The diagnostic test accuracy of rectal examination for prostate cancer diagnosis in symptomatic patients: a systematic review

The diagnostic test accuracy of rectal examination for prostate cancer diagnosis in symptomatic... Background: Prostate cancer is the most common cancer in men in the UK. NICE guidelines on recognition and referral of suspected cancer, recommend performing digital rectal examination (DRE) on patients with urinary symptoms and urgently referring if the prostate feels malignant. However, this is based on the results of one case control study, so it is not known if DRE performed in primary care is an accurate method of detecting prostate cancer. Methods: The aim of this review is to ascertain the sensitivity, specificity, positive and negative predictive value of DRE for the detection of prostate cancer in symptomatic patients in primary care. CENTRAL, MEDLINE, EMBASE and CINAHL databases were searched in august 2015 for studies in which a DRE was performed in primary care on symptomatic patients and compared against a reference diagnostic procedure. Results: Four studies were included with a total of 3225 patients. The sensitivity and specificity for DRE as a predictor of prostate cancer in symptomatic patients was 28.6 and 90.7%, respectively. The positive and negative predictive values were 42.3 and 84.2%, respectively. Conclusion: This review found that DRE performed in general practice is accurate, and supports the UK NICE guidelines that patients with a malignant prostate on examination are referred urgently for suspected prostate cancer. Abnormal DRE carried a 42.3% chance of malignancy, above the 3% risk threshold which NICE guidance suggests warrants an urgent referral. However this review questions the benefit of performing a DRE in primary care in the first instance, suggesting that a patient’s risk of prostate cancer based on symptoms alone would warrant urgent referral even if the DRE feels normal. Keywords: General practice, Digital rectal examination, Prostate Cancer, Primary care, Early diagnosis Background cancer. Survival from prostate cancer is relatively good Prostate cancer is the most common cancer amongst with a five-year survival rate of 85% [1]. men with 41,736 cases diagnosed in the UK in 2011. There has been considerable debate about the benefits Over the last 35 years, the incidence of prostate cancer and harms of early diagnosis of prostate cancer, with has more than tripled, though much of this increase is much of the discussion focused around the use of PSA. likely to be due to the increasing use of prostate specific Evidence suggests survival is closely related to stage at antigen (PSA) blood tests. The mortality rate from pros- diagnosis, with 100% five year survival in patients diag- tate cancer in the UK is falling after reaching a peak in nosed with the earliest stage disease compared to less the 1990s, but in 2012, over 10,000 men died of prostate than 33% five year survival if diagnosed at the latest stage [1]. This suggests that early diagnosis of prostate cancer is important. Certainly once a patient is symp- * Correspondence: ugm4djj@gmail.com tomatic, there seems to be little benefit in delaying the Hull York Medical School, Hertford Building, University of Hull, Cottingham Road, Hull HU6 7RX, UK diagnosis. Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Jones et al. BMC Family Practice (2018) 19:79 Page 2 of 6 Asymptomatic screening using PSA is undertaken, and the PROSPERO register of systematic reviews (registra- accepted in some countries, including the US, however tion number PROSPERO 2015:CRD42015025764) [9]. the U.S. Preventative Services Task Force recommend a discussion on the potential benefits and harms of PSA Search strategy screening, stating that screening offers a “small potential A search was undertaken for empirical research using benefit of reducing the chance of dying of prostate MEDLINE, CINAHL, EMBASE and the Cochrane cancer” but also highlighting that “many men will ex- Register of Controlled Trials (CENTRAL). Each database perience potential harms of screening” [2]. In the UK, was searched from commencement to August 2015. screening is not recommended routinely, instead Public Grey literature was searched using the OpenGrey data- Health England runs a ‘prostate cancer risk management base. Citations of all potentially relevant reviews and program’ in which patients who are concerned about research papers were hand searched. No date or lan- prostate cancer are able to have a PSA test after a dis- guage restrictions were applied to the database searches. cussion with a GP on the benefits and harms of the test The following terms were used in the search all data- in order to make an informed choice [3]. As a result bases: prostate cancer, DRE, primary care. The search most prostate cancers in the UK are identified when pa- strategy and protocol and be accessed here http:// tients present to general practice with a symptom suspi- www.crd.york.ac.uk/PROSPERO/display_record.asp?ID= cious of prostate cancer such as nocturia or urinary CRD42015025764. Two reviewers (CF and AD) inde- frequency. It is also worth noting however that there is a pendently screened the title and abstract of all articles diagnostic challenge as both urinary tract infections and identified by the search to determine eligibility. Full texts benign prostatic hypertrophy often present in similar were obtained for all potentially relevant articles and ways and are much more common diagnoses [4, 5]. these were independently assessed by two authors (CF The National Institute for Health and Care Excellence and AD) to determine eligibility. Final inclusion was (NICE) has recently updated the guidance on recogni- determined by agreement between both reviewers. If no tion and referral of suspected cancer in the UK [6]. The consensus was reached, a third study author (DJ) was latest NICE guidelines give recommendations on the consulted. recognition and referral of prostate cancer. These guide- lines state patients should be referred urgently if the Eligibility criteria prostate feels malignant on digital rectal examination We searched for studies that evaluated the use of DRE and recommends performing digital rectal examination in primary care for the detection of prostate cancer. To (DRE) on patients presenting with any lower urinary be included in the review studies had to meet three in- tract symptoms including nocturia, urinary frequency, clusion criteria: studies should be randomized controlled hesitancy, urgency or retention [6]. A recommendation trials, case control or cohort studies; they needed to in- supported by Walsh et al. who reviewed DREs under- clude symptomatic patients with any of the symptoms taken in primary care and urology clinics for the diagno- listed in the NICE guidelines for referral of prostate sis of prostate cancer and concluded that DRE is a key cancer; and they studies needed to be conducted in pri- part of the assessment [7]. However, the evidence base mary care setting. Studies undertaken in secondary care for DRE in symptomatic patients is poor, with NICE or screening studies of asymptomatic patients were ex- guidelines documenting only one case control study by cluded. As this was a review of a diagnostic procedure Hamilton et al. [4]. As a result it is not known if DRE the studies should compare DRE to a reference test. The performed in primary care is an accurate method of reference for this review was histological diagnosis of detecting prostate cancer, or what the risk of prostate prostate cancer. The NICE guidelines do not define an cancer is, if the general practitioner deems the prostate abnormal DRE so definitions from all included studies to be malignant on examination. were considered. Methods Outcomes The aim of this review was to evaluate the effectiveness The primary outcomes were the sensitivity, specificity, of DRE performed by general practitioners as a predictor positive (PPV) and negative predictive value (NPV) of of prostate cancer in symptomatic patients in a primary DRE in primary care for the detection of prostate cancer care setting according to the latest NICE guideline in symptomatic patients. This was calculated using the recommendations. Meta-DiSc software [10]. Secondary outcomes were The reporting of this systematic review follows the cost-effectiveness and adverse effects as a result of the recommendations of the PRISMA (Preferred Reporting intervention. Heterogeneity is almost always presumed Items for Systematic Reviews and Meta-Analyses) state- in diagnostic test accuracy systematic reviews, and ment [8]. A protocol was developed and registered in hence, a random-effects model was used [11]. Jones et al. BMC Family Practice (2018) 19:79 Page 3 of 6 Data extraction patients with the exception of Issa [14] who used the Two reviewers (CF and AD) independently extracted international prostate symptom score (IPSS). All four data from included articles using a pre-defined data ex- papers included patients with at least one of symptoms traction form. Disagreements were resolved by discus- listed in the NICE cancer guidelines, however these were sion between the two reviewers with a third reviewer different in each paper. Three of the studies explicitly (DJ) consulted if necessary. Data were extracted on study defined an ‘abnormal DRE’ with the exception of participants including age, ethnicity, setting and symp- Gelabert Mas [16]. The three papers used very similar toms, the studies inclusion and exclusion criteria, the in- definitions of an abnormal prostate. Hamilton et al. state formation on the DRE and gold standard test of the that “hard, craggy or nodular glands were classified as study and study outcomes. malignant” [4], Issa et al. state that “DRE findings were classified as abnormal in the presence of prostate indur- Quality assessment ation and/or nodularity” [14] and Mettlin et al. state that The Newcastle Ottawa quality assessment scale [12]was “a suspicious DRE outcome is defined by the presence of used to evaluate the quality of included studies. This significant induration, nodularity or asymmetry” [15]. scale is recommended by the Cochrane Handbook for assessing methodological quality of non-randomised Diagnostic accuracy of DRE studies and was chosen as it was highlighted as a simple There were 3225 participants included from 4 different tool to apply using eight assessment domains [13]. studies. For each of the included studies we were able to Hamilton [4] was a case control study and was deter- calculate a 2 × 2 table for reference test (biopsy / diagno- mined to be of high methodological quality. The study sis of prostate cancer) results versus the diagnostic test adequately defined a case, stating they were identified (DRE). This data was then combined to give an overall from the cancer registry at the Royal Devon and Exeter sensitivity, specificity, PPV and NPV. This was calculated Hospital and controls were selected from the community using Meta-Disc software. Overall, the pooled sensitivity with no history of disease. The study adequately con- and specificity for DRE as a predictor of prostate cancer trolled for age and location. Exposure for both cases and in symptomatic patients was found to be 28.6% (95% CI controls was ascertained from the GP and hospital re- 25.1–32.3%) and 90.7% (95% CI 89.5–91.8%), respect- cords. All cases and controls were included in the final ively. These results are shown in Fig. 2. The pooled PPV results with no drop outs. and NPV were found to be 42.3 and 84.2%, respectively. Three cohort studies [14–16] were included and were There was no relevant data extractable regarding sec- judged to be of high methodological quality. All were ondary outcomes of adverse events or cost effectiveness. representative of the average age of men with prostate As three out of the four studies were cohort cancer in the community. Ascertainment of exposure for studies, we performed a sub-analysis of the cohort all studies was determined from a secure patient medical studies alone. This produced a sensitivity of 42.7% record. Participants with a history of prostate cancer (95% CI 37.8–47.7%), a specificity of 86.7% (95% CI were excluded in all studies. All studies controlled for 84.9–88.4%), a PPV of 46.1% and a NPV of 85.1%. symptomatic patients, location and performance of DRE. Showing that excluding the case control study did not However, it should be noted that none of the cohort significantly affect the results. studies included documentation of how biopsy was taken and whether the individual performing the biopsy Discussion was blinded of symptoms and DRE findings. To the authors´ knowledge, this is the first review to evaluate the specificity, sensitivity, positive and negative Results predictive value of DRE as a predictor of prostate cancer Study characteristics in symptomatic patients in a primary care setting. Four studies met the inclusion criteria and were in- With the release of the new cancer referral guidelines cluded in the review (see Fig. 1). The characteristics of in the UK the threshold of risk for referral for possible the included studies are shown in Table 1. Three of the cancer was reduced from 5 to 3%. This suggests that all studies were cohort studies [14–16] and one was a case patients with signs and symptoms which carry a risk of control study [4]. Two of the studies were conducted in cancer greater than 3% should be referred urgently to the US [14, 15], one was conducted in the UK [4] and secondary care. This review found the pooled positive one in Spain [16]. A total of 3225 patients were included predictive value of DRE to detect prostate cancer was in the four papers. The largest study had 1297 partici- 42.3%. This suggests that if a patient with symptoms sug- pants [4] and the smallest had just 82 [16]. The age of gestive of prostate cancer presents to primary care and participants in included studies ranged from 40 to 89. has an abnormal feeling prostate examination, then that All studies documented the symptoms suffered by patients risk of cancer is 42.3%. This clearly warrants an Jones et al. BMC Family Practice (2018) 19:79 Page 4 of 6 Fig. 1 PRISMA Diagram urgent referral for suspected cancer and supports the UK that DRE performed in primary care is an unnecessary NICE guidelines. investigation, adding little to the decision to refer, which However, the pooled sensitivity in this review was low, should be made on the basis of symptoms alone. In 28.6% suggesting that many patients diagnosed with addition to this, it is possible that DRE may delay the prostate cancer do not have an abnormal DRE. In patient in seeking help with some qualitative research addition to the low sensitivity, the pooled negative pre- finding that the prospect of a DRE may deter some men dictive value was 84.2%, this suggests that symptomatic from seeking medical help for symptoms suggestive of patients who present to primary care and have a normal prostate cancer and prostate cancer screening [17–19]. prostate examination still have a risk of cancer of 15.8%, This qualitative research suggests that performing DRE which above the 3% risk threshold suggested by NICE. in primary may in fact be delaying the diagnosis of These findings show that patients in these included prostate cancer. studies should be urgently referred for suspected pros- The UK NICE guidelines make their recommendations tate cancer regardless of the DRE result. This suggests to refer patients with a prostate deemed malignant on Table 1 Characteristics of included studies Study ID Country Evidence Methods Number of Age range Index test Reference Outcomes level participants (years) Mettlin 1991 USA 2b Prospective 1218 55–70 PSA, DRE and TRUS Biopsy Sensitivity, specificity and cohort study PPV of DRE, PSA and TRUS. Gelabert Mas 1997 Spain 2b Prospective 82 > 50 PSA/DRE Biopsy Sensitivity, specificity, and cohort study PPV of DRE and PSA. Hamilton 2006 UK 4 Case control 1297 ≥ 40 PSA/DRE Diagnosis of PPV of symptoms, DRE prostate cancer and PSA. Issa 2006 USA 2b Retrospective 628 40–89 PSA/DRE Biopsy Sensitivity, specificity, PPV cohort study and NPV of DRE and PSA. Jones et al. BMC Family Practice (2018) 19:79 Page 5 of 6 Fig. 2 Pooled sensitivity and specificity for DRE as a predictor of prostate cancer in symptomatic patients examination on the evidence from just one study. This Due to the nature of using secondary data, there were systematic review includes four studies which consider some papers in which full information was not available. the effectiveness of DRE for diagnosing prostate cancer It was agreed in each study the DRE had been performed in symptomatic patients in primary care and thus in primary care, however it was often not clear who had provides stronger evidence for performing DRE in these performed the examination. In addition to this, only patients. However, the majority of the available literature three of the four studies adequately defined an abnormal concentrates on using DRE as a screening test in unse- DRE, the forth study did not provide a definition of lected asymptomatic patients. More research on the abnormal or positive DRE. effectiveness of DRE in primary care would help to pro- One of the papers (Issa 2006) caused some difficulty in vide further evidence for the NICE guidelines and ensure analysis due to a possible typing error. In the text of the that DRE is a useful investigation when performed by study they state symptoms were classified as mild mod- GPs. erate or severe using IPSS with mild symptoms classified Whilst the included studies were judged to be of high between 1 and 7, however in the results they present methodological quality it is difficult to draw conclusions mild symptoms as 0–7, this could mean patients with an based on a small number of studies, all of which were IPSS score of 0, who may be asymptomatic were published over ten years ago, are of low impact and are included in the results. Clarification was sought from largely heterogeneous. In addition, there are limitations the authors however no response was received. of including case control studies in reviews of diagnostic The vast majority of existing literature focuses on the test accuracy as they tend to overestimate diagnostic use of DRE as a screening tool. A Cochrane review on accuracy. In addition to this Hamilton et al. included pa- screening for prostate cancer included five studies and tients diagnosed with prostate cancer by a urologist found that screening did not significantly decrease pros- without having a biopsy which means not all participants tate cancer-specific mortality [20]. This review supports in the study received the same index test. Whilst this the recommendations of NICE which suggests that GPs clinically makes sense and is common in studies in refer patients urgently on the basis of an abnormal DRE. which the reference test is invasive, it is nonetheless a The NICE recommendation was made on the basis of limitation of the study. These limitations were investi- the Hamilton 2006 paper which is included in this gated using a sensitivity analysis which excluded the review. There is also qualitative literature to suggest that Hamilton et al. study, it was found that excluding the the prospect of a DRE may deter men from presenting case control study did not significantly affect the results. to primary care. To be included in this review the papers had to include patients with at least one of the symptoms sug- Conclusion gested by NICE. However, in each paper the combin- The most recent UK NICE guidelines recommend that ation of symptoms in the patients was different and in general practitioners undertake a digital rectal examin- some was poorly defined. ation on all patients with lower urinary tract symptoms. Jones et al. BMC Family Practice (2018) 19:79 Page 6 of 6 The guidelines suggest referring patients under the two Received: 27 September 2016 Accepted: 18 May 2018 week wait referral pathway if the prostate feels malig- nant. This is the first review to look at the accuracy of References digital rectal examination by general practitioners for 1. Cancer Research UK. Cancer Statistics for the UK 2015 [cited 2015 27th July]. 2. Preventative Services US, Force T. Draft recommendation statement: the diagnosis of prostate cancer in symptomatic patients. prostate Cancer. Screening. 2017; We found only four studies on the effectiveness of DRE 3. Public Health England. Prostate Cancer Risk Management Programme 2015 for the diagnosis of prostate cancer in symptomatic pa- [cited 2015 27th July]. 4. Hamilton W, Sharp DJ, Peters TJ, Round AP. Clinical features of prostate tients in primary care, with much of the available litera- cancer before diagnosis: a population-based, case-control study. The British ture focusing on screening. DRE is widely used and journal of general practice : the journal of the Royal College of General recommended for the assessment of patients in primary Practitioners. 2006;56(531):756–62. 5. Frankel S, Smith GD, Donovan J, Neal D. Screening for prostate cancer. care. It is a simple, safe and cost-effective diagnostic Lancet. 2003;361(9363):1122–8. tool, The findings of the review support the NICE guide- 6. NICE. Suspected cancer: recognition and referral. 2015. lines and recommend urgent referral for suspected can- 7. Walsh AL, Considine SW, Thomas AZ, Lynch TH, Manecksha RP. Digital rectal examination in primary care is important for early detection of prostate cer in patients with an abnormal DRE, however the cancer: a retrospective cohort analysis study. The British journal of general review casts doubt on the use of DRE as a diagnostic practice : the journal of the Royal College of General Practitioners. tool in primary care due to the low sensitivity and nega- 2014;64(629):e783–7. 8. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting tive predictive value. More research is needed to assess items for systematic reviews and meta-analyses: the PRISMA statement. its effectiveness in diagnosing prostate cancer in symp- Open medicine : a peer-reviewed, independent, open-access journal. tomatic patients. 2009;3(3):e123–30. 9. Jones D, Dreher A, Friend C, Macleod U. How effective is digital rectal examination for diagnosis of prostate cancer for symptomatic patients in primary care? : PROSPERO international prospective register of. Syst Rev. 2015; Available from: http://www.crd.york.ac.uk/PROSPERO/display_record. Abbreviations asp?ID=CRD42015025764 DRE: Digital rectal examination; NICE: National Institute for Health and Care 10. Zamora J, Abraira V, Muriel A, Khan K, Coomarasamy A. Meta-DiSc: a Excellence; PRISMA: Preferred Reporting Items for Systematic Reviews and software for meta-analysis of test accuracy data. BMC Med Res Methodol. Meta-Analyses; PSA: Prostate specific antigen 2006;6:31. 11. Lee J, Kim KW, Choi SH, Huh J, Park SH. Systematic review and meta-analysis of studies evaluating diagnostic test accuracy: a practical review for clinical Acknowledgements researchers-part II. Statistical methods of meta-analysis. Korean J Radiol. The authors would like to thank Dr. Carla Reigada for her help translating the 2015;16(6):1188–96. studies that were in Spanish. We would also like to thank the Haxby 12. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the Group, Kingswood Health Centre, Hull for allowing AD the time to assessment of the quality of nonrandomized studies in meta-analyses. complete this review. Eur J Epidemiol. 2010;25(9):603–5. 13. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions Version 5.1.0 2011. Available from: http://training.cochrane.org/ Authors’ contributions handbook. DJ designed the initial project and protocol, performed the searches, acted 14. Issa MM, Zasada W, Ward K, Hall JA, Petros JA, Ritenour CW, et al. The value as a third party for disagreements on inclusion or data extraction, supervised of digital rectal examination as a predictor of prostate cancer diagnosis CF and AD and wrote up the manuscript. CF and AD performed the among United States veterans referred for prostate biopsy. Cancer Detect searches at abstract and full text stages, undertook citation and grey Prev. 2006;30(3):269–75. literature searches, carried out the data extraction and assessed the 15. Mettlin C, Lee F, Drago J, Murphy GP. The American Cancer Society National methodological quality of the studies as well as contributing to the write up. Prostate Cancer Detection Project. Findings on the detection of early VA assisted with the analysis and data extraction and contributed to the prostate cancer in 2425 men. Cancer. 1991;67(12):2949–58. write up. UM oversaw the project as a whole, provided guidance at the 16. Gelabert Mas A, Arango Toro O, Carles Galceran J, Bielsa Gali O, Cortadellas initial planning and design of the project and contributed to the write up. Angel R, Herrero Polo M, et al. Early diagnosis by opportunistic screening in All authors read and approved the final manuscript. cancer of the prostate. Results of a 1-year protocol. Comparison with historical data. Actas urologicas espanolas. 1997;21(9):835–42. 17. Ferrante JM, Shaw EK, Scott JG. Factors influencing men's decisions Ethical approval and consent to participate regarding prostate cancer screening: a qualitative study. J Community Not required for this systematic review. Health. 2011;36(5):839–44. 18. Forrester-Anderson IT. Prostate cancer screening perceptions, knowledge Competing interests and behaviors among African American men: focus group findings. J Health The authors declared that they have no competing interests. Care Poor Underserved. 2005;16(4 Suppl A):22–30. 19. Lee DJ, Consedine NS, Spencer BA. Barriers and facilitators to digital rectal examination screening among African-American and African-Caribbean men. Urology. 2011;77(4):891–8. Publisher’sNote 20. Ilic D, O'Connor D, Green S, Wilt TJ. Screening for prostate cancer: an Springer Nature remains neutral with regard to jurisdictional claims in updated Cochrane systematic review. BJU Int. 2011;107(6):882–91. published maps and institutional affiliations. Author details Hull York Medical School, Hertford Building, University of Hull, Cottingham Road, Hull HU6 7RX, UK. Goethe University Frankfurt, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Germany. Faculty of Health Sciences, University of York, Heslington, York YO10 5DD, UK. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Family Practice Springer Journals

The diagnostic test accuracy of rectal examination for prostate cancer diagnosis in symptomatic patients: a systematic review

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Abstract

Background: Prostate cancer is the most common cancer in men in the UK. NICE guidelines on recognition and referral of suspected cancer, recommend performing digital rectal examination (DRE) on patients with urinary symptoms and urgently referring if the prostate feels malignant. However, this is based on the results of one case control study, so it is not known if DRE performed in primary care is an accurate method of detecting prostate cancer. Methods: The aim of this review is to ascertain the sensitivity, specificity, positive and negative predictive value of DRE for the detection of prostate cancer in symptomatic patients in primary care. CENTRAL, MEDLINE, EMBASE and CINAHL databases were searched in august 2015 for studies in which a DRE was performed in primary care on symptomatic patients and compared against a reference diagnostic procedure. Results: Four studies were included with a total of 3225 patients. The sensitivity and specificity for DRE as a predictor of prostate cancer in symptomatic patients was 28.6 and 90.7%, respectively. The positive and negative predictive values were 42.3 and 84.2%, respectively. Conclusion: This review found that DRE performed in general practice is accurate, and supports the UK NICE guidelines that patients with a malignant prostate on examination are referred urgently for suspected prostate cancer. Abnormal DRE carried a 42.3% chance of malignancy, above the 3% risk threshold which NICE guidance suggests warrants an urgent referral. However this review questions the benefit of performing a DRE in primary care in the first instance, suggesting that a patient’s risk of prostate cancer based on symptoms alone would warrant urgent referral even if the DRE feels normal. Keywords: General practice, Digital rectal examination, Prostate Cancer, Primary care, Early diagnosis Background cancer. Survival from prostate cancer is relatively good Prostate cancer is the most common cancer amongst with a five-year survival rate of 85% [1]. men with 41,736 cases diagnosed in the UK in 2011. There has been considerable debate about the benefits Over the last 35 years, the incidence of prostate cancer and harms of early diagnosis of prostate cancer, with has more than tripled, though much of this increase is much of the discussion focused around the use of PSA. likely to be due to the increasing use of prostate specific Evidence suggests survival is closely related to stage at antigen (PSA) blood tests. The mortality rate from pros- diagnosis, with 100% five year survival in patients diag- tate cancer in the UK is falling after reaching a peak in nosed with the earliest stage disease compared to less the 1990s, but in 2012, over 10,000 men died of prostate than 33% five year survival if diagnosed at the latest stage [1]. This suggests that early diagnosis of prostate cancer is important. Certainly once a patient is symp- * Correspondence: ugm4djj@gmail.com tomatic, there seems to be little benefit in delaying the Hull York Medical School, Hertford Building, University of Hull, Cottingham Road, Hull HU6 7RX, UK diagnosis. Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Jones et al. BMC Family Practice (2018) 19:79 Page 2 of 6 Asymptomatic screening using PSA is undertaken, and the PROSPERO register of systematic reviews (registra- accepted in some countries, including the US, however tion number PROSPERO 2015:CRD42015025764) [9]. the U.S. Preventative Services Task Force recommend a discussion on the potential benefits and harms of PSA Search strategy screening, stating that screening offers a “small potential A search was undertaken for empirical research using benefit of reducing the chance of dying of prostate MEDLINE, CINAHL, EMBASE and the Cochrane cancer” but also highlighting that “many men will ex- Register of Controlled Trials (CENTRAL). Each database perience potential harms of screening” [2]. In the UK, was searched from commencement to August 2015. screening is not recommended routinely, instead Public Grey literature was searched using the OpenGrey data- Health England runs a ‘prostate cancer risk management base. Citations of all potentially relevant reviews and program’ in which patients who are concerned about research papers were hand searched. No date or lan- prostate cancer are able to have a PSA test after a dis- guage restrictions were applied to the database searches. cussion with a GP on the benefits and harms of the test The following terms were used in the search all data- in order to make an informed choice [3]. As a result bases: prostate cancer, DRE, primary care. The search most prostate cancers in the UK are identified when pa- strategy and protocol and be accessed here http:// tients present to general practice with a symptom suspi- www.crd.york.ac.uk/PROSPERO/display_record.asp?ID= cious of prostate cancer such as nocturia or urinary CRD42015025764. Two reviewers (CF and AD) inde- frequency. It is also worth noting however that there is a pendently screened the title and abstract of all articles diagnostic challenge as both urinary tract infections and identified by the search to determine eligibility. Full texts benign prostatic hypertrophy often present in similar were obtained for all potentially relevant articles and ways and are much more common diagnoses [4, 5]. these were independently assessed by two authors (CF The National Institute for Health and Care Excellence and AD) to determine eligibility. Final inclusion was (NICE) has recently updated the guidance on recogni- determined by agreement between both reviewers. If no tion and referral of suspected cancer in the UK [6]. The consensus was reached, a third study author (DJ) was latest NICE guidelines give recommendations on the consulted. recognition and referral of prostate cancer. These guide- lines state patients should be referred urgently if the Eligibility criteria prostate feels malignant on digital rectal examination We searched for studies that evaluated the use of DRE and recommends performing digital rectal examination in primary care for the detection of prostate cancer. To (DRE) on patients presenting with any lower urinary be included in the review studies had to meet three in- tract symptoms including nocturia, urinary frequency, clusion criteria: studies should be randomized controlled hesitancy, urgency or retention [6]. A recommendation trials, case control or cohort studies; they needed to in- supported by Walsh et al. who reviewed DREs under- clude symptomatic patients with any of the symptoms taken in primary care and urology clinics for the diagno- listed in the NICE guidelines for referral of prostate sis of prostate cancer and concluded that DRE is a key cancer; and they studies needed to be conducted in pri- part of the assessment [7]. However, the evidence base mary care setting. Studies undertaken in secondary care for DRE in symptomatic patients is poor, with NICE or screening studies of asymptomatic patients were ex- guidelines documenting only one case control study by cluded. As this was a review of a diagnostic procedure Hamilton et al. [4]. As a result it is not known if DRE the studies should compare DRE to a reference test. The performed in primary care is an accurate method of reference for this review was histological diagnosis of detecting prostate cancer, or what the risk of prostate prostate cancer. The NICE guidelines do not define an cancer is, if the general practitioner deems the prostate abnormal DRE so definitions from all included studies to be malignant on examination. were considered. Methods Outcomes The aim of this review was to evaluate the effectiveness The primary outcomes were the sensitivity, specificity, of DRE performed by general practitioners as a predictor positive (PPV) and negative predictive value (NPV) of of prostate cancer in symptomatic patients in a primary DRE in primary care for the detection of prostate cancer care setting according to the latest NICE guideline in symptomatic patients. This was calculated using the recommendations. Meta-DiSc software [10]. Secondary outcomes were The reporting of this systematic review follows the cost-effectiveness and adverse effects as a result of the recommendations of the PRISMA (Preferred Reporting intervention. Heterogeneity is almost always presumed Items for Systematic Reviews and Meta-Analyses) state- in diagnostic test accuracy systematic reviews, and ment [8]. A protocol was developed and registered in hence, a random-effects model was used [11]. Jones et al. BMC Family Practice (2018) 19:79 Page 3 of 6 Data extraction patients with the exception of Issa [14] who used the Two reviewers (CF and AD) independently extracted international prostate symptom score (IPSS). All four data from included articles using a pre-defined data ex- papers included patients with at least one of symptoms traction form. Disagreements were resolved by discus- listed in the NICE cancer guidelines, however these were sion between the two reviewers with a third reviewer different in each paper. Three of the studies explicitly (DJ) consulted if necessary. Data were extracted on study defined an ‘abnormal DRE’ with the exception of participants including age, ethnicity, setting and symp- Gelabert Mas [16]. The three papers used very similar toms, the studies inclusion and exclusion criteria, the in- definitions of an abnormal prostate. Hamilton et al. state formation on the DRE and gold standard test of the that “hard, craggy or nodular glands were classified as study and study outcomes. malignant” [4], Issa et al. state that “DRE findings were classified as abnormal in the presence of prostate indur- Quality assessment ation and/or nodularity” [14] and Mettlin et al. state that The Newcastle Ottawa quality assessment scale [12]was “a suspicious DRE outcome is defined by the presence of used to evaluate the quality of included studies. This significant induration, nodularity or asymmetry” [15]. scale is recommended by the Cochrane Handbook for assessing methodological quality of non-randomised Diagnostic accuracy of DRE studies and was chosen as it was highlighted as a simple There were 3225 participants included from 4 different tool to apply using eight assessment domains [13]. studies. For each of the included studies we were able to Hamilton [4] was a case control study and was deter- calculate a 2 × 2 table for reference test (biopsy / diagno- mined to be of high methodological quality. The study sis of prostate cancer) results versus the diagnostic test adequately defined a case, stating they were identified (DRE). This data was then combined to give an overall from the cancer registry at the Royal Devon and Exeter sensitivity, specificity, PPV and NPV. This was calculated Hospital and controls were selected from the community using Meta-Disc software. Overall, the pooled sensitivity with no history of disease. The study adequately con- and specificity for DRE as a predictor of prostate cancer trolled for age and location. Exposure for both cases and in symptomatic patients was found to be 28.6% (95% CI controls was ascertained from the GP and hospital re- 25.1–32.3%) and 90.7% (95% CI 89.5–91.8%), respect- cords. All cases and controls were included in the final ively. These results are shown in Fig. 2. The pooled PPV results with no drop outs. and NPV were found to be 42.3 and 84.2%, respectively. Three cohort studies [14–16] were included and were There was no relevant data extractable regarding sec- judged to be of high methodological quality. All were ondary outcomes of adverse events or cost effectiveness. representative of the average age of men with prostate As three out of the four studies were cohort cancer in the community. Ascertainment of exposure for studies, we performed a sub-analysis of the cohort all studies was determined from a secure patient medical studies alone. This produced a sensitivity of 42.7% record. Participants with a history of prostate cancer (95% CI 37.8–47.7%), a specificity of 86.7% (95% CI were excluded in all studies. All studies controlled for 84.9–88.4%), a PPV of 46.1% and a NPV of 85.1%. symptomatic patients, location and performance of DRE. Showing that excluding the case control study did not However, it should be noted that none of the cohort significantly affect the results. studies included documentation of how biopsy was taken and whether the individual performing the biopsy Discussion was blinded of symptoms and DRE findings. To the authors´ knowledge, this is the first review to evaluate the specificity, sensitivity, positive and negative Results predictive value of DRE as a predictor of prostate cancer Study characteristics in symptomatic patients in a primary care setting. Four studies met the inclusion criteria and were in- With the release of the new cancer referral guidelines cluded in the review (see Fig. 1). The characteristics of in the UK the threshold of risk for referral for possible the included studies are shown in Table 1. Three of the cancer was reduced from 5 to 3%. This suggests that all studies were cohort studies [14–16] and one was a case patients with signs and symptoms which carry a risk of control study [4]. Two of the studies were conducted in cancer greater than 3% should be referred urgently to the US [14, 15], one was conducted in the UK [4] and secondary care. This review found the pooled positive one in Spain [16]. A total of 3225 patients were included predictive value of DRE to detect prostate cancer was in the four papers. The largest study had 1297 partici- 42.3%. This suggests that if a patient with symptoms sug- pants [4] and the smallest had just 82 [16]. The age of gestive of prostate cancer presents to primary care and participants in included studies ranged from 40 to 89. has an abnormal feeling prostate examination, then that All studies documented the symptoms suffered by patients risk of cancer is 42.3%. This clearly warrants an Jones et al. BMC Family Practice (2018) 19:79 Page 4 of 6 Fig. 1 PRISMA Diagram urgent referral for suspected cancer and supports the UK that DRE performed in primary care is an unnecessary NICE guidelines. investigation, adding little to the decision to refer, which However, the pooled sensitivity in this review was low, should be made on the basis of symptoms alone. In 28.6% suggesting that many patients diagnosed with addition to this, it is possible that DRE may delay the prostate cancer do not have an abnormal DRE. In patient in seeking help with some qualitative research addition to the low sensitivity, the pooled negative pre- finding that the prospect of a DRE may deter some men dictive value was 84.2%, this suggests that symptomatic from seeking medical help for symptoms suggestive of patients who present to primary care and have a normal prostate cancer and prostate cancer screening [17–19]. prostate examination still have a risk of cancer of 15.8%, This qualitative research suggests that performing DRE which above the 3% risk threshold suggested by NICE. in primary may in fact be delaying the diagnosis of These findings show that patients in these included prostate cancer. studies should be urgently referred for suspected pros- The UK NICE guidelines make their recommendations tate cancer regardless of the DRE result. This suggests to refer patients with a prostate deemed malignant on Table 1 Characteristics of included studies Study ID Country Evidence Methods Number of Age range Index test Reference Outcomes level participants (years) Mettlin 1991 USA 2b Prospective 1218 55–70 PSA, DRE and TRUS Biopsy Sensitivity, specificity and cohort study PPV of DRE, PSA and TRUS. Gelabert Mas 1997 Spain 2b Prospective 82 > 50 PSA/DRE Biopsy Sensitivity, specificity, and cohort study PPV of DRE and PSA. Hamilton 2006 UK 4 Case control 1297 ≥ 40 PSA/DRE Diagnosis of PPV of symptoms, DRE prostate cancer and PSA. Issa 2006 USA 2b Retrospective 628 40–89 PSA/DRE Biopsy Sensitivity, specificity, PPV cohort study and NPV of DRE and PSA. Jones et al. BMC Family Practice (2018) 19:79 Page 5 of 6 Fig. 2 Pooled sensitivity and specificity for DRE as a predictor of prostate cancer in symptomatic patients examination on the evidence from just one study. This Due to the nature of using secondary data, there were systematic review includes four studies which consider some papers in which full information was not available. the effectiveness of DRE for diagnosing prostate cancer It was agreed in each study the DRE had been performed in symptomatic patients in primary care and thus in primary care, however it was often not clear who had provides stronger evidence for performing DRE in these performed the examination. In addition to this, only patients. However, the majority of the available literature three of the four studies adequately defined an abnormal concentrates on using DRE as a screening test in unse- DRE, the forth study did not provide a definition of lected asymptomatic patients. More research on the abnormal or positive DRE. effectiveness of DRE in primary care would help to pro- One of the papers (Issa 2006) caused some difficulty in vide further evidence for the NICE guidelines and ensure analysis due to a possible typing error. In the text of the that DRE is a useful investigation when performed by study they state symptoms were classified as mild mod- GPs. erate or severe using IPSS with mild symptoms classified Whilst the included studies were judged to be of high between 1 and 7, however in the results they present methodological quality it is difficult to draw conclusions mild symptoms as 0–7, this could mean patients with an based on a small number of studies, all of which were IPSS score of 0, who may be asymptomatic were published over ten years ago, are of low impact and are included in the results. Clarification was sought from largely heterogeneous. In addition, there are limitations the authors however no response was received. of including case control studies in reviews of diagnostic The vast majority of existing literature focuses on the test accuracy as they tend to overestimate diagnostic use of DRE as a screening tool. A Cochrane review on accuracy. In addition to this Hamilton et al. included pa- screening for prostate cancer included five studies and tients diagnosed with prostate cancer by a urologist found that screening did not significantly decrease pros- without having a biopsy which means not all participants tate cancer-specific mortality [20]. This review supports in the study received the same index test. Whilst this the recommendations of NICE which suggests that GPs clinically makes sense and is common in studies in refer patients urgently on the basis of an abnormal DRE. which the reference test is invasive, it is nonetheless a The NICE recommendation was made on the basis of limitation of the study. These limitations were investi- the Hamilton 2006 paper which is included in this gated using a sensitivity analysis which excluded the review. There is also qualitative literature to suggest that Hamilton et al. study, it was found that excluding the the prospect of a DRE may deter men from presenting case control study did not significantly affect the results. to primary care. To be included in this review the papers had to include patients with at least one of the symptoms sug- Conclusion gested by NICE. However, in each paper the combin- The most recent UK NICE guidelines recommend that ation of symptoms in the patients was different and in general practitioners undertake a digital rectal examin- some was poorly defined. ation on all patients with lower urinary tract symptoms. Jones et al. BMC Family Practice (2018) 19:79 Page 6 of 6 The guidelines suggest referring patients under the two Received: 27 September 2016 Accepted: 18 May 2018 week wait referral pathway if the prostate feels malig- nant. This is the first review to look at the accuracy of References digital rectal examination by general practitioners for 1. Cancer Research UK. Cancer Statistics for the UK 2015 [cited 2015 27th July]. 2. Preventative Services US, Force T. Draft recommendation statement: the diagnosis of prostate cancer in symptomatic patients. prostate Cancer. Screening. 2017; We found only four studies on the effectiveness of DRE 3. Public Health England. Prostate Cancer Risk Management Programme 2015 for the diagnosis of prostate cancer in symptomatic pa- [cited 2015 27th July]. 4. Hamilton W, Sharp DJ, Peters TJ, Round AP. Clinical features of prostate tients in primary care, with much of the available litera- cancer before diagnosis: a population-based, case-control study. The British ture focusing on screening. DRE is widely used and journal of general practice : the journal of the Royal College of General recommended for the assessment of patients in primary Practitioners. 2006;56(531):756–62. 5. Frankel S, Smith GD, Donovan J, Neal D. Screening for prostate cancer. care. It is a simple, safe and cost-effective diagnostic Lancet. 2003;361(9363):1122–8. tool, The findings of the review support the NICE guide- 6. NICE. Suspected cancer: recognition and referral. 2015. lines and recommend urgent referral for suspected can- 7. Walsh AL, Considine SW, Thomas AZ, Lynch TH, Manecksha RP. Digital rectal examination in primary care is important for early detection of prostate cer in patients with an abnormal DRE, however the cancer: a retrospective cohort analysis study. The British journal of general review casts doubt on the use of DRE as a diagnostic practice : the journal of the Royal College of General Practitioners. tool in primary care due to the low sensitivity and nega- 2014;64(629):e783–7. 8. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting tive predictive value. More research is needed to assess items for systematic reviews and meta-analyses: the PRISMA statement. its effectiveness in diagnosing prostate cancer in symp- Open medicine : a peer-reviewed, independent, open-access journal. tomatic patients. 2009;3(3):e123–30. 9. Jones D, Dreher A, Friend C, Macleod U. How effective is digital rectal examination for diagnosis of prostate cancer for symptomatic patients in primary care? : PROSPERO international prospective register of. Syst Rev. 2015; Available from: http://www.crd.york.ac.uk/PROSPERO/display_record. Abbreviations asp?ID=CRD42015025764 DRE: Digital rectal examination; NICE: National Institute for Health and Care 10. Zamora J, Abraira V, Muriel A, Khan K, Coomarasamy A. Meta-DiSc: a Excellence; PRISMA: Preferred Reporting Items for Systematic Reviews and software for meta-analysis of test accuracy data. BMC Med Res Methodol. Meta-Analyses; PSA: Prostate specific antigen 2006;6:31. 11. Lee J, Kim KW, Choi SH, Huh J, Park SH. Systematic review and meta-analysis of studies evaluating diagnostic test accuracy: a practical review for clinical Acknowledgements researchers-part II. Statistical methods of meta-analysis. Korean J Radiol. The authors would like to thank Dr. Carla Reigada for her help translating the 2015;16(6):1188–96. studies that were in Spanish. We would also like to thank the Haxby 12. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the Group, Kingswood Health Centre, Hull for allowing AD the time to assessment of the quality of nonrandomized studies in meta-analyses. complete this review. Eur J Epidemiol. 2010;25(9):603–5. 13. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions Version 5.1.0 2011. Available from: http://training.cochrane.org/ Authors’ contributions handbook. DJ designed the initial project and protocol, performed the searches, acted 14. Issa MM, Zasada W, Ward K, Hall JA, Petros JA, Ritenour CW, et al. The value as a third party for disagreements on inclusion or data extraction, supervised of digital rectal examination as a predictor of prostate cancer diagnosis CF and AD and wrote up the manuscript. CF and AD performed the among United States veterans referred for prostate biopsy. Cancer Detect searches at abstract and full text stages, undertook citation and grey Prev. 2006;30(3):269–75. literature searches, carried out the data extraction and assessed the 15. Mettlin C, Lee F, Drago J, Murphy GP. The American Cancer Society National methodological quality of the studies as well as contributing to the write up. Prostate Cancer Detection Project. Findings on the detection of early VA assisted with the analysis and data extraction and contributed to the prostate cancer in 2425 men. Cancer. 1991;67(12):2949–58. write up. UM oversaw the project as a whole, provided guidance at the 16. Gelabert Mas A, Arango Toro O, Carles Galceran J, Bielsa Gali O, Cortadellas initial planning and design of the project and contributed to the write up. Angel R, Herrero Polo M, et al. Early diagnosis by opportunistic screening in All authors read and approved the final manuscript. cancer of the prostate. Results of a 1-year protocol. Comparison with historical data. Actas urologicas espanolas. 1997;21(9):835–42. 17. Ferrante JM, Shaw EK, Scott JG. Factors influencing men's decisions Ethical approval and consent to participate regarding prostate cancer screening: a qualitative study. J Community Not required for this systematic review. Health. 2011;36(5):839–44. 18. Forrester-Anderson IT. Prostate cancer screening perceptions, knowledge Competing interests and behaviors among African American men: focus group findings. J Health The authors declared that they have no competing interests. Care Poor Underserved. 2005;16(4 Suppl A):22–30. 19. Lee DJ, Consedine NS, Spencer BA. Barriers and facilitators to digital rectal examination screening among African-American and African-Caribbean men. Urology. 2011;77(4):891–8. Publisher’sNote 20. Ilic D, O'Connor D, Green S, Wilt TJ. Screening for prostate cancer: an Springer Nature remains neutral with regard to jurisdictional claims in updated Cochrane systematic review. BJU Int. 2011;107(6):882–91. published maps and institutional affiliations. Author details Hull York Medical School, Hertford Building, University of Hull, Cottingham Road, Hull HU6 7RX, UK. Goethe University Frankfurt, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Germany. Faculty of Health Sciences, University of York, Heslington, York YO10 5DD, UK.

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BMC Family PracticeSpringer Journals

Published: Jun 2, 2018

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