Brian D Nicholson

Can safety-netting improve cancer detection in patients with vague symptoms?

#### What you need to know Patients present daily about symptoms that could represent a new diagnosis of cancer.1 Some will present with easily recognised high risk symptoms such as dysphagia (5% likelihood of cancer if age >55 years), postmenopausal bleeding (4% likelihood if age >55 years), or haemoptysis (2% likelihood if age >40 years). But most will have vague or non-specific symptoms such as cough, fatigue, or abdominal pain.2 3 4 As these symptoms are shared with benign, chronic, or self limiting conditions, the likelihood of cancer is low (mostly under 0.5%).1 The clinical consequence is that diagnosis of cancers with vague symptoms tend to be delayed: for example, about half of patients in England with multiple myeloma have to consult three or more times before referral,5 and over a third present to hospital as emergencies.6 Depending on the cancer site, reducing diagnostic delay can lead to improved survival, earlier stage at diagnosis, and improved quality of life.7 The answer to this diagnostic problem is not to investigate every low risk symptom at first consultation.8 Doctors have a responsibility to avoid causing unnecessary alarm and wasting scarce resources through over-investigation, which may result in harm to the patient. Teasing out serious disease by following up patients over time, with planned sequential investigation, is usually the best approach for …

Overtesting and undertesting in primary care: a systematic review and meta-analysis

Background Health systems are currently subject to unprecedented financial strains. Inappropriate test use wastes finite health resources (overuse) and delays diagnoses and treatment (underuse). As most patient care is provided in primary care, it represents an ideal setting to mitigate waste. Objective To identify overuse and underuse of diagnostic tests in primary care. Design Systematic review and meta-analysis. Data sources and eligibility criteria We searched MEDLINE and Embase from January 1999 to October 2017 for studies that measured the inappropriateness of any diagnostic test (measured against a national or international guideline) ordered for adult patients in primary care. Results We included 357 171 patients from 63 studies in 15 countries. We extracted 103 measures of inappropriateness (41 underuse and 62 overuse) from included studies for 47 different diagnostic tests. The overall rate of inappropriate diagnostic test ordering varied substantially (0.2%–100%)%). 17 tests were underused >50% of the time. Of these, echocardiography (n=4 measures) was consistently underused (between 54% and 89%, n=4). There was large variation in the rate of inappropriate underuse of pulmonary function tests (38%–78%, n=8). Eleven tests were inappropriately overused >50% of the time. Echocardiography was consistently overused (77%–92%), whereas inappropriate overuse of urinary cultures, upper endoscopy and colonoscopy varied widely, from 36% to 77% (n=3), 10%–54% (n=10) and 8%–52% (n=2), respectively. Conclusions There is marked variation in the appropriate use of diagnostic tests in primary care. Specifically, the use of echocardiography (both underuse and overuse) is consistently poor. There is substantial variation in the rate of inappropriate underuse of pulmonary function tests and the overuse of upper endoscopy, urinary cultures and colonoscopy. PROSPERO registration number CRD42016048832.

Carcinoembryonic Antigen Monitoring to Detect Recurrence of Colorectal Cancer: How Should We Interpret the Test Results?

To the Editor: It is routine clinical practice, supported by national guidelines in both North America and Europe, to measure blood carcinoembryonic antigen (CEA)1 to detect recurrence of colorectal cancer during follow-up after primary treatment. Blood CEA is usually measured every 3–6 months, and patients with a CEA concentration above an absolute threshold (5 μg/L according to American Society of Clinical Oncology guidelines) are investigated further by radiological imaging. However, the evidence underpinning both guidelines and routine practice is weak. We recently reported the interim results of the Follow-up After Colorectal Surgery (FACS) trial, a clinical trial comparing different types of posttreatment follow-up in 1200 patients with colorectal cancer (1). This trial confirmed that measuring CEA is an effective way of detecting recurrence at an early stage, thus increasing the number of recurrences that can be treated with curative intent. However, the threshold we applied to define an abnormal CEA concentration (7 μg/L above the patients postoperative concentration at trial entry) was more conservative than current guidelines, so we decided to reevaluate our data to assess retrospectively whether we could have done better by applying a different strategy to interpret the CEA …

The diagnostic accuracy of a single CEA blood test in detecting colorectal cancer recurrence: Results from the FACS trial

Objective To evaluate the diagnostic accuracy of a single CEA (carcinoembryonic antigen) blood test in detecting colorectal cancer recurrence. Background Patients who have undergone curative resection for primary colorectal cancer are typically followed up with scheduled CEA testing for 5 years. Decisions to investigate further (usually by CT imaging) are based on single test results, reflecting international guidelines. Methods A secondary analysis was undertaken of data from the FACS trial (two arms included CEA testing). The composite reference standard applied included CT-CAP imaging, clinical assessment and colonoscopy. Accuracy in detecting recurrence was evaluated in terms of sensitivity, specificity, likelihood ratios, predictive values, time-dependent area under the ROC curves, and operational performance when used prospectively in clinical practice are reported. Results Of 582 patients, 104 (17.9%) developed recurrence during the 5 year follow-up period. Applying the recommended threshold of 5μg/L achieves at best 50.0% sensitivity (95% CI: 40.1–59.9%); in prospective use in clinical practice it would lead to 56 missed recurrences (53.8%; 95% CI: 44.2–64.4%) and 89 false alarms (56.7% of 157 patients referred for investigation). Applying a lower threshold of 2.5μg/L would reduce the number of missed recurrences to 36.5% (95% CI: 26.5–46.5%) but would increase the false alarms to 84.2% (924/1097 referred). Some patients are more prone to false alarms than others—at the 5μg/L threshold, the 89 episodes of unnecessary investigation were clustered in 29 individuals. Conclusion Our results demonstrated very low sensitivity for CEA, bringing to question whether it could ever be used as an independent triage test. It is not feasible to improve the diagnostic performance of a single test result by reducing the recommended action threshold because of the workload and false alarms generated. Current national and international guidelines merit re-evaluation and options to improve performance, such as making clinical decisions on the basis of CEA trend, should be further assessed.

Detecting cancer in primary care: Where does early diagnosis stop and overdiagnosis begin?

Overdiagnosis is the detection of cancer that would never cause symptoms or premature death (Welch & Black, 2010). Without intervention, these cancers may never progress, may regress or may progress so slowly that the patient dies of another cause. The (now) patient is exposed to the risks posed by the diagnosis, further investigation and treatment, but without the benefits. Autopsy studies confirm a reservoir of asymptomatic cancer in populations who die of other causes (Bell, del Mar, Wright, Dickinson, & Glasziou, 2015).

Home-use faecal immunochemical testing: primary care diagnostic technology update

#### Clinical Question What is the evidence base for home faecal immunochemical testing for colorectal cancer? A variety of home-use faecal occult blood testing (FOBt) kits remain commercially available to UK patients despite caution regarding their safety and accuracy. FOBt is a relatively non-invasive and inexpensive test. The NHS Bowel Cancer Screening Programme (BCSP) and the majority of European screening programmes uses guaiac FOBt (gFOB). A Cochrane Review has shown that biennial population screening with card-based postal laboratory-analysed gFOB can reduce colorectal mortality by 15% (relative risk [RR] 0.85, confidence interval [CI] = 0.78 to 0.92) in people aged 45–74 years.1 Those who attend screening have a 25% reduction (RR 0.75, CI = 0.66 to 0.84) in their risk of death, but only 40% return all three BCSP gFOB kits, although involving GPs in screening increases uptake.1,2 Faecal immunochemical testing (FIT) measures the globin component of human haemoglobin. Unlike gFOB, FIT does not require dietary restriction, is specific to lower gastrointestinal (GI) cancers as upper GI enzymes degrade human globin, and is less affected by concomitant medication use. FIT has started to replace gFOB in some regions (for example, the Czech Republic and Italy) and guidelines (for example, the US) given these gains in diagnostic accuracy. Home FIT kits are designed to obtain samples from multiple parts of a single stool and use immunochromatography to provide an immediate (qualitative) positive or negative result, avoiding the delay and costs associated with laboratory (quantitative) FIT and gFOB. Patients may present to primary care having used home bowel-testing kits, and so this report outlines the existing evidence detailing the potential accuracy and utility of the home FIT available to the adult consumer. Based on a search conducted in December 2013, Box 1 shows the CE approved FIT kits retailing to the UK …

Blood Measurement of Carcinoembryonic Antigen Level for Detecting Recurrence of Colorectal Cancer

CLINICAL QUESTION What is the trade-off between sensitivity and specificity at specific carcinoembryonic antigen (CEA) thresholds for detecting recurrent colorectal cancer? BOTTOM LINE To detect colorectal cancer recurrence, the sensitivity of CEA ranges from 68% for a threshold of 10 µg/L to 82% for a threshold of 2.5 µg/L and the specificity ranges from 97% for a threshold of 10 µg/L to 80% for a threshold of 2.5 µg/L.

Early detection of multiple myeloma in primary care using blood tests: a case–control study in primary care

Background Multiple myeloma is a haematological cancer characterised by numerous non-specific symptoms leading to diagnostic delay in a large proportion of patients. Aim To identify which blood tests are useful in suggesting or excluding a diagnosis of myeloma. Design and setting A matched case–control study set in UK primary care using routinely collected data from the Clinical Practice Research Datalink. Method Symptom prevalence and blood tests were analysed up to 5 years before diagnosis in 2703 cases and 12 157 matched controls. Likelihood ratios (LR) were used to classify tests or their combinations as useful rule-in tests (LR+ = ≥5), or rule-out tests (LR− = ≤0.2). Results Raised plasma viscosity (PV) had an LR+ = 2.0, 95% confidence interval [CI] = 1.7 to 2.3; erythrocyte sedimentation rate (ESR) 1.9, 95% CI = 1.7 to 2.0; and C-reactive protein (CRP) 1.2, 95% CI = 1.1 to 1.4. A normal haemoglobin had an LR− = 0.42, 95% CI = 0.39 to 0.45; calcium LR− = 0.81, 95% CI = 0.78 to 0.83; and creatinine LR− = 0.80, 95% CI = 0.77 to 0.83. The test combination with the lowest LR− was all normal haemoglobin with calcium and PV, which had an LR− = 0.06, 95% CI = 0.02 to 0.18, though the LR− for normal haemoglobin and PV together was 0.12 (95% CI = 0.07 to 0.23). Conclusion Plasma viscosity and ESR are better for both ruling in and ruling out the disease compared with C-reactive protein. A combination of a normal ESR or PV and normal haemoglobin is a simple rule-out approach for patients currently being tested in primary care.

Variation in Direct Access to Tests to Investigate Cancer: A Survey of English General Practitioners.

Background The 2015 NICE guidelines for suspected cancer recommend that English General Practitioners have direct access to diagnostic tests to investigate symptoms of cancer that do not meet the criteria for urgent referral. We aimed to identify the proportion of GPs in England with direct access to these tests. Methods We recruited 533 English GPs through a national clinical research network to complete an online survey about direct access to laboratory, radiology, and endoscopy tests in the three months leading up to the release of the 2015 NICE guidance. If they had direct access to a diagnostic test, GPs were asked about the time necessary to arrange a test and receive a report. Results are reported by NHS sub-region and, adjusting for sampling, for England as a whole. Results Almost all GPs reported direct access to x-ray and laboratory investigations except faecal occult blood testing (54%, 95% CI 49–59%) and urine protein electrophoresis (89%, 95% CI 84–92%). Fewer GPs had direct access to CT scans (54%, 95% CI 49–59%) or endoscopy (colonoscopy 32%, 95% CI 28–37%; gastroscopy 72%, 95% CI 67–77%). There was significant variation in direct access between NHS regions for the majority of imaging tests—for example, from 20 to 85% to MRI. Apart from x-ray, very few GPs (1–22%) could access radiology and endoscopy within the timescales recommended by NICE. The modal request to test time was 2–4 weeks for routine radiology and 4–6 weeks for routine endoscopy with results taking another 1–2 weeks. Conclusion At the time that the 2015 NICE guideline was released, local investment was required to not only provide direct access but also reduce the interval between request and test and speed up reporting. Further research using our data as a benchmark is now required to identify whether local improvements in direct access have been achieved in response to the NICE targets. If alternative approaches to test access are to be proposed they must be piloted comprehensively and underpinned by robust effectiveness data.

Comment on: 'Trends in the lifetime risk of developing cancer in Great Britain: comparison of risk for those born from 1930 to 1960'--cancer predictions need more context.

Comment on: ‘Trends in the lifetime risk of developing cancer in great Britain: comparison of risk for those born from 1930 to 1960’—cancer predictions need more context