Cancer Research UKNational Institute for Health Research (NIHR)Policy Research Unit in Cancer Awareness, Screening and Early DiagnosisDepartment of Healt

Bailey, SER

Cooper, SL

Hamilton, W

Mounce, L

Watson, J

English

Watson, Jessica

Mounce, Luke

Bailey, Sarah

Cooper, Sharon

Hamilton, Willie

Explore Bristol Research

                          Watson, J., Mounce, L., Bailey, S., Cooper, S., & Hamilton, W. (2019).Rational Testing: Blood markers for cancer. BMJ, 367, [l5774].https://doi.org/10.1136/bmj.l5774Publisher's PDF, also known as Version of recordLicense (if available):CC BY-NCLink to published version (if available):10.1136/bmj.l5774Link to publication record in Explore Bristol ResearchPDF-documentThis is the final published version of the article (version of record). It first appeared online via BMJ PublishingGroup at https://www.bmj.com/content/367/bmj.l5774 . Please refer to any applicable terms of use of thepublisher.University of Bristol - Explore Bristol ResearchGeneral rightsThis document is made available in accordance with publisher policies. Please cite only the publishedversion using the reference above. Full terms of use are available:http://www.bristol.ac.uk/pure/about/ebr-termsRATIONAL TESTINGBlood markers for cancerJessica Watson NIHR doctoral research fellow 1, Luke Mounce research fellow 2, Sarah ER Baileyresearch fellow 2, Sharon L Cooper patient contributor 2, Willie Hamilton professor of primary carediagnostics 21Centre for Academic Primary Care, Bristol Medical School, University of Bristol, Bristol, UK; 2University of Exeter, Exeter, UKWhat you need to know• “Triage” blood tests in primary care, such as haemoglobin, platelets,serum calcium level, liver function tests, and inflammatory markers suchas C reactive protein and erythrocyte sedimentation rate may provide“clues” to cancer in patients with non-specific symptoms• Triage tests do not have the performance characteristics of rule-outtests• Evidence supports the use of only a small number of specific cancermarkers, such as CA125 and PSA, in primary careA 61 year old man with a one month history of back pain visitshis general practitioner (GP). He has hypertension, has neversmoked, and reports fatigue for several months. The pain iskeeping him awake at night. He has not lost weight. Clinicalexamination is normal. The differential diagnosis for this patientis wide, including potential malignant causes such as pancreatic,myeloma, and prostate cancer or metastatic disease.Cancer can be difficult to identifymany of the commonsymptoms are non-specific and low risk, and even the most wellknown “alarm” symptoms have relatively low positive predictivevalues (PPVs) for underlying malignancy1; for example, weightloss has a PPV for underlying malignancy of only 0-3.3%,2while rectal bleeding has a PPV of 2.2-15.8%.3 Cancer markersused in hospital settings, when applied to low risk primary carepatients, have low positive predictive values and high falsepositive rates.4 Identifying patients whose non-specificsymptoms may be caused by cancer, rather than benign disease,is therefore a challenge for primary care physicians.While formal diagnosis usually happens in secondary care, thefirst suspicion of cancer generally occurs in primary care.Patients whose symptoms represent an approximate risk ofcancer of ≥3% are recommended by the National Institute forHealth and Care Excellence (NICE) for urgent investigation,often by referral.5 Those with estimated risk <3% may receivean initial panel of primary care investigations, or triage testing,to stratify risk. Triage tests can provide clues to help identifypatients for referral, and crucially can point towards the site ofan underlying malignancy. This is particularly useful when thepatient’s vague symptoms could be caused by several differentcancer types, and can guide decision making on any need forfurther investigation.This article discusses blood tests to detect or stratify risk forpossible cancer in primary care and presents evidence for theiruse in symptomatic patients. First we consider tests that are notspecific for any one type of cancer but which may help primarycare providers stratify risk of malignancy. Then we discussspecific markers for certain types of cancer. Blood tests thatmight be used for screening asymptomatic patients, tests forless common malignancies (eg, gastrin, prolactin) or formonitoring patients with known malignancies, are beyond thescope of this article.Search strategyIn August 2019 we replicated the search strategy used by NICE in its mostrecent guidance, NG12, restricted to papers published after 2014 (2011 forovary) as the NICE searches had been performed before that date. LM, SB,and WH worked in pairs to assess candidate abstracts for blood tests usedin primary care, and extracted full texts for relevant hits, supplemented by alarge personal library of existing references.What is the next investigation?Non-specific blood tests or clues for cancerSeveral non-specific tests, commonly used in primary care, canprovide “clues” towards possible cancer. Tests with a PPV forcancer of >1%, including haemoglobin, platelet count, serumcalcium, liver function tests, and inflammatory markers suchas C reactive protein (CRP) and erythrocyte sedimentation rateCorrespondence to W Hamilton W.Hamilton@exeter.ac.ukThis series of occasional articles provides an update on the best use of key diagnostic tests in the initial investigation of common or important clinical presentations. Theseries advisers are Steve Atkin, professor of medicine, Weill Cornell Medical College Qatar; and Eric Kilpatrick, Division Chief, Clinical Chemistry, Sidra Medical andResearch Center, Qatar; honorary professor, department of clinical biochemistry, Hull Royal Infirmary, Hull York Medical School. You can read more about how to prepareand submit an Education article on our Instructions for Authors pageshttps://www.bmj.com/about-bmj/resources-authors/article-typesFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2019;367:l5774 doi: 10.1136/bmj.l5774 (Published 14 October 2019) Page 1 of 4PracticePRACTICE on 15 October 2019 at University of Bristol Library. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l5774 on 14 October 2019. Downloaded from (ESR), are summarised in fig 1 (infographic). Tests with PPVs<1% for certain underlying malignancies are reported in thesame graphic. These blood tests should not be measuredroutinely but should be considered in patients with low risk, butnot no risk symptoms, such as unexplained weight loss orpersistent tiredness. Rarely, the full blood count may identifya haematological cancer, but most tests act in a bayesian fashion,whereby a “positive test” makes cancer a more likelyexplanation.Although non-cancer diagnoses can also commonly causeabnormal test results, further investigations or referral to ruleout malignancy may be warranted. Conversely, a “negative”test makes cancer less likely, though neither result is definitive;that is, if these test results are normal, cancer may still bepresent.6 None of these tests has sufficient sensitivity to act asa “rule out” test, with the possible exception of the combinationof a normal plasma viscosity or ESR plus normal full bloodcount, which may be used as a simple rule out for myeloma.7In the context of low risk symptoms, negative tests providesome reassurance. However, if symptoms continue or change,further investigation may still be warranted. Ideally, the rationalefor and implications of a negative or positive test result shouldbe discussed before ordering these tests so as to allow for shareddecision making with patients.Specific cancer markersDespite the proliferation of cancer biomarker research insecondary care, there is a shortage of relevant primary carestudies, with no new markers entering primary care usage sinceSturgeon et al’s review in 2009.8 The small number of cancerspecific tests validated for diagnosis of cancer in primary caresettings are summarised in the infographic (fig 1).These testsshould be used in symptomatic patients, rather than as anon-specific cancer screen. Even well known cancer markersthat are part of routine clinical practice, such as prostate specificantigen (PSA) and cancer antigen 125 (CA125), have a limitedprimary care evidence base. In the case of PSA, because somany men who develop prostate cancer will be asymptomatic,11positive predictive value of a positive test does not necessarilytranslate into clinical benefit.OutcomeThe general practitioner was concerned by the presence of nightpain and fatigue, which, in combination with the patient’s age,raised the possibility of underlying malignancy. The patient wastherefore referred for initial blood tests, which included a fullblood count, liver function tests, serum calcium, and ESR.Results were significant for a slightly raised platelet count(495×109/L) and a moderately raised ESR (34 mm/h). Furtherspecific blood tests were therefore performed, including serumelectrophoresis and Bence Jones protein. Monoclonalimmunoglobulins were detected, suggestive of multiplemyeloma. The patient was referred urgently to a suspectedcancer clinic, where the diagnosis was confirmed.Future researchMany cancer biomarkers are being investigated, particularly forcancers considered “hard to diagnose,” such as pancreas andovary,12 or for early detection of cancer recurrences.9 However,of the candidate cancer biomarkers, few are expected to be testedfor in clinical practice.13 Future research to evaluate markersfor a potential diagnostic role should aim to quantify thefalse-positive rates, clinician and patient acceptability, and healtheconomic aspects in order to determine how these tests shouldbest be used.How patients were involved in the creation of this articleA first patient contributor was involved in the early stages of the article butwas unavailable during the main creation of the piece. SC joined at that stage,and has helped interpret our findings, especially the patient aspects, and incritical review of the whole manuscript, ensuring it remained patient centred.Contributors LM performed the searches, LM, SB, and WH reviewed abstracts andextracted full texts. JW, WH, and SB wrote the first draft of the article with inputfrom LM and SC. All authors contributed to the intellectual content, edited themanuscript and approved the final version for submission.Competing interestsThe BMJ has judged that there are no disqualifying financialties to commercial companies. The authors declare the following other interests:Funding: The author WH is co-Principal Investigator of, and the author SERB isfunded by, a Cancer Research UK Population Research Catalyst award(C8640/A23385). JW is funded by a Doctoral Research Fellow from the NationalInstitute for Health Research (DRF-2016-09-034). LM is funded by The PolicyResearch Unit in Cancer Awareness, Screening and Early Diagnosis which receivesfunding for a research programme from the Department of Health Policy ResearchProgramme. It is a collaboration between researchers from seven institutions(Queen Mary University of London, UCL, King's College London, London Schoolof Hygiene and Tropical Medicine, Hull York Medical School, Durham Universityand Exeter Medical School). WH is supported by the National Institute for HealthResearch (NIHR) Collaboration for Leadership in Applied Health Research andCare South West Peninsula at the Royal Devon and Exeter NHS Foundation Trust.Further details of The BMJ policy on financial interests are here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interestsThe views expressed are those of the authors and not necessarily those of theNHS, the NIHR or the Department of Health.Patient consent not required (patient anonymised or hypothetical)Provenance and peer review: commissioned, based on an idea from the author;externally peer reviewed.1 Jones R, Latinovic R, Charlton J, Gulliford MC. Alarm symptoms in early diagnosis ofcancer in primary care: cohort study using General Practice Research Database. BMJ2007;334:1040. 10.1136/bmj.39171.637106.AE 174939822 Nicholson BD, Hamilton W, O’Sullivan J, Aveyard P, Hobbs FR. Weight loss as a predictorof cancer in primary care: a systematic review and meta-analysis. Br J Gen Pract2018;68:e311-22. 10.3399/bjgp18X695801 296320043 Astin M, Griffin T, Neal RD, Rose P, Hamilton W. The diagnostic value of symptoms forcolorectal cancer in primary care: a systematic review. Br J Gen Pract 2011;61:e231-43.10.3399/bjgp11X572427 216197474 Usher-Smith JA, Sharp SJ, Griffin SJ. The spectrum effect in tests for risk prediction,screening, and diagnosis. BMJ 2016;353:i3139. 10.1136/bmj.i3139 273342815 National Institute for Health and Care Excellence Suspected cancer: recognition andreferral: NICE guidelines NG12. 2015. https://www.nice.org.uk/guidance/ng126 Watson JBS, Hamilton F, Hamilton W, Mounce L. Lessons from biases in electronic healthrecord data: the importance of clinical vigilance with negative test results. BMJ2018;361:k1479.7 Koshiaris C, Van den Bruel A, Oke JL, etal . Early detection of multiple myeloma in primarycare using blood tests: a case-control study in primary care. Br J Gen Pract2018;68:e586-93. 10.3399/bjgp18X698357 301043268 Sturgeon CM, Lai LC, Duffy MJ. Serum tumour markers: how to order and interpret them.BMJ 2009;339:b3527. 10.1136/bmj.b3527 197733289 Crawford SM, Evans C. Outcome of elevated CA125 values from primary care followingimplementation of ovarian cancer guidelines. Fam Pract 2018;35:199-202.10.1093/fampra/cmx096 2902912310 Young GJ, Harrison S, Turner EL, etal . Prostate-specific antigen (PSA) testing of menin UK general practice: a 10-year longitudinal cohort study. BMJ Open2017;7:e017729.2908479711 Jahn JL, Giovannucci EL, Stampfer MJ. The high prevalence of undiagnosed prostatecancer at autopsy: implications for epidemiology and treatment of prostate cancer in theProstate-specific Antigen-era. Int J Cancer 2015;137:2795-802.10.1002/ijc.29408 2555775312 Lyratzopoulos G, Wardle J, Rubin G. Rethinking diagnostic delay in cancer: how difficultis the diagnosis?BMJ 2014;349:g7400. 10.1136/bmj.g7400 2549179113 Rhea JM, Molinaro RJ. Cancer biomarkers: surviving the journey from bench to bedside.MLO 2011;43:10-2, 16, 18, 20, 22.14 Schmidt-Hansen M, Berendse S, Hamilton W. The association between symptoms andbladder or renal tract cancer in primary care: a systematic review. Br J Gen Pract2015;65:e769-75. 10.3399/bjgp15X687421 2650032515 Bailey SE, Ukoumunne OC, Shephard EA, Hamilton W. Clinical relevance ofthrombocytosis in primary care: a prospective cohort study of cancer incidence usingFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2019;367:l5774 doi: 10.1136/bmj.l5774 (Published 14 October 2019) Page 2 of 4PRACTICE on 15 October 2019 at University of Bristol Library. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l5774 on 14 October 2019. Downloaded from English electronic medical records and cancer registry data. Br J Gen Pract2017;67:e405-13. 10.3399/bjgp17X691109 2853319916 Hamilton W, Peters TJ, Round A, Sharp D. What are the clinical features of lung cancerbefore the diagnosis is made? A population based case-control study. Thorax2005;60:1059-65. 10.1136/thx.2005.045880 1622732617 Hamilton F, Carroll R, Hamilton W, Salisbury C. The risk of cancer in primary care patientswith hypercalcaemia: a cohort study using electronic records. Br J Cancer2014;111:1410-2. 10.1038/bjc.2014.433 2509349518 Merriel SWD, Carroll R, Hamilton F, Hamilton W. Association between unexplainedhypoalbuminaemia and new cancer diagnoses in UK primary care patients. Fam Pract2016;33:449-52. 10.1093/fampra/cmw051 2734386019 Schmidt-Hansen M, Berendse S, Hamilton W. Symptoms of pancreatic cancer in primarycare: a systematic review. Pancreas 2016;45:814-8.10.1097/MPA.0000000000000527 2649579520 Hamilton W. The CAPER studies: five case-control studies aimed at identifying andquantifying the risk of cancer in symptomatic primary care patients. Br J Cancer2009;101(Suppl 2):S80-6. 10.1038/sj.bjc.6605396 19956169Published by the BMJ Publishing Group Limited. For permission to use (where not alreadygranted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissionsFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2019;367:l5774 doi: 10.1136/bmj.l5774 (Published 14 October 2019) Page 3 of 4PRACTICE on 15 October 2019 at University of Bristol Library. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l5774 on 14 October 2019. Downloaded from FigureFig 1 Primary care studies or review investigating the diagnostic role of blood tests as non-specific cancer markers: withpositive predictive values (PPVs) ≥1% and <1%For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2019;367:l5774 doi: 10.1136/bmj.l5774 (Published 14 October 2019) Page 4 of 4PRACTICE on 15 October 2019 at University of Bristol Library. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l5774 on 14 October 2019. Downloaded from 

Rational Testing:Blood markers for cancer

Open Research Exeter

RATIONAL TESTINGBlood markers for cancerJessica Watson NIHR doctoral research fellow 1, Luke Mounce research fellow 2, Sarah ER Baileyresearch fellow 2, Sharon L Cooper patient contributor 2, Willie Hamilton professor of primary carediagnostics 21Centre for Academic Primary Care, Bristol Medical School, University of Bristol, Bristol, UK; 2University of Exeter, Exeter, UKWhat you need to know• “Triage” blood tests in primary care, such as haemoglobin, platelets,serum calcium level, liver function tests, and inflammatory markers suchas C reactive protein and erythrocyte sedimentation rate may provide“clues” to cancer in patients with non-specific symptoms• Triage tests do not have the performance characteristics of rule-outtests• Evidence supports the use of only a small number of specific cancermarkers, such as CA125 and PSA, in primary careA 61 year old man with a one month history of back pain visitshis general practitioner (GP). He has hypertension, has neversmoked, and reports fatigue for several months. The pain iskeeping him awake at night. He has not lost weight. Clinicalexamination is normal. The differential diagnosis for this patientis wide, including potential malignant causes such as pancreatic,myeloma, and prostate cancer or metastatic disease.Cancer can be difficult to identify, as many of the commonsymptoms are non-specific and low risk, and even the most wellknown “alarm” symptoms have relatively low positive predictivevalues (PPVs) for underlying malignancy.1 For example, weightloss has a PPV for underlying malignancy of only 0-3.3%,2while rectal bleeding has a PPV of 2.2-15.8%.3 Cancer markersused in hospital settings, when applied to low risk primary carepatients, have low positive predictive values and high falsepositive rates.4 Identifying patients whose non-specificsymptoms may be caused by cancer, rather than benign disease,is therefore a challenge for primary care physicians.While formal diagnosis usually happens in secondary care, thefirst suspicion of cancer generally occurs in primary care.Patients whose symptoms represent an approximate risk ofcancer of ≥3% are recommended by the National Institute forHealth and Care Excellence (NICE) for urgent investigation,often by referral.5 Those with estimated risk <3% may receivean initial panel of primary care investigations, or triage testing,to stratify risk. Triage tests can provide clues to help identifypatients for referral, and crucially can point towards the site ofan underlying malignancy. This is particularly useful when thepatient’s vague symptoms could be caused by several differentcancer types, and can guide decision making on any need forfurther investigation.This article discusses blood tests to detect or stratify risk forpossible cancer in primary care and presents evidence for theiruse in symptomatic patients. First we consider tests that are notspecific for any one type of cancer but which may help primarycare providers stratify risk of malignancy. Then we discussspecific markers for certain types of cancer. Blood tests thatmight be used for screening asymptomatic patients, tests forless common malignancies (eg, gastrin, prolactin) or formonitoring patients with known malignancies, are beyond thescope of this article.Search strategyIn August 2019 we replicated the search strategy used by NICE in its mostrecent guidance, NG12, restricted to papers published after 2014 (2011 forovary) as the NICE searches had been performed before that date. LM, SB,and WH worked in pairs to assess candidate abstracts for blood tests usedin primary care, and extracted full texts for relevant hits, supplemented by alarge personal library of existing references.What is the next investigation?Non-specific blood tests or clues for cancerSeveral non-specific tests, commonly used in primary care, canprovide “clues” towards possible cancer. Tests with a PPV forcancer of >1%, including haemoglobin, platelet count, serumcalcium, liver function tests, and inflammatory markers suchas C reactive protein (CRP) and erythrocyte sedimentation rateCorrespondence to W Hamilton W.Hamilton@exeter.ac.ukThis series of occasional articles provides an update on the best use of key diagnostic tests in the initial investigation of common or important clinical presentations. Theseries advisers are Steve Atkin, professor of medicine, Weill Cornell Medical College Qatar; and Eric Kilpatrick, Division Chief, Clinical Chemistry, Sidra Medical andResearch Center, Qatar; honorary professor, department of clinical biochemistry, Hull Royal Infirmary, Hull York Medical School. You can read more about how to prepareand submit an Education article on our Instructions for Authors pageshttps://www.bmj.com/about-bmj/resources-authors/article-typesFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2019;367:l5774 doi: 10.1136/bmj.l5774 (Published 14 October 2019) Page 1 of 5PracticePRACTICE on 16 October 2019 at University of Exeter. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l5774 on 14 October 2019. Downloaded from (ESR), are summarised in fig 1 (infographic). Tests with PPVs<1% for certain underlying malignancies are reported in thesame graphic. These blood tests should not be measuredroutinely but should be considered in patients with low risk, butnot no risk symptoms, such as unexplained weight loss orpersistent tiredness. Rarely, the full blood count may identifya haematological cancer, but most tests act in a bayesian fashion,whereby a “positive test” makes cancer a more likelyexplanation.Although non-cancer diagnoses can also commonly causeabnormal test results, further investigations or referral to ruleout malignancy may be warranted. Conversely, a “negative”test makes cancer less likely, though neither result is definitive;that is, if these test results are normal, cancer may still bepresent.6 None of these tests has sufficient sensitivity to act asa “rule out” test, with the possible exception of the combinationof a normal plasma viscosity or ESR plus normal full bloodcount, which may be used as a simple rule out for myeloma.7In the context of low risk symptoms, negative tests providesome reassurance. However, if symptoms continue or change,further investigation may still be warranted. Ideally, the rationalefor and implications of a negative or positive test result shouldbe discussed before ordering these tests so as to allow for shareddecision making with patients.Specific cancer markersDespite the proliferation of cancer biomarker research insecondary care, there is a shortage of relevant primary carestudies, with no new markers entering primary care usage sinceSturgeon et al’s review in 2009.8 The small number of cancerspecific tests validated for diagnosis of cancer in primary caresettings are summarised in table 1. These tests should be usedin symptomatic patients, rather than as a non-specific cancerscreen. Even well known cancer markers that are part of routineclinical practice, such as prostate specific antigen (PSA) andcancer antigen 125 (CA125), have a limited primary careevidence base. In the case of PSA, because so many men whodevelop prostate cancer will be asymptomatic,11 positivepredictive value of a positive test does not necessarily translateinto clinical benefit.OutcomeThe general practitioner was concerned by the presence of nightpain and fatigue, which, in combination with the patient’s age,raised the possibility of underlying malignancy. The patient wastherefore referred for initial blood tests, which included a fullblood count, liver function tests, serum calcium, and ESR.Results were significant for a slightly raised platelet count(495×109/L) and a moderately raised ESR (34 mm/h). Furtherspecific blood tests were therefore performed, including serumelectrophoresis and Bence Jones protein. Monoclonalimmunoglobulins were detected, suggestive of multiplemyeloma. The patient was referred urgently to a suspectedcancer clinic, where the diagnosis was confirmed.Future researchMany cancer biomarkers are being investigated, particularly forcancers considered “hard to diagnose,” such as pancreas andovary,12 or for early detection of cancer recurrences.9 However,of the candidate cancer biomarkers, few are expected to be testedfor in clinical practice.13 Future research to evaluate markersfor a potential diagnostic role should aim to quantify thefalse-positive rates, clinician and patient acceptability, and healtheconomic aspects in order to determine how these tests shouldbest be used.How patients were involved in the creation of this articleA first patient contributor was involved in the early stages of the article butwas unavailable during the main creation of the piece. SC joined at that stage,and has helped interpret our findings, especially the patient aspects, and incritical review of the whole manuscript, ensuring it remained patient centred.Contributors LM performed the searches, LM, SB, and WH reviewed abstracts andextracted full texts. JW, WH, and SB wrote the first draft of the article with inputfrom LM and SC. All authors contributed to the intellectual content, edited themanuscript and approved the final version for submission.Competing interestsThe BMJ has judged that there are no disqualifying financialties to commercial companies. The authors declare the following other interests:Funding: The author WH is co-Principal Investigator of, and the author SERB isfunded by, a Cancer Research UK Population Research Catalyst award(C8640/A23385). JW is funded by a Doctoral Research Fellow from the NationalInstitute for Health Research (DRF-2016-09-034). LM is funded by The PolicyResearch Unit in Cancer Awareness, Screening and Early Diagnosis which receivesfunding for a research programme from the Department of Health Policy ResearchProgramme. It is a collaboration between researchers from seven institutions(Queen Mary University of London, UCL, King's College London, London Schoolof Hygiene and Tropical Medicine, Hull York Medical School, Durham Universityand Exeter Medical School). WH is supported by the National Institute for HealthResearch (NIHR) Collaboration for Leadership in Applied Health Research andCare South West Peninsula at the Royal Devon and Exeter NHS Foundation Trust.Further details of The BMJ policy on financial interests are here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interestsThe views expressed are those of the authors and not necessarily those of theNHS, the NIHR or the Department of Health.Patient consent not required (patient anonymised or hypothetical)Provenance and peer review: commissioned, based on an idea from the author;externally peer reviewed.1 Jones R, Latinovic R, Charlton J, Gulliford MC. Alarm symptoms in early diagnosis ofcancer in primary care: cohort study using General Practice Research Database. BMJ2007;334:1040. 10.1136/bmj.39171.637106.AE 174939822 Nicholson BD, Hamilton W, O’Sullivan J, Aveyard P, Hobbs FR. Weight loss as a predictorof cancer in primary care: a systematic review and meta-analysis. Br J Gen Pract2018;68:e311-22. 10.3399/bjgp18X695801 296320043 Astin M, Griffin T, Neal RD, Rose P, Hamilton W. The diagnostic value of symptoms forcolorectal cancer in primary care: a systematic review. Br J Gen Pract 2011;61:e231-43.10.3399/bjgp11X572427 216197474 Usher-Smith JA, Sharp SJ, Griffin SJ. The spectrum effect in tests for risk prediction,screening, and diagnosis. BMJ 2016;353:i3139. 10.1136/bmj.i3139 273342815 National Institute for Health and Care Excellence Suspected cancer: recognition andreferral: NICE guidelines NG12. 2015. https://www.nice.org.uk/guidance/ng126 Watson JBS, Hamilton F, Hamilton W, Mounce L. Lessons from biases in electronic healthrecord data: the importance of clinical vigilance with negative test results. BMJ2018;361:k1479.7 Koshiaris C, Van den Bruel A, Oke JL, etal . Early detection of multiple myeloma in primarycare using blood tests: a case-control study in primary care. Br J Gen Pract2018;68:e586-93. 10.3399/bjgp18X698357 301043268 Sturgeon CM, Lai LC, Duffy MJ. Serum tumour markers: how to order and interpret them.BMJ 2009;339:b3527. 10.1136/bmj.b3527 197733289 Crawford SM, Evans C. Outcome of elevated CA125 values from primary care followingimplementation of ovarian cancer guidelines. Fam Pract 2018;35:199-202.10.1093/fampra/cmx096 2902912310 Young GJ, Harrison S, Turner EL, etal . Prostate-specific antigen (PSA) testing of menin UK general practice: a 10-year longitudinal cohort study. BMJ Open2017;7:e017729.2908479711 Jahn JL, Giovannucci EL, Stampfer MJ. The high prevalence of undiagnosed prostatecancer at autopsy: implications for epidemiology and treatment of prostate cancer in theProstate-specific Antigen-era. Int J Cancer 2015;137:2795-802.10.1002/ijc.29408 2555775312 Lyratzopoulos G, Wardle J, Rubin G. Rethinking diagnostic delay in cancer: how difficultis the diagnosis?BMJ 2014;349:g7400. 10.1136/bmj.g7400 2549179113 Rhea JM, Molinaro RJ. Cancer biomarkers: surviving the journey from bench to bedside.MLO 2011;43:10-2, 16, 18, 20, 22.14 Schmidt-Hansen M, Berendse S, Hamilton W. The association between symptoms andbladder or renal tract cancer in primary care: a systematic review. Br J Gen Pract2015;65:e769-75. 10.3399/bjgp15X687421 2650032515 Bailey SE, Ukoumunne OC, Shephard EA, Hamilton W. Clinical relevance ofthrombocytosis in primary care: a prospective cohort study of cancer incidence usingFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2019;367:l5774 doi: 10.1136/bmj.l5774 (Published 14 October 2019) Page 2 of 5PRACTICE on 16 October 2019 at University of Exeter. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l5774 on 14 October 2019. Downloaded from English electronic medical records and cancer registry data. Br J Gen Pract2017;67:e405-13. 10.3399/bjgp17X691109 2853319916 Hamilton W, Peters TJ, Round A, Sharp D. What are the clinical features of lung cancerbefore the diagnosis is made? A population based case-control study. Thorax2005;60:1059-65. 10.1136/thx.2005.045880 1622732617 Hamilton F, Carroll R, Hamilton W, Salisbury C. The risk of cancer in primary care patientswith hypercalcaemia: a cohort study using electronic records. Br J Cancer2014;111:1410-2. 10.1038/bjc.2014.433 2509349518 Merriel SWD, Carroll R, Hamilton F, Hamilton W. Association between unexplainedhypoalbuminaemia and new cancer diagnoses in UK primary care patients. Fam Pract2016;33:449-52. 10.1093/fampra/cmw051 2734386019 Schmidt-Hansen M, Berendse S, Hamilton W. Symptoms of pancreatic cancer in primarycare: a systematic review. Pancreas 2016;45:814-8.10.1097/MPA.0000000000000527 2649579520 Hamilton W. The CAPER studies: five case-control studies aimed at identifying andquantifying the risk of cancer in symptomatic primary care patients. Br J Cancer2009;101(Suppl 2):S80-6. 10.1038/sj.bjc.6605396 19956169Published by the BMJ Publishing Group Limited. For permission to use (where not alreadygranted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissionsFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2019;367:l5774 doi: 10.1136/bmj.l5774 (Published 14 October 2019) Page 3 of 5PRACTICE on 16 October 2019 at University of Exeter. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l5774 on 14 October 2019. Downloaded from TableTable 1| Specific blood tests for diagnosing cancer in symptomatic patients in primary care settingsWhen to consider testPositive predictive values (95%confidence interval)Available evidenceTestTarget cancerWomen with persistent abdominal distension,feeling full, loss of appetite, pelvic/abdominalpain, urgency or frequency (especially if aged>50) 510.5% (5.6 to 15.4)Cohort study: 4379 women with primarycare CA125 results; 152 with newly raisedCA125  >35u/mL and follow-up data.Sixteen incident ovarian cancersdiagnosed9CA125Ovarian cancerIn patients with symptoms of possiblemyeloma, plus either a raised inflammatorymarker or a raised calciumNo primary care evidence foundSerum proteinelectrophoresisMyelomaMen with lower urinary tract symptoms,erectile dysfunction or haematuria 5PSA <3ng/ml: <1%3 ≤PSA <4: 1%4 ≤PSA <6: 6%6 ≤PSA <10: 18%PSA ≥10: 45%*Cohort study: 120 697 men aged ≥45years with PSA results; 7538 incidenceprostate cancers diagnosed 10PSAProstate cancerCurrently not recommended in primary careby NICENo/minimal primary care evidence could be foundAFPLiverCEAColorectalCA19-9Pancreatic* confidence intervals not reported. CA125=cancer antigen 125. PSA=prostate specific antigenFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2019;367:l5774 doi: 10.1136/bmj.l5774 (Published 14 October 2019) Page 4 of 5PRACTICE on 16 October 2019 at University of Exeter. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l5774 on 14 October 2019. Downloaded from FigureFig 1 Primary care studies or review investigating the diagnostic role of blood tests as non-specific cancer markers: withpositive predictive values (PPVs) ≥1% and <1%For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2019;367:l5774 doi: 10.1136/bmj.l5774 (Published 14 October 2019) Page 5 of 5PRACTICE on 16 October 2019 at University of Exeter. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l5774 on 14 October 2019. Downloaded from 

Blood markers for cancer

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Blood markers for cancer

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