist would be the safest option.
Re. We disagree, because the non-evidence-based argument would lead to much overdiagnosis of PCa
*Failure to perform a PSA in a patient with LUTS, possibly initiating treatment for presumed BPH, would place a GP at risk of a successful case of negligence if the patient is subsequently diagnosed with advanced PCa a year or two later.
Re. Our paper can be used as best available evidence that PSA testing is NOT indicated in men with LUTS. Our paper can also be used as best available evidence to show that if PSA testing is conducted routinely in men with LUTS this lead to substantial harms - overdiagnosis and thereby overtreatment of PCa.
* This third bullet point is straying into the territory of the screening debate but fails to mention the benefits of PSA screening where European programmes are reporting falls above 40% in PCa mortality. Balanced counselling must present the benefits as well as the accepted harms, only then can a patient make an Informed Choice as recommended by all the guidelines.
Re. Here the author conducts cherry picking by not using best available evidence: The Cochrane review the USPSTF systematic review on PSA screening. Moreover, the author does not tell the reader how much overdiagnosis of PCa PSA screening leads to.
In conclusion, the 4th UK National Prostate Cancer Audit reports that over-treatment of non-aggressive PCa has now fallen to 8%. By contrast our annual death rate from PCa is one of the worst in the western world at over 11,800 cases. Surely a case for a more informed use of PSA.
Re. Our conclusion from best available evidence is that PSA screening and PSA testing in men with LUTS do not reduce the mortality of PCa.
Dr. Christopher M Booth and Dr. Paul Male indicate that GPs should conduct a PSA test in patients with LUTS for legal reasons and to avoid patient complaints – despite the fact that this practice results in overdiagnosis. We hope and believe that this article, representing best available evidence, can be used as a legal argument that there is no medical argument for routinely conducting a PSA test in men with no other symptom or risk factor than LUTS. In practice it can be a challenge, but we do not find that potential patient complaints can justify patients being harmed by overdiagnosis and overtreatment.
Competing interests: No competing interests
This paper illustrates a disconnect between UK clinical practice in Primary Care, standard practice in Secondary Care and what increasingly well informed patients now expect in relation to the diagnosis of Prostate Cancer (PCa) at an early, curable stage. Consequently, the message of the paper, summarised into 3 bullet points "WHAT YOU NEED TO KNOW", seriously risks leading GPs into dangerous medico-legal territory:
* LUTS are not a risk factor for PCa but PCa may present with LUTS, therefore a PSA should be performed. A result >1.4ng/ml but within the age-related normal range suggests a likely diagnosis of BPH. If above the upper limit of the range, UTI etc should be ruled out, the PSA repeated and if still abnormal, referral to a urologist would be the safest option.
*Failure to perform a PSA in a patient with LUTS, possibly initiating treatment for presumed BPH, would place a GP at risk of a successful case of negligence if the patient is subsequently diagnosed with advanced PCa a year or two later.
* This third bullet point is straying into the territory of the screening debate but fails to mention the benefits of PSA screening where European programmes are reporting falls above 40% in PCa mortality. Balanced counselling must present the benefits as well as the accepted harms, only then can a patient make an Informed Choice as recommended by all the guidelines.
In conclusion, the 4th UK National Prostate Cancer Audit reports that over-treatment of non-aggressive PCa has now fallen to 8%. By contrast our annual death rate from PCa is one of the worst in the western world at over 11,800 cases. Surely a case for a more informed use of PSA.
Competing interests: No competing interests
Thank you for your fascinating educational article on the uncertainties of PSA testing.
As a junior doctor I read with interest. Would you agree that the algorithm (link below) would accurately sum up the pragmatic approach you advise?
With thanks
David
link:
https://thoughtfresh.wordpress.com/2018/05/10/bmj-rapid-response-psa-tes...
Competing interests: No competing interests
The spectrum effect tells us that using evidence from PSA screening (1-4) or LUTS survey data from the general population (5-7) to inform diagnostic practice in primary care may not result in the right answer, and possibly leads to the wrong question (8).
Studies including populations of men with LUTS attending primary care, not cited in Jákupsstovu and Brodersen’s insightful article about the perils of prostate cancer overdiagnosis in men with LUTS (9), show that men who attend their GP with LUTS are at a higher risk of prostate cancer than those who don’t (10, 11). They show that men attending primary care with LUTS are at higher risk of prostate cancer than ‘asymptomatic’ screened men or men from the general population asked if they suffer LUTS. The difference is the higher prior odds of prostate cancer in men visiting their GP with LUTS: men who choose to visit their GP with LUTS are different from those that don’t. Whilst the risk may be higher, these studies do not document the method used to assess the LUTS present or differentiate clinically significant from non-significant cancers. They are reliant on routinely collected primary care records data without linkage to stage and grade information from the cancer registry.
Jákupsstovu and Brodersen’s call for research to improve our investigative approach to detect clinically significant prostate cancer is timely (9). However, whilst focussing on testing to detect advanced prostate cancer may prevent the overdiagnosis of non-significant cancers, it could miss clinically significant tumours at an early stage that have the potential to advance. A test (or tests) that could detect a clinically significant tumour at an early stage would have greater utility as curative treatment is still possible. Recent trials have shown that multiparametric MRI holds promise to triage men with a raised PSA into those men likely to have clinically significant tumours that could necessitate a biopsy and those for whom no further investigation is indicated (12, 13). Once biopsy is performed, further refinement of active surveillance strategies could reduce downstream harms further by reducing overtreatment of men with low-risk disease (14).
We cannot disagree with Jákupsstovu and Brodersen’s assessment that the type and severity of LUTS does not appear to relate to prostate cancer stage. We agree that GPs should communicate the uncertainties of testing male patients attending with LUTS prior to initiating investigations for prostate cancer. However, if investigation was focused on the detection of clinically significant disease it could allow non-indolent cancers to be detected in time for meaningful intervention in men with LUTS attending primary care.
Dr Brian D Nicholson GP, Clinical Researcher, University of Oxford.
Dr Samuel W D Merriel, NIHR Academic Clinical Fellow in General Practice, Honorary Lecturer, University of Bristol.
References
1. Collin SM, Metcalfe C, Donovan J, Lane JA, Davis M, Neal D, et al. Associations of lower urinary tract symptoms with prostate-specific antigen levels, and screen-detected localized and advanced prostate cancer: a case-control study nested within the UK population-based ProtecT (Prostate testing for cancer and Treatment) study. BJU international. 2008;102(10):1400-6.
2. Franlund M, Carlsson S, Stranne J, Aus G, Hugosson J. The absence of voiding symptoms in men with a prostate-specific antigen (PSA) concentration of >/=3.0 ng/mL is an independent risk factor for prostate cancer: results from the Gothenburg Randomized Screening Trial. BJU international. 2012;110(5):638-43.
3. Ilic D, Neuberger MM, Djulbegovic M, Dahm P. Screening for prostate cancer. The Cochrane database of systematic reviews. 2013(1):Cd004720.
4. Matsubara A, Yasumoto H, Teishima J, Seki M, Mita K, Hasegawa Y, et al. Lower urinary tract symptoms and risk of prostate cancer in Japanese men. International journal of urology : official journal of the Japanese Urological Association. 2006;13(8):1098-102.
5. Martin RM, Vatten L, Gunnell D, Romundstad P, Nilsen TI. Lower urinary tract symptoms and risk of prostate cancer: the HUNT 2 Cohort, Norway. International journal of cancer. 2008;123(8):1924-8.
6. Rosen R, Altwein J, Boyle P, Kirby RS, Lukacs B, Meuleman E, et al. Lower Urinary Tract Symptoms and Male Sexual Dysfunction: The Multinational Survey of the Aging Male (MSAM-7). European Urology. 2003;44(6):637-49.
7. Boyle P, Robertson C, Mazzetta C, Keech M, Hobbs R, Fourcade R, et al. The association between lower urinary tract symptoms and erectile dysfunction in four centres: the UrEpik study. BJU international. 2003;92(7):719-25.
8. Usher-Smith JA, Sharp SJ, Griffin SJ. The spectrum effect in tests for risk prediction, screening, and diagnosis. Bmj. 2016;353:i3139.
9. Østerø í Jákupsstovu J, Brodersen J. Do men with lower urinary tract symptoms have an increased risk of advanced prostate cancer? BMJ. 2018;361.
10. Hamilton W, Sharp DJ, Peters TJ, Round AP. Clinical features of prostate cancer before diagnosis: a population-based, case-control study. The British journal of general practice : the journal of the Royal College of General Practitioners. 2006;56(531):756-62.
11. Hippisley-Cox J, Coupland C. Symptoms and risk factors to identify men with suspected cancer in primary care: derivation and validation of an algorithm. The British journal of general practice : the journal of the Royal College of General Practitioners. 2013;63(606):e1-10.
12. Ahmed HU, El-Shater Bosaily A, Brown LC, Gabe R, Kaplan R, Parmar MK, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet (London, England). 2017;389(10071):815-22.
13. Kasivisvanathan V, Rannikko AS, Borghi M, Panebianco V, Mynderse LA, Vaarala MH, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. The New England journal of medicine. 2018.
14. Tosoian JJ, Carter HB, Lepor A, Loeb S. Active surveillance for prostate cancer: current evidence and contemporary state of practice. Nature reviews Urology. 2016;13(4):205-15.
Competing interests: No competing interests
Do not routinely offer prostate specific antigen (PSA) testing in men with only lower urinary tract symptoms and no risk factors for prostate cancer.
This advice clearly illustrates the limits of evidence based medicine in guiding real life practice. Consider that both LUTS and prostate cancer are both very common. Just by chance a patient will see you with LUTS and will be diagnosed with prostate cancer perhaps 2 years later. You did not offer a PSA at the original consultation. We now know that the patient’s complaint of a missed diagnosis would be unjustified. But you will wish that you had offered a PSA after all.
In my view we should always routinely offer a PSA in such situations, with perhaps a leaflet pointing out what a useless test it is.
Competing interests: No competing interests
Author's reply
Thank you for the comment about the prostatic health index (PHI). We have not included PHI in our research question and we did not come across any evidence about PHI in our work. Therefore, we are unable to give an answer to surgeon Arthur Edward van Langenberg.
Competing interests: No competing interests