Primary care blood tests before cancer diagnosis: National Cancer Diagnosis Audit data

Background Blood tests can support the diagnostic process in patients with cancer but how often they are used is unclear. Aim To explore use of common blood tests before cancer diagnosis in primary care. Design and setting English National Cancer Diagnosis Audit data on 39 752 patients with cancer diagnosed in 2018. Method Common blood test use (full blood count [FBC], urea and electrolytes [U&E], and liver function tests [LFTs]), variation by patient and symptom group, and associations with the primary care interval and the diagnostic interval were assessed. Results At least one common blood test was used in 41% (n = 16 427/39 752) of patients subsequently diagnosed with cancer. Among tested patients, (n = 16 427), FBC was used in 95% (n = 15 540), U&E in 89% (n = 14 555), and LFTs in 76% (n = 12 414). Blood testing was less common in females (adjusted odds ratio versus males: 0.92, 95% confidence interval [CI] = 0.87 to 0.98) and Black and minority ethnic patients (0.89, 95% CI = 0.82 to 0.97 versus White), and more common in older patients (1.12, 95% CI = 1.06 to 1.18 for ≥70 years versus 50–69 years). Test use varied greatly by cancer site (melanoma 2% [ n = 55/2297]; leukaemia 84% [ n = 552/661]). Fewer patients presenting with alarm symptoms alone were tested (24% [ n = 3341/13 778]) than those with non-alarm symptoms alone (50% [ n = 8223/16 487]). Median primary care interval and diagnostic interval were longer in tested than non-tested patients (primary care interval: 10 versus 0 days; diagnostic interval: 49 versus 32 days, respectively, P<0.001 for both), including among tested patients with alarm symptoms (primary care interval: 4 versus 0 days; diagnostic interval: 41 versus 22 days). Conclusion Two-fifths of patients subsequently diagnosed with cancer have primary care blood tests as part of their diagnostic process. Given variable test use, research is needed on the clinical context in which blood tests are ordered.


INTRODUCTION
Half of the UK population will be diagnosed with a form of cancer in their lifetime. 1ncreasing cancer survival requires improvements in both treatment and stage at diagnosis.The latter may be achieved through earlier diagnosis of patients who are symptomatic.
The majority of patients subsequently diagnosed with cancer first present to a GP with symptoms. 2Decision making for managing symptomatic presentations can be guided by the results of tests carried out in primary care.][5][6] Use of common blood tests in primary care has increased over time, 7 although how often such tests form part of care in patients who are subsequently diagnosed with cancer is unclear.Earlier research on patients with six common cancers (lung, colorectal, oesophagus, stomach, pancreas, and ovarian) indicates that between 24% (ovarian cancer) and 55% (stomach cancer) of patients had at least one blood test as part of their primary care management pre-referral. 8Whether there is potential for greater use of common blood tests in patients subsequently diagnosed with cancer is unclear.
Using common blood tests may represent an appealing diagnostic strategy for the large group of patients presenting with non-specific symptoms not meeting referral criteria for specialist investigations or referrals.][11] Using data on patients diagnosed in 2018 with common and rarer cancers in England, the aim in this study was to examine how often patients who are subsequently diagnosed with cancer are investigated using common blood tests in primary care as part of the management of their initial presentation and to explore the related variation in blood test use by patient characteristic, positing a priori that variation is likely by age, sex, cancer site, and symptoms, and potentially by deprivation and ethnicity.

Conclusion
Two-fifths of patients subsequently diagnosed with cancer have primary care blood tests as part of their diagnostic process.Given variable test use, research is needed on the clinical context in which blood tests are ordered.
2018 were collected by participating GPs based on information in the primary care records.Included patients were identified by the English Cancer Registry (National Disease Registration Service).In a previous audit, included patients were representative of the national incident population of patients with cancer, and participating practices had comparable characteristics to non-participating practices, although they were slightly larger. 12he analysis sample included 39 752 patients with non-screen-detected cancer who were aged ≥15 years and who first presented in general practice and had complete information on investigation status (Figure 1).

Outcome variable
The audit questionnaire collected information on whether blood tests were used in primary care before referral for suspected cancer, as a series of binary items: 'Primary care led investigations that were ordered as part of the diagnostic assessment, and before referral, decided by the GP and in response to symptoms complained of, signs elicited, or abnormal test results'.In the current study common blood tests were defined as a binary variable indicating the use of at least one of: full blood count (FBC), urea and electrolytes (U&E), or liver function tests (LFTs).These blood tests were focused on as they are the ones most commonly ordered, and because abnormalities can arise from a large range of disease processes.This is unlike other, more specialist, blood tests with more specific affinity to diseases of a given body organ or system, some of which, however, were considered in addition (see below).

Other variables
Exposure variables included: age group (15-29, 30-49, 50-69, ≥70 years), sex (male and female), ethnicity (White, Black and minority ethnic, and unknown), Index of Multiple Deprivation quintile group (based on income domain), count of pre-existing morbidities (0, 1, 2, and ≥3 conditions, and missing), cancer site (a 29-group categorical variable), and presenting symptom group. 12nformation on presenting symptoms was collected regarding the presence of one or more of 83 pre-specified symptoms in the audit questionnaire.In the current study alarm symptoms were defined as those where the 2015 National Institute for Health and Care Excellence guidelines recommended urgent or immediate referral or specialist investigation (Supplementary Table S1). 13Three main groups are defined: patients presenting with alarm symptoms; those with non-alarm symptoms; and those with both alarm and non-alarm symptoms.Additionally, two further groups were considered, one group with alarm symptoms likely to indicate a medical emergency in whom primary care blood testing is not expected to be used and a group with missing information on the nature of symptoms.

How this fits in
Evidence relating to the predictive value of blood tests for cancer diagnosis is growing, yet how often they are used by GPs in patients with cancer before its diagnosis is currently unclear.In England, two-fifths of patients subsequently diagnosed with cancer in 2018 had a full blood count, urea and electrolytes, or liver function test.Blood test use was less likely in females, Black and minority ethnic, and younger patients, and more likely in those presenting with non-specific symptoms.Longer intervals to referral and diagnosis were observed in patients who were tested.This research highlights the need for interventions to obviate (in populations presenting with more specific symptoms requiring referral) and increase use (in patients presenting with less specific symptoms) of blood tests in cancer populations.The length of the primary care interval was defined consistent with the Aarhus statement: the time from first symptomatic presentation to first referral to specialist care, as was the diagnostic interval: the time from first symptomatic presentation to diagnosis, and examined by investigation status. 14

Analysis
Logistic regression was used to estimate crude and adjusted odds ratios (ORs) of common blood test use by age, sex, ethnicity, morbidity status, deprivation group, and symptom category.To explore whether cancer-specific factors may influence blood test use beyond these variables, in a further model, the authors additionally adjusted for cancer site.Joint Wald tests were used to assess overall variation by variable category.
The median and interquartile range (IQR) of primary care interval and diagnostic interval by test status (use/non-use of common blood tests) are described, assessing differences between symptom type groups and cancers using Kruskal-Wallis tests.To account for potential confounding or effect mediation of the observed associations between blood test use and length of the primary care interval or the diagnostic interval, quantile regression models were used, adjusting for blood test use, sex, cancer site, and symptom category (age was not included because of model non-convergence).To examine potential interactions between blood test use and symptom category, the above model was further expanded to include such an interaction term.Patients with missing information on the primary care interval (16%) and diagnostic interval (12%) were excluded from this analysis.Statistical analysis was conducted in Stata SE V.15 (StataCorp).Supplementary analysis.The proportion of tested patients who received a specific common blood test or combination of tests was calculated (hereafter, patients who had a common blood test are referred to as 'tested' patients for brevity) and the distribution of blood tests by cancer site (Supplementary Table S2 and Table 3, respectively).Furthermore, interactions between ethnicity and deprivation were assessed within the adjusted models and no evidence for such interactions was found.
A sensitivity analysis repeated the main analysis but after excluding patients recorded as having no consultations although also recorded as having presented to their GP surgery (n = 2048, 5% of the main analysis sample).This group were kept in the main analysis, as a large proportion of them (n = 1554, 76%) were diagnosed after being referred via 2-week-wait or routinely by their GP.

Study population
Of 39 752 included patients, approximately half were ≥70 years old (49%), most were of White ethnicity (87%), and with a slight preponderance of males (55%, Table 1).Of included patients 74% had at least one chronic condition, whereas 19% had three or more.Patients were most commonly diagnosed with prostate (19%), breast (12%), or lung cancer (11%).Over one- third of patients presented with alarm symptoms alone (35%) and over two-fifths with non-alarm symptoms alone (41%), whereas less than one in five presented with both alarm and non-alarm symptoms (15%).The median primary care interval was 3 (IQR 0-20) days, and the median diagnostic interval was 39 (IQR 17-81) days.

Use of common blood tests
A total of 16 427/39 752 (41%) patients had at least one common blood test in primary care before being diagnosed with cancer; variation in blood test use by exposure variable is described in Table 1.
Considering patient characteristics, blood test use was more frequent in males compared with females (48% versus 34%, respectively, P<0.001) and older patients (ranging from <32% in patients <50 years and 46% in those ≥70 years, P<0.001).Blood test use was less frequent in Black and minority ethnic compared with White patients (38% versus 42%, respectively, P = 0.002), without a clear pattern of variation by deprivation group.Use of blood tests increased with greater number of morbidities (no morbidities: 36%, ≥3 morbidities: 45%, P<0.001).Multivariable analysis provided concordant findings, with the exception of the association with comorbidities, which was no longer apparent.
There was very large variation in common blood test use by subsequently diagnosed cancer, ranging from 84%, 76%, and 71% in patients diagnosed with leukaemia, myeloma, and pancreatic cancer, respectively; to 8%, 4%, and 2% for patients with vulval cancer, breast cancer, and melanoma, respectively.Adjusted analyses confirmed similar patterns of variation by cancer site.
Common blood tests were used in primary care before cancer diagnosis in around half of patients presenting with either non-e97 British Journal of General Practice, February 2023 alarm symptoms alone or both alarm and non-alarm symptoms together (50% and 56%), but in less than a quarter (24%) of patients presenting with alarm symptoms alone.In adjusted analysis, variation by presenting symptom group remained, that

Figure 1 .
Figure 1.Derivation of the analysis sample (n = 39 752).a Includes 571 patients with more than one tumour.NCDA = National Cancer Diagnosis Audit.

a
a P-value from Kruskal-Wallis test, comparing intervals in tested versus non-tested patient groups.b Median (50th) quantile regression (with 500 bootstrap replications), adjusted for blood test use, symptom category, sex, cancer site, and interaction between blood test use and symptom category.Further adjusting of the diagnostic interval model for age made little difference to the findings.Adjusting of the primary care interval model for age, IMD, and comorbidities was not possible because of lack of convergence.CI = confidence interval.IMD = Index of Multiple Deprivation.IQR = interquartile range.Ref = reference group.e99 British Journal of General Practice, February 2023Table 3. Table showing frequency of blood test use by cancer siteThe boundaries for green-yellow-red are set at the upper, median, and lower values for each blood test.All other values are coloured proportionally.b Cancer biomarkers are stratified by sex and include PSA, CEA, CA125, CA19.9, and other (unspecified).c Cancer sites with <397 patients (that is, <1% of study population) were grouped together, including Hodgkin lymphoma, mesothelioma, brain, cervical, larynx, oral cavity, testicular, and vulval cancers.CA125 = cancer antigen 125.CA19.9 = cancer antigen 19-9.CEA = carcinoembryonic antigen.FBC = full blood count.U&E = urea and electrolytes.LFT = liver function test.PSA = prostate-specific antigen.British Journal of General Practice, February 2023 e100

Table 1 continued. Proportions and crude/adjusted ORs examining variation in common blood test use in primary care among individuals diagnosed with cancer
After excluding 692 patients with missing information on morbidities, 39 060 patients remained for the logistic regression models.bPostestimations using Wald tests explained the significance of the explanatory variables on predicting blood test use.cTheBlack and minority ethnic group comprised South East Asian (n = 858, 2% of total population), Black a d Cancer site is presented in descending order of blood test use.CI = confidence interval.CUP = cancer of unknown primary.IMD = Index of Multiple Deprivation.N/A = not applicable.OR = odds ratio.Ref = reference group.