Protocol for a pragmatic cluster randomised controlled trial assessing the clinical effectiveness and cost-effectiveness of Electronic RIsk-assessment for CAncer for patients in general practice (ERICA).

INTRODUCTION: The UK has worse cancer outcomes than most comparable countries, with a large contribution attributed to diagnostic delay. Electronic risk assessment tools (eRATs) have been developed to identify primary care patients with a ≥2% risk of cancer using features recorded in the electronic record. METHODS AND ANALYSIS: This is a pragmatic cluster randomised controlled trial in English primary care. Individual general practices will be randomised in a 1:1 ratio to intervention (provision of eRATs for six common cancer sites) or to usual care. The primary outcome is cancer stage at diagnosis, dichotomised to stage 1 or 2 (early) or stage 3 or 4 (advanced) for these six cancers, assessed from National Cancer Registry data. Secondary outcomes include stage at diagnosis for a further six cancers without eRATs, use of urgent referral cancer pathways, total practice cancer diagnoses, routes to cancer diagnosis and 30-day and 1-year cancer survival. Economic and process evaluations will be performed along with service delivery modelling. The primary analysis explores the proportion of patients with early-stage cancer at diagnosis. The sample size calculation used an OR of 0.8 for a cancer being diagnosed at an advanced stage in the intervention arm compared with the control arm, equating to an absolute reduction of 4.8% as an incidence-weighted figure across the six cancers. This requires 530 practices overall, with the intervention active from April 2022 for 2 years. ETHICS AND DISSEMINATION: The trial has approval from London City and East Research Ethics Committee, reference number 19/LO/0615; protocol version 5.0, 9 May 2022. It is sponsored by the University of Exeter. Dissemination will be by journal publication, conferences, use of appropriate social media and direct sharing with cancer policymakers. TRIAL REGISTRATION NUMBER: ISRCTN22560297.

How do electronic risk assessment tools affect the communication and understanding of diagnostic uncertainty in the primary care consultation? A systematic review and thematic synthesis.

OBJECTIVES: To conduct a systematic review and synthesise qualitative research of electronic risk assessment tools (eRATs) in primary care, examining how they affect the communication and understanding of diagnostic risk and uncertainty. eRATs are computer-based algorithms designed to help clinicians avoid missing important diagnoses, pick up possible symptoms early and facilitate shared decision-making. DESIGN: Systematic search, using predefined criteria of the published literature and synthesis of the qualitative data, using Thematic Synthesis. Database searches on 27 November 2019 were of MEDLINE, Embase, CINAHL and Web of Science, and a secondary search of the references of included articles. Included studies were those involving electronic risk assessment or decision support, pertaining to diagnosis in primary care, where qualitative data were presented. Non-empirical studies and non-English language studies were excluded. 5971 unique studies were identified of which 441 underwent full-text review. 26 studies were included for data extraction. A further two were found from citation searches. Quality appraisal was via the CASP (Critical Appraisal Skills Program) tool. Data extraction was via line by line coding. A thematic synthesis was performed. SETTING: Primary care. RESULTS: eRATs included differential diagnosis suggestion tools, tools which produce a future risk of disease development or recurrence or calculate a risk of current undiagnosed disease. Analytical themes were developed to describe separate aspects of the clinical consultation where risk and uncertainty are both central and altered via the use of an eRAT: 'Novel risk', 'Risk refinement', 'Autonomy', 'Communication', 'Fear' and 'Mistrust'. CONCLUSION: eRATs may improve the understanding and communication of risk in the primary care consultation. The themes of 'Fear' and 'Mistrust' could represent potential challenges with eRATs. TRIAL REGISTRATION NUMBER: CRD219446.

Quantifying the impact of pre-existing conditions on the stage of oesophagogastric cancer at diagnosis: a primary care cohort study using electronic medical records.

BACKGROUND: Pre-existing conditions interfere with cancer diagnosis by offering diagnostic alternatives, competing for clinical attention or through patient surveillance. OBJECTIVE: To investigate associations between oesophagogastric cancer stage and pre-existing conditions. METHODS: Retrospective cohort study using Clinical Practice Research Datalink (CPRD) data, with English cancer registry linkage. Participants aged ≥40 years had consulted primary care in the year before their incident diagnosis of oesophagogastric cancer in 01/01/2010-31/12/2015. CPRD records pre-diagnosis were searched for codes denoting clinical features of oesophagogastric cancer and for pre-existing conditions, including those providing plausible diagnostic alternatives for those features. Logistic regression analysed associations between stage and multimorbidity (≥2 conditions; reference category: no multimorbidity) and having 'diagnostic alternative(s)', controlling for age, sex, deprivation and cancer site. RESULTS: Of 2444 participants provided, 695 (28%) were excluded for missing stage, leaving 1749 for analysis (1265/1749, 72.3% had advanced-stage disease). Multimorbidity was associated with stage [odds ratio 0.63, 95% confidence interval (CI) 0.47-0.85, P = 0.002], with moderate evidence of an interaction term with sex (1.76, 1.08-2.86, P = 0.024). There was no association between alternative explanations and stage (odds ratio 1.18, 95% CI 0.87-1.60, P = 0.278). CONCLUSIONS: In men, multimorbidity is associated with a reduced chance of advanced-stage oesophagogastric cancer, to levels seen collectively for women.

Diagnosing cancer is complicated by existing medical conditions. Diagnosis may be delayed if conditions explain cancer symptoms, or dominate appointments. Diagnosis may be quicker if conditions increase doctor­patient contact. We studied the association between existing illness and stage (early or advanced) of diagnosis with cancer of the stomach or gullet. We studied the primary-care records of patients aged ≥40 years, diagnosed in 01/01/2010­31/12/2015, and got stage from English cancer registry data. We searched the primary-care records for cancer symptoms (e.g. difficulty swallowing), and for 27 conditions that were common or explained cancer symptoms (e.g. difficulty swallowing following a stroke). We analysed cancer stage, looking at age, sex, multimorbidity (two or more conditions) and explanations for symptoms. We studied 1749 patients, of whom 1265 (72.3%) had advanced-stage cancer. The chance of advanced stage was similar in women with (71%, 95% CI 66­75%) or without (69%, 62­76%) multimorbidity. It was lower for men with (70%, 67­74%) than without (79%, 75­83%) multimorbidity. Stage of cancer was not affected by having explanations for cancer symptoms. In summary, for men, multimorbidity is associated with a reduced chance of advanced-stage cancer of the stomach or gullet to levels seen collectively for women.

Effect of pre-existing conditions on bladder cancer stage at diagnosis: a cohort study using electronic primary care records in the UK.

BACKGROUND: Pre-existing concurrent medical conditions (multimorbidity) complicate cancer diagnosis when they provide plausible diagnostic alternatives for cancer symptoms. AIM: To investigate associations in bladder cancer between: first, pre-existing condition count and advanced-stage diagnosis; and, second, comorbidities that share symptoms with bladder cancer and advanced-stage diagnosis. DESIGN AND SETTING: This observational UK cohort study was set in the Clinical Practice Research Datalink with Public Health England National Cancer Registration and Analysis Service linkage. METHOD: Included participants were aged ≥40 years with an incident diagnosis of bladder cancer between 1 January 2000 and 31 December 2015, and primary care records of attendance for haematuria, dysuria, or abdominal mass in the year before diagnosis. Stage at diagnosis (stage 1 or 2 versus stage 3 or 4) was the outcome variable. Putative explanatory variables using logistic regression were examined, including patient-level count of pre-existing conditions and 'alternative-explanations', indicating whether pre-existing condition(s) were plausible diagnostic alternatives for the index cancer symptom. RESULTS: In total, 1468 patients (76.4% male) were studied, of which 399 (35.6%) males and 217 (62.5%) females had alternative explanations for their index cancer symptom, the most common being urinary tract infection with haematuria. Females were more likely than males to be diagnosed with advanced-stage cancer (adjusted odds ratio [aOR] 1.62; 95% confidence interval [CI] = 1.20 to 2.18; P = 0.001). Alternative explanations were strongly associated with advanced-stage diagnosis in both sexes (aOR 1.69; 95% CI = 1.20 to 2.39; P = 0.003). CONCLUSION: Alternative explanations were associated with advanced-stage diagnosis of bladder cancer. Females were more likely than males to be diagnosed with advanced-stage disease, but the effect was not driven entirely by alternative explanations.

Symptoms of adult chronic and acute leukaemia before diagnosis: large primary care case-control studies using electronic records.

BACKGROUND: Leukaemia is the eleventh commonest UK cancer. The four main subtypes have different clinical profiles, particularly between chronic and acute types. AIM: To identify the symptom profiles of chronic and acute leukaemia in adults in primary care. DESIGN AND SETTING: Matched case-control studies using Clinical Practice Research Datalink records. METHOD: Putative symptoms of leukaemia were identified in the year before diagnosis. Conditional logistic regression was used for analysis, and positive predictive values (PPVs) were calculated to estimate risk. RESULTS: Of cases diagnosed between 2000 and 2009, 4655 were aged ≥40 years (2877 chronic leukaemia (CL), 937 acute leukaemia (AL), 841 unreported subtype). Ten symptoms were independently associated with CL, the three strongest being: lymphadenopathy (odds ratio [OR] 22, 95% confidence interval [CI] = 13 to 36), weight loss (OR 3.0, 95% CI = 2.1 to 4.2), and bruising (OR 2.3, 95% CI = 1.6 to 3.2). Thirteen symptoms were independently associated with AL, the three strongest being: nosebleeds and/or bleeding gums (OR 5.7, 95% CI = 3.1 to 10), fever (OR 5.3, 95% CI = 2.7 to 10), and fatigue (OR 4.4, 95% CI = 3.3 to 6.0). No individual symptom or combination of symptoms had a PPV >1%. CONCLUSION: The symptom profiles of CL and AL have both overlapping and distinct features. This presents a dichotomy for GPs: diagnosis, by performing a full blood count, is easy; however, the symptoms of leukaemia are non-specific and of relatively low risk. This explains why many leukaemia diagnoses are unexpected findings.

Quantifying the risk of non-Hodgkin lymphoma in symptomatic primary care patients aged ≥40 years: a large case-control study using electronic records.

BACKGROUND: Non-Hodgkin lymphoma (NHL) is the sixth most common cancer in the UK; approximately 35 people are diagnosed and 13 die from the disease daily. AIM: To identify the primary care clinical features of NHL and quantify their risk in symptomatic patients. DESIGN AND SETTING: Matched case-control study using Clinical Practice Research Datalink patient records. METHOD: Putative clinical features of NHL were identified in the year before diagnosis. Results were analysed using conditional logistic regression and positive predictive values (PPVs). RESULTS: A total of 4362 patients aged ≥40 years, diagnosed with NHL between 2000 and 2009, and 19 468 age, sex, and general practice-matched controls were studied. Twenty features were independently associated with NHL. The five highest risk symptoms were lymphadenopathy, odds ratio (OR) 263 (95% CI = 133 to 519), head and neck mass not described as lymphadenopathy OR 49 (95% CI = 32 to 74), other mass OR 12 (95% CI = 10 to 16), weight loss OR 3.2 (95% CI = 2.3 to 4.4), and abdominal pain OR 2.5 (95% CI = 2.1 to 2.9). Lymphadenopathy has a PPV of 13% for NHL in patients ≥60 years. Weight loss in conjunction with repeated back pain or raised gamma globulin had PPVs >2%. CONCLUSION: Unexplained lymphadenopathy in patients aged ≥60 years produces a very high risk of NHL in primary care. These patients warrant urgent investigation, potentially sooner than 6 weeks from initial presentation where the GP is particularly concerned.

Quantifying the risk of Hodgkin lymphoma in symptomatic primary care patients aged ≥40 years: a case-control study using electronic records.

BACKGROUND: In the UK, approximately five people are diagnosed with Hodgkin lymphoma (HL) daily. One-tenth of diagnoses are in those aged >75 years. AIM: To establish a symptom profile of HL and quantify their risk in primary care patients aged ≥40 years. DESIGN AND SETTING: Matched case-control study using Clinical Practice Research Datalink patient records. METHOD: Putative clinical features of HL were identified in the year before diagnosis. Results were analysed using conditional logistic regression and positive predictive values (PPVs) calculated for the consulting population. RESULTS: Two-hundred and eighty-three patients aged ≥40 years, diagnosed with HL between 2000 and 2009, and 1237 age, sex, and general practice-matched participants were studied. Six features were independently associated with HL: lymphadenopathy (OR 280, 95% confidence interval [CI] = 25 to 3100), head and neck mass not described as lymphadenopathy (OR 260, 95% CI = 21 to 3200), other mass (OR 12, 95% CI = 4.4 to 35), thrombocytosis (OR 6.0, 95% CI = 2.6 to 14), raised inflammatory markers (OR 5.2, 95% CI = 3.0 to 9.0), and low full blood count (OR 2.8, 95% CI = 1.6 to 4.8). Lymphadenopathy per se has a positive predictive value (PPV) of 5.6% for HL in patients aged ≥60 years. CONCLUSION: Consistent with secondary care findings, lymphadenopathy is the clinical feature with the highest risk of HL in primary care and warrants urgent investigation.

Quantifying the risk of multiple myeloma from symptoms reported in primary care patients: a large case-control study using electronic records.

BACKGROUND: Patients with myeloma experience the longest diagnostic delays compared with patients with other cancers in the UK; 37% are diagnosed through emergency presentations. AIM: To identify and quantify the risk of myeloma from specific clinical features reported by primary care patients. DESIGN AND SETTING: Matched case-control study using General Practice Research Database primary care electronic records. METHOD: Putative clinical features of myeloma were identified and analysed using conditional logistic regression. Positive predictive values (PPVs) were calculated for the consulting population. RESULTS: A total of 2703 patients aged ≥40 years, diagnosed with myeloma between 2000 and 2009, and 12 157 age, sex, and general practice-matched controls were identified. Sixteen features were independently associated with myeloma: hypercalcaemia, odds ratio 11.4 (95% confidence interval [CI] = 7.1 to 18), cytopenia 5.4 (95% CI = 4.6 to 6.4), raised inflammatory markers 4.9 (95% CI = 4.2 to 5.8), fracture 3.1 (95% CI = 2.3 to 4.2), raised mean corpuscular volume 3.1 (95% CI = 2.4 to 4.1), weight loss 3.0 (95% CI = 2.0 to 4.5), nosebleeds 3.0 (95% CI = 1.9 to 4.7), rib pain 2.5 (95% CI = 1.5 to 4.4), back pain 2.2 (95% CI = 2.0 to 2.4), other bone pain 2.1 (95% CI = 1.4 to 3.1), raised creatinine 1.8 (95% CI = 1.5 to 2.2), chest pain 1.6 (95% CI = 1.4 to 1.8), joint pain 1.6 (95% CI = 1.2 to 2.2), nausea 1.5 (95% CI = 1.1 to 2.1), chest infection 1.4 (95% CI = 1.2 to 1.6), and shortness of breath 1.3 (95% CI = 1.1 to 1.5). Individual symptom PPVs were generally <1%, although were >10% for some symptoms when combined with leucopenia or hypercalcaemia. CONCLUSION: Individual symptoms of myeloma in primary care are generally low risk, probably explaining diagnostic delays. Once simple primary care blood tests are taken, risk estimates change. Hypercalcaemia and leucopenia are particularly important abnormalities, and coupled with symptoms, strongly suggest myeloma.

Non-visible versus visible haematuria and bladder cancer risk: a study of electronic records in primary care.

BACKGROUND: Diagnosis of bladder cancer relies on investigation of symptoms presented to primary care, notably visible haematuria. The importance of non-visible haematuria has never been estimated. AIM: To estimate the risk of bladder cancer with non-visible haematuria. DESIGN AND SETTING: A case-control study using UK electronic primary care medical records, including uncoded data to supplement coded records. METHOD: A total of 4915 patients (aged ≥40 years) diagnosed with bladder cancer between January 2000 and December 2009 were selected from the Clinical Practice Research Datalink and matched to 21 718 controls for age, sex, and practice. Variables for visible and non-visible haematuria were derived from coded and uncoded data. Analyses used multivariable conditional logistic regression, followed by estimation of positive predictive values (PPVs) for bladder cancer using Bayes' theorem. RESULTS: Non-visible haematuria (coded/uncoded data) was independently associated with bladder cancer: odds ratio (OR) 20 (95% confidence interval [CI] =12 to 33). The PPV of non-visible haematuria was 1.6% (95% CI = 1.2 to 2.1) in those aged ≥60 years and 0.8% (95% CI = 0.1 to 5.6) in 40-59-year-olds. The PPV of visible haematuria was 2.8% (95% CI = 2.5 to 3.1) and 1.2% (95% CI = 0.6 to 2.3) for the same age groups respectively, lower than those calculated using coded data alone. The proportion of records of visible haematuria in coded, rather than uncoded, format was higher in cases than in controls (P<0.002, χ(2) test). There was no evidence for such differential recording of non-visible haematuria by case/control status (P = 0.78), although, overall, the uncoded format was preferred (P<0.001). CONCLUSION: Both non-visible and visible haematuria are associated with bladder cancer, although the visible form confers nearly twice the risk of cancer compared with the non-visible form. GPs' style of record keeping varies by symptom and possible diagnosis.

Clinical features of kidney cancer in primary care: a case-control study using primary care records.

BACKGROUND: Kidney cancer accounts for over 4000 UK deaths annually, and is one of the cancer sites with a poor mortality record compared with Europe. AIM: To identify and quantify all clinical features of kidney cancer in primary care. DESIGN: Case-control study, using General Practice Research Database records. METHOD: A total of 3149 patients aged ≥40 years, diagnosed with kidney cancer between 2000 and 2009, and 14 091 age, sex and practice-matched controls, were selected. Clinical features associated with kidney cancer were identified, and analysed using conditional logistic regression. Positive predictive values for features of kidney cancer were estimated. RESULTS: Cases consulted more frequently than controls in the year before diagnosis: median 16 consultations (interquartile range 10-25) versus 8 (4-15): P<0.001. Fifteen features were independently associated with kidney cancer: visible haematuria, odds ratio 37 (95% confidence interval [CI] = 28 to 49), abdominal pain 2.8 (95% CI = 2.4 to 3.4), microcytosis 2.6 (95% CI = 1.9 to 3.4), raised inflammatory markers 2.4 (95% CI = 2.1 to 2.8), thrombocytosis 2.2 (95% CI = 1.7 to 2.7), low haemoglobin 1.9 (95% CI = 1.6 to 2.2), urinary tract infection 1.8 (95% CI = 1.5 to 2.1), nausea 1.8 (95% CI = 1.4 to 2.3), raised creatinine 1.7 (95% CI = 1.5 to 2.0), leukocytosis 1.5 (95% CI = 1.2 to 1.9), fatigue 1.5 (95% CI = 1.2 to 1.9), constipation 1.4 (95% CI = 1.1 to 1.7), back pain 1.4 (95% CI = 1.2 to 1.7), abnormal liver function 1.3 (95% CI = 1.2 to 1.5), and raised blood sugar 1.2 (95% CI = 1.1 to 1.4). The positive predictive value for visible haematuria in patients aged ≥60 years was 1.0% (95% CI = 0.8 to 1.3). CONCLUSION: Visible haematuria is the commonest and most powerful single predictor of kidney cancer, and the risk rises when additional symptoms are present. When considered alongside the risk of bladder cancer, the overall risk of urinary tract cancer from haematuria warrants referral.