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

Background: Blood tests can support the diagnostic process but how often they are used in cancer patients 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 cancer patients diagnosed in 2018. Methods: We assessed common blood test use (full blood count (FBC), urea and electrolytes (U&Es), and liver function tests (LFTs)), related variation by patient and symptom group, and associations with the primary care and the diagnostic intervals (PCI, DI). Results: At least one common blood test was used in 41% of cancer patients. Among tested patients, FBC was used in 95%, U&Es in 88% and LFTs in 74%) Blood testing was less common in women (adjusted odds ratio (aOR) vs men: 0.92, 95%CI: 0.87-0.98) and non-white patients (0.89, 0.82-0.97 vs white) and more common in older patients (1.12, 1.06-1.18 for 70+ vs 50-69 years). Test use varied greatly by cancer-site, (melanoma: 2%, leukaemia 84%). Fewer patients presenting with alarm symptoms alone were tested (24%) than those with non-alarm symptoms alone (50%). Median PCI and DI were longer in tested than non-tested patients (PCI: 10 vs 0; DI: 49 vs 32 days, respectively, p<0.001 for both), including among tested patients with alarm symptoms (PCI: 4 vs 0; DI: 41 vs 22). Conclusions: Two-fifths of patients subsequently diagnosed with cancer have primary care blood tests. Given variable test use, research is needed on the clinical context in which blood tests are ordered

National Cancer Diagnosis Audits for England 2018 versus 2014: a comparative analysis

BACKGROUND: Timely diagnosis of cancer in patients who present with symptoms in primary care is a quality-improvement priority. AIM: To examine possible changes to aspects of the diagnostic process, and its timeliness, before and after publication of the National Institute for Health and Care Excellence's (2015) guidance on the referral of suspected cancer in primary care. DESIGN AND SETTING: Comparison of findings from population-based clinical audits of cancer diagnosis in general practices in England for patients diagnosed in 2018 or 2014. METHOD: GPs in 1878 (2018) and 439 (2014) practices collected primary care information on the diagnostic pathway of cancer patients. Key measures including patient characteristics, place of presentation, number of pre-referral consultations, use of primary care investigations, and referral type were compared between the two audits by descriptive analysis and regression models. RESULTS: Among 64 489 (2018) and 17 042 (2014) records of a new cancer diagnosis, the percentage of patients with same-day referral (denoted by a primary care interval of 0 days) was higher in 2018 (42.7% versus 37.7%) than in 2014, with similar improvements in median diagnostic interval (36 days versus 40 days). Compared with 2014, in 2018: fewer patients had ≥3 pre-referral consultations (18.8% versus 26.2%); use of primary care investigations increased (47.9% versus 45.4%); urgent cancer referrals increased (54.8% versus 51.8%); emergency referrals decreased (13.4% versus 16.5%); and recorded use of safety netting decreased (40.0% versus 44.4%). CONCLUSION: In the 5-year period, including the year when national guidelines were updated (that is, 2015), there were substantial improvements to the diagnostic process of patients who present to general practice in England with symptoms of a subsequently diagnosed cancer

Presenting symptoms of cancer and stage at diagnosis: evidence from a cross-sectional, population-based study.

BACKGROUND: Early diagnosis interventions such as symptom awareness campaigns increasingly form part of global cancer control strategies. However, these strategies will have little impact in improving cancer outcomes if the targeted symptoms represent advanced stage of disease. Therefore, we aimed to examine associations between common presenting symptoms of cancer and stage at diagnosis. METHODS: In this cross-sectional study, we analysed population-level data from the English National Cancer Diagnosis Audit 2014 for patients aged 25 years and older with one of 12 types of solid tumours (bladder, breast, colon, endometrial, laryngeal, lung, melanoma, oral or oropharyngeal, ovarian, prostate, rectal, and renal cancer). We considered 20 common presenting symptoms and examined their associations with stage at diagnosis (TNM stage IV vs stage I-III) using logistic regression. For each symptom, we estimated these associations when reported as a single presenting symptom and when reported together with other symptoms. FINDINGS: We analysed data for 7997 patients. The proportion of patients diagnosed with stage IV cancer varied substantially by presenting symptom, from 1% (95% CI 1-3; eight of 584 patients) for abnormal mole to 80% (71-87; 84 of 105 patients) for neck lump. Three of the examined symptoms (neck lump, chest pain, and back pain) were consistently associated with increased odds of stage IV cancer, whether reported alone or with other symptoms, whereas the opposite was true for abnormal mole, breast lump, postmenopausal bleeding, and rectal bleeding. For 13 of the 20 symptoms (abnormal mole, breast lump, post-menopausal bleeding, rectal bleeding, lower urinary tract symptoms, haematuria, change in bowel habit, hoarseness, fatigue, abdominal pain, lower abdominal pain, weight loss, and the "any other symptom" category), more than 50% of patients were diagnosed at stages other than stage IV; for 19 of the 20 studied symptoms (all except for neck lump), more than a third of patients were diagnosed at stages other than stage IV. INTERPRETATION: Despite specific presenting symptoms being more strongly associated with advanced stage at diagnosis than others, for most symptoms, large proportions of patients are diagnosed at stages other than stage IV. These findings provide support for early diagnosis interventions targeting common cancer symptoms, countering concerns that they might be simply expediting the detection of advanced stage disease. FUNDING: UK Department of Health's Policy Research Unit in Cancer Awareness, Screening and Early Diagnosis; and Cancer Research UK

Pre-Referral Primary Care Blood Tests and Symptom Presentation before Cancer Diagnosis: National Cancer Diagnosis Audit Data

Background: Blood tests can support the diagnostic process in primary care. Understanding how symptomatic presentations are associated with blood test use in patients subsequently diagnosed with cancer can help to benchmark current practices and guide interventions. Methods: English National Cancer Diagnosis Audit data on 39,751 patients with incident cancer in 2018 were analysed. The frequency of four generic (full blood count, urea and electrolytes, liver function tests, and inflammatory markers) and five organ-specific (cancer biomarkers (PSA or CA125), serum protein electrophoresis, ferritin, bone profile, and amylase) blood tests was described for a total of 83 presenting symptoms. The adjusted analysis explored variation in blood test use by the symptom-positive predictive value (PPV) group. Results: There was a large variation in generic blood test use by presenting symptoms, being higher in patients subsequently diagnosed with cancer who presented with nonspecific symptoms (e.g., fatigue 81% or loss of appetite 79%), and lower in those who presented with alarm symptoms (e.g., breast lump 3% or skin lesion 1%). Serum protein electrophoresis (reflecting suspicion of multiple myeloma) was most frequently used in cancer patients who presented with back pain (18%), and amylase measurement (reflecting suspicion of pancreatic cancer) was used in those who presented with upper abdominal pain (14%). Prostate-specific antigen (PSA) use was greatest in men with cancer who presented with lower urinary tract symptoms (88%), and CA125 in women with cancer who presented with abdominal distention (53%). Symptoms with PPV values between 2.00–2.99% were associated with greater test use (64%) compared with 52% and 51% in symptoms with PPVs in the 0.01–0.99 or 1.00–1.99% range and compared with 42% and 31% in symptoms with PPVs in either the 3.00–4.99 or ≥5% range (p < 0.001). Conclusions: Generic blood test use reflects the PPV of presenting symptoms, and the use of organ-specific tests is greater in patients with symptomatic presentations with known associations with certain cancer sites. There are opportunities for greater blood test use in patients presenting with symptoms that do not meet referral thresholds (i.e., <3% PPV for cancer) where information gain to support referral decisions is likely greatest. The findings benchmark blood test use in cancer patients, highlighting opportunities for increasing use

Diagnosing cancer in primary care: results from the National Cancer Diagnosis Audit.

BACKGROUND: Continual improvements in diagnostic processes are needed to minimise the proportion of patients with cancer who experience diagnostic delays. Clinical audit is a means of achieving this. AIM: To characterise key aspects of the diagnostic process for cancer and to generate baseline measures for future re-audit. DESIGN AND SETTING: Clinical audit of cancer diagnosis in general practices in England. METHOD: Information on patient and tumour characteristics held in the English National Cancer Registry was supplemented by information from GPs in participating practices. Data items included diagnostic timepoints, patient characteristics, and clinical management. RESULTS: Data were collected on 17 042 patients with a new diagnosis of cancer during 2014 from 439 practices. Participating practices were similar to non-participating ones, particularly regarding population age, urban/rural location, and practice-based patient experience measures. The median diagnostic interval for all patients was 40 days (interquartile range [IQR] 15-86 days). Most patients were referred promptly (median primary care interval 5 days [IQR 0-27 days]). Where GPs deemed diagnostic delays to have occurred (22% of cases), patient, clinician, or system factors were responsible in 26%, 28%, and 34% of instances, respectively. Safety netting was recorded for 44% of patients. At least one primary care-led investigation was carried out for 45% of patients. Most patients (76%) had at least one existing comorbid condition; 21% had three or more. CONCLUSION: The findings identify avenues for quality improvement activity and provide a baseline for future audit of the impact of 2015 National Institute for Health and Care Excellence guidance on management and referral of suspected cancer

Risk factors and prognostic implications of diagnosis of cancer within 30 days after an emergency hospital admission (emergency presentation): an International Cancer Benchmarking Partnership (ICBP) population-based study

BACKGROUND: Greater understanding of international cancer survival differences is needed. We aimed to identify predictors and consequences of cancer diagnosis through emergency presentation in different international jurisdictions in six high-income countries. METHODS: Using a federated analysis model, in this cross-sectional population-based study, we analysed cancer registration and linked hospital admissions data from 14 jurisdictions in six countries (Australia, Canada, Denmark, New Zealand, Norway, and the UK), including patients with primary diagnosis of invasive oesophageal, stomach, colon, rectal, liver, pancreatic, lung, or ovarian cancer during study periods from Jan 1, 2012, to Dec 31, 2017. Data were collected on cancer site, age group, sex, year of diagnosis, and stage at diagnosis. Emergency presentation was defined as diagnosis of cancer within 30 days after an emergency hospital admission. Using logistic regression, we examined variables associated with emergency presentation and associations between emergency presentation and short-term mortality. We meta-analysed estimates across jurisdictions and explored jurisdiction-level associations between cancer survival and the percentage of patients diagnosed as emergencies. FINDINGS: In 857 068 patients across 14 jurisdictions, considering all of the eight cancer sites together, the percentage of diagnoses through emergency presentation ranged from 24·0% (9165 of 38 212 patients) to 42·5% (12 238 of 28 794 patients). There was consistently large variation in the percentage of emergency presentations by cancer site across jurisdictions. Pancreatic cancer diagnoses had the highest percentage of emergency presentations on average overall (46·1% [30 972 of 67 173 patients]), with the jurisdictional range being 34·1% (1083 of 3172 patients) to 60·4% (1317 of 2182 patients). Rectal cancer had the lowest percentage of emergency presentations on average overall (12·1% [10 051 of 83 325 patients]), with a jurisdictional range of 9·1% (403 of 4438 patients) to 19·8% (643 of 3247 patients). Across the jurisdictions, older age (ie, 75-84 years and 85 years or older, compared with younger patients) and advanced stage at diagnosis compared with non-advanced stage were consistently associated with increased emergency presentation risk, with the percentage of emergency presentations being highest in the oldest age group (85 years or older) for 110 (98%) of 112 jurisdiction-cancer site strata, and in the most advanced (distant spread) stage category for 98 (97%) of 101 jurisdiction-cancer site strata with available information. Across the jurisdictions, and despite heterogeneity in association size (I2=93%), emergency presenters consistently had substantially greater risk of 12-month mortality than non-emergency presenters (odds ratio >1·9 for 112 [100%] of 112 jurisdiction-cancer site strata, with the minimum lower bound of the related 95% CIs being 1·26). There were negative associations between jurisdiction-level percentage of emergency presentations and jurisdiction-level 1-year survival for colon, stomach, lung, liver, pancreatic, and ovarian cancer, with a 10% increase in percentage of emergency presentations in a jurisdiction being associated with a decrease in 1-year net survival of between 2·5% (95% CI 0·28-4·7) and 7·0% (1·2-13·0). INTERPRETATION: Internationally, notable proportions of patients with cancer are diagnosed through emergency presentation. Specific types of cancer, older age, and advanced stage at diagnosis are consistently associated with an increased risk of emergency presentation, which strongly predicts worse prognosis and probably contributes to international differences in cancer survival. Monitoring emergency presentations, and identifying and acting on contributing behavioural and health-care factors, is a global priority for cancer control. FUNDING: Canadian Partnership Against Cancer; Cancer Council Victoria; Cancer Institute New South Wales; Cancer Research UK; Danish Cancer Society; National Cancer Registry Ireland; The Cancer Society of New Zealand; National Health Service England; Norwegian Cancer Society; Public Health Agency Northern Ireland, on behalf of the Northern Ireland Cancer Registry; the Scottish Government; Western Australia Department of Health; and Wales Cancer Network

Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476)

Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10−9) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group

Deciphering Normal Blood Gene Expression Variation—The NOWAC Postgenome Study

There is growing evidence that gene expression profiling of peripheral blood cells is a valuable tool for assessing gene signatures related to exposure, drug-response, or disease. However, the true promise of this approach can not be estimated until the scientific community has robust baseline data describing variation in gene expression patterns in normal individuals. Using a large representative sample set of postmenopausal women (N = 286) in the Norwegian Women and Cancer (NOWAC) postgenome study, we investigated variability of whole blood gene expression in the general population. In particular, we examined changes in blood gene expression caused by technical variability, normal inter-individual differences, and exposure variables at proportions and levels relevant to real-life situations. We observe that the overall changes in gene expression are subtle, implying the need for careful analytic approaches of the data. In particular, technical variability may not be ignored and subsequent adjustments must be considered in any analysis. Many new candidate genes were identified that are differentially expressed according to inter-individual (i.e. fasting, BMI) and exposure (i.e. smoking) factors, thus establishing that these effects are mirrored in blood. By focusing on the biological implications instead of directly comparing gene lists from several related studies in the literature, our analytic approach was able to identify significant similarities and effects consistent across these reports. This establishes the feasibility of blood gene expression profiling, if they are predicated upon careful experimental design and analysis in order to minimize confounding signals, artifacts of sample preparation and processing, and inter-individual differences

Use of radiotherapy in patients with oesophageal, stomach, colon, rectal, liver, pancreatic, lung, and ovarian cancer: an International Cancer Benchmarking Partnership (ICBP) population-based study.

BACKGROUND: There is little evidence on variation in radiotherapy use in different countries, although it is a key treatment modality for some patients with cancer. Here we aimed to examine such variation. METHODS: This population-based study used data from Norway, the four UK nations (England, Northern Ireland, Scotland, and Wales), nine Canadian provinces (Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Nova Scotia, Ontario, Prince Edward Island, and Saskatchewan), and two Australian states (New South Wales and Victoria). Patients aged 15-99 years diagnosed with cancer in eight different sites (oesophageal, stomach, colon, rectal, liver, pancreatic, lung, or ovarian cancer), with no other primary cancer diagnosis occurring within the 5 years before to 1 year after the index cancer diagnosis or during the study period were included in the study. We examined variation in radiotherapy use from 31 days before to 365 days after diagnosis and time to its initiation, alongside related variation in patient group differences. Information was obtained from cancer registry records linked to clinical or patient management system data, or hospital administration data. Random-effects meta-analyses quantified interjurisdictional variation using 95% prediction intervals (95% PIs). FINDINGS: Between Jan 1, 2012, and Dec 31, 2017, of 902 312 patients with a new diagnosis of one of the studied cancers, 115 357 (12·8%) did not meet inclusion criteria, and 786,955 were included in the analysis. There was large interjurisdictional variation in radiotherapy use, with wide 95% PIs: 17·8 to 82·4 (pooled estimate 50·2%) for oesophageal cancer, 35·5 to 55·2 (45·2%) for rectal cancer, 28·6 to 54·0 (40·6%) for lung cancer, and 4·6 to 53·6 (19·0%) for stomach cancer. For patients with stage 2-3 rectal cancer, interjurisdictional variation was greater than that for all patients with rectal cancer (95% PI 37·0 to 84·6; pooled estimate 64·2%). Radiotherapy use was infrequent but variable in patients with pancreatic (95% PI 1·7 to 16·5%), liver (1·8 to 11·2%), colon (1·6 to 5·0%), and ovarian (0·8 to 7·6%) cancer. Patients aged 85-99 years had three-times lower odds of radiotherapy use than those aged 65-74 years, with substantial interjurisdictional variation in this age difference (odds ratio [OR] 0·38; 95% PI 0·20-0·73). Women had slightly lower odds of radiotherapy use than men (OR 0·88, 95% PI 0·77-1·01). There was large variation in median time to first radiotherapy (from diagnosis date) by cancer site, with substantial interjurisdictional variation (eg, oesophageal 95% PI 11·3 days to 112·8 days; pooled estimate 62·0 days; rectal 95% PI 34·7 days to 77·3 days; pooled estimate 56·0 days). Older patients had shorter median time to radiotherapy with appreciable interjurisdictional variation (-9·5 days in patients aged 85-99 years vs 65-74 years, 95% PI -26·4 to 7·4). INTERPRETATION: Large interjurisdictional variation in both use and time to radiotherapy initiation were observed, alongside large and variable age differences. To guide efforts to improve patient outcomes, underlying reasons for these differences need to be established. FUNDING: International Cancer Benchmarking Partnership (funded by the Canadian Partnership Against Cancer, Cancer Council Victoria, Cancer Institute New South Wales, Cancer Research UK, Danish Cancer Society, National Cancer Registry Ireland, The Cancer Society of New Zealand, National Health Service England, Norwegian Cancer Society, Public Health Agency Northern Ireland on behalf of the Northern Ireland Cancer Registry, DG Health and Social Care Scottish Government, Western Australia Department of Health, and Public Health Wales NHS Trust)

Use of chemotherapy in patients with oesophageal, stomach, colon, rectal, liver, pancreatic, lung, and ovarian cancer: an International Cancer Benchmarking Partnership (ICBP) population-based study

BACKGROUND: There are few data on international variation in chemotherapy use, despite it being a key treatment type for some patients with cancer. Here, we aimed to examine the presence and size of such variation. METHODS: This population-based study used data from Norway, the four UK nations (England, Northern Ireland, Scotland, and Wales), eight Canadian provinces (Alberta, British Columbia, Manitoba, Newfoundland and Labrador, Nova Scotia, Ontario, Prince Edward Island, and Saskatchewan), and two Australian states (New South Wales and Victoria). Patients aged 15-99 years diagnosed with cancer in eight different sites (oesophageal, stomach, colon, rectal, liver, pancreatic, lung, or ovarian cancer), with no other primary cancer diagnosis occurring from within the 5 years before to 1 year after the index cancer diagnosis or during the study period were included in the study. We examined variation in chemotherapy use from 31 days before to 365 days after diagnosis and time to its initiation, alongside related variation in patient group differences. Information was obtained from cancer registry records linked to clinical or patient management system data or hospital administration data. Random-effects meta-analyses quantified interjurisdictional variation using 95% prediction intervals (95% PIs). FINDINGS: Between Jan 1, 2012, and Dec 31, 2017, of 893 461 patients with a new diagnosis of one of the studied cancers, 111 569 (12·5%) did not meet the inclusion criteria, and 781 892 were included in the analysis. There was large interjurisdictional variation in chemotherapy use for all studied cancers, with wide 95% PIs: 47·5 to 81·2 (pooled estimate 66·4%) for ovarian cancer, 34·9 to 59·8 (47·2%) for oesophageal cancer, 22·3 to 62·3 (40·8%) for rectal cancer, 25·7 to 55·5 (39·6%) for stomach cancer, 17·2 to 56·3 (34·1%) for pancreatic cancer, 17·9 to 49·0 (31·4%) for lung cancer, 18·6 to 43·8 (29·7%) for colon cancer, and 3·5 to 50·7 (16·1%) for liver cancer. For patients with stage 3 colon cancer, the interjurisdictional variation was greater than that for all patients with colon cancer (95% PI 38·5 to 78·4; 60·1%). Patients aged 85-99 years had 20-times lower odds of chemotherapy use than those aged 65-74 years, with very large interjurisdictional variation in this age difference (odds ratio 0·05; 95% PI 0·01 to 0·19). There was large variation in median time to first chemotherapy (from diagnosis date) by cancer site, with substantial interjurisdictional variation, particularly for rectal cancer (95% PI -15·5 to 193·9 days; pooled estimate 89·2 days). Patients aged 85-99 years had slightly shorter median time to first chemotherapy compared with those aged 65-74 years, consistently between jurisdictions (-3·7 days, 95% PI -7·6 to 0·1). INTERPRETATION: Large variation in use and time to chemotherapy initiation were observed between the participating jurisdictions, alongside large and variable age group differences in chemotherapy use. To guide efforts to improve patient outcomes, the underlying reasons for these patterns need to be established. FUNDING: International Cancer Benchmarking Partnership (funded by the Canadian Partnership Against Cancer, Cancer Council Victoria, Cancer Institute New South Wales, Cancer Research UK, Danish Cancer Society, National Cancer Registry Ireland, The Cancer Society of New Zealand, National Health Service England, Norwegian Cancer Society, Public Health Agency Northern Ireland on behalf of the Northern Ireland Cancer Registry, DG Health and Social Care Scottish Government, Western Australia Department of Health, and Public Health Wales NHS Trust)