Symptom Signatures and Diagnostic Timeliness in Cancer Patients: A Review of Current Evidence

Early diagnosis is an important aspect of contemporary cancer prevention and control strategies, as the majority of patients are diagnosed following symptomatic presentation. The nature of presenting symptoms can critically influence the length of the diagnostic intervals from symptom onset to presentation (the patient interval), and from first presentation to specialist referral (the primary care interval). Understanding which symptoms are associated with longer diagnostic intervals to help the targeting of early diagnosis initiatives is an area of emerging research. In this Review, we consider the methodological challenges in studying the presenting symptoms and intervals to diagnosis of cancer patients, and summarize current evidence on presenting symptoms associated with a range of common and rarer cancer sites. We propose a taxonomy of cancer sites considering their symptom signature and the predictive value of common presenting symptoms. Finally, we consider evidence on associations between symptomatic presentations and intervals to diagnosis before discussing implications for the design, implementation, and evaluation of public health or health system interventions to achieve the earlier detection of cancer

Reply: Timeliness, risk communication and patient preferences for investigations or referral

This is the final version. Available from the publisher via the DOI in this record.Letter to the Edito

Measures of promptness of cancer diagnosis in primary care: Secondary analysis of national audit data on patients with 18 common and rarer cancers

This is the final version. Available on open access from Springer Nature via the DOI in this recordBackground: Evidence is needed about the promptness of cancer diagnosis and associations between its measures. Methods: We analysed data from the National Audit of Cancer Diagnosis in Primary Care 2009-10 exploring the association between the interval from first symptomatic presentation to specialist referral (the primary care interval, or 'interval' hereafter) and the number of pre-referral consultations. Results: Among 13 035 patients with any of 18 different cancers, most (82%) were referred after 1 (58%) or 2 (25%) consultations (median intervals 0 and 15 days, respectively) while 9%, 4% and 5% patients required 3, 4 or 5+ consultations (median intervals 34, 47 and 97 days, respectively) (Spearman's r=0.70). The association was at least moderate for any cancer (Spearman's r range: 0.55 (prostate)-0.77 (brain)). Patients with cancers with a higher proportion of three or more pre-referral consultations typically also had longer median intervals (e.g., multiple myeloma) and vice versa (e.g., breast cancer). Conclusion: The number of pre-referral consultations has construct validity as a measure of the primary care interval. Developing interventions to reduce the number of pre-referral consultations can help improve the timeliness of cancer diagnosis, and constitutes a priority for early diagnosis initiatives and research. © 2013 Cancer Research UK. All rights reserved.National Institute for Health Research (NIHR

Gender inequalities in the promptness of diagnosis of bladder and renal cancer after symptomatic presentation: Evidence from secondary analysis of an English primary care audit survey

This is the final published version. Available from BMJ Publishing group via the DOI in this record.Data sharing statement: Please contact the corresponding author.Objectives: To explore whether women experience greater delays in the diagnosis of bladder and renal cancer when first presenting to a general practitioner with symptoms caused by those cancers and potential reasons for such gender inequalities. Design: Prospective national audit survey of cancer diagnosis. Setting: English primary care (2009-2010). Participants: 920 patients with bladder and 398 patients with renal cancer (252 (27%) and 165 (42%), respectively, were women). Primary and secondary outcome measures: Proportion of patients with three or more pre-referral consultations; number of days from first presentation to referral; proportion of patients who presented with haematuria and proportion of patients investigated in primary care. Results: Women required three or more prereferral consultations more often than men (27% (95% CI 21% to 33%) vs 11% (9% to 14%) for bladder (p<0.001); and 30% (22% to 39%) vs 18% (13% to 25%) for renal cancer (p=0.025)) and had a greater number of days from presentation to referral. In multivariable analysis (adjusting for age, haematuria status and use of primary care-led investigations), being a woman was independently associated with higher odds of three or more pre-referral consultations (OR=3.29 (2.06 to 5.25, p<0.001) for bladder cancer; and OR=1.90 (1.06 to 3.42, p=0.031) for renal cancer). Although presentation with haematuria was associated with more timely diagnosis of bladder cancer, gender inequalities did not vary by haematuria status for either cancer (p=0.18 for bladder and p=0.27 for renal). Each year in the UK, approximately 700 women with either bladder or renal cancer experience a delayed diagnosis because of their gender, of whom more than a quarter (197, or 28%) present with haematuria. Conclusions: There are notable gender inequalities in the timeliness of diagnosis of urological cancers. There is a need to both reinforce existing guidelines on haematuria investigation and develop new diagnostic decision aids and tests for patients who present without haematuria. Copyright © 2013 BMJ Publishing Group. All rights reserved.National Institute for Health Research (NIHR

Impact of investigations in general practice on timeliness of referral for patients subsequently diagnosed with cancer: Analysis of national primary care audit data

This is the final published version. Available from Springer Nature via the DOI in this record.Background:For patients with symptoms of possible cancer who do not fulfil the criteria for urgent referral, initial investigation in primary care has been advocated in the United Kingdom and supported by additional resources. The consequence of this strategy for the timeliness of diagnosis is unknown.Methods:We analysed data from the English National Audit of Cancer Diagnosis in Primary Care on patients with lung (1494), colorectal (2111), stomach (246), oesophagus (513), pancreas (327), and ovarian (345) cancer relating to the ordering of investigations by the General Practitioner and their nature. Presenting symptoms were categorised according to National Institute for Health and Care Excellence (NICE) guidance on referral for suspected cancer. We used linear regression to estimate the mean difference in primary-care interval by cancer, after adjustment for age, gender, and the symptomatic presentation category.Results:Primary-care investigations were undertaken in 3198/5036 (64%) of cases. The median primary-care interval was 16 days (IQR 5-45) for patients undergoing investigation and 0 days (IQR 0-10) for those not investigated. Among patients whose symptoms mandated urgent referral to secondary care according to NICE guidelines, between 37% (oesophagus) and 75% (pancreas) were first investigated in primary care. In multivariable linear regression analyses stratified by cancer site, adjustment for age, sex, and NICE referral category explained little of the observed prolongation associated with investigation.Interpretation:For six specified cancers, investigation in primary care was associated with later referral for specialist assessment. This effect was independent of the nature of symptoms. Some patients for whom urgent referral is mandated by NICE guidance are nevertheless investigated before referral. Reducing the intervals between test order, test performance, and reporting can help reduce the prolongation of primary-care intervals associated with investigation use. Alternative models of assessment should be considered.National Institute for Health Research (NIHR

Typical and atypical presenting symptoms of breast cancer and their associations with diagnostic intervals: Evidence from a national audit of cancer diagnosis

This is the final published version. Available from Elsevier via the DOI in this record.Introduction Most symptomatic women with breast cancer have relatively short diagnostic intervals but a substantial minority experience prolonged journeys to diagnosis. Atypical presentations (with symptoms other than breast lump) may be responsible. Methods We examined the presenting symptoms of breast cancer in women using data from a national audit initiative (n = 2316). Symptoms were categorised topographically. We investigated variation in the length of the patient interval (time from symptom onset to presentation) and the primary care interval (time from presentation to specialist referral) across symptom groups using descriptive analyses and quantile regression. Results A total of 56 presenting symptoms were described: breast lump was the most frequent (83%) followed by non-lump breast symptoms, (e.g. nipple abnormalities (7%) and breast pain (6%)); and non-breast symptoms (e.g. back pain (1%) and weight loss (0.3%)). Greater proportions of women with ‘non-lump only’ and ‘both lump and non-lump’ symptoms waited 90 days or longer before seeking help compared to those with ‘breast lump only’ (15% and 20% vs. 7% respectively). Quantile regression indicated that the differences in the patient interval persisted after adjusting for age and ethnicity, but there was little variation in primary care interval for the majority of women. Conclusions About 1 in 6 women with breast cancer present with a large spectrum of symptoms other than breast lump. Women who present with non-lump breast symptoms tend to delay seeking help. Further emphasis of breast symptoms other than breast lump in symptom awareness campaigns is warranted.UK Department of HealthCancer Research U

Morbidity and measures of the diagnostic process in primary care for patients subsequently diagnosed with cancer

Background: There is uncertainty regarding how pre-existing conditions (morbidities) may influence the primary care investigation and management of individuals subsequently diagnosed with cancer. / Methods: We identified morbidities using information from both primary and secondary care records among 11,716 patients included in the English National Cancer Diagnosis Audit (NCDA) 2014. We examined variation in 5 measures of the diagnostic process (the primary care interval, diagnostic interval, number of pre-referral consultations, use of primary care-led investigations, and referral type) by both primary care- and hospital records-derived measures of morbidity. / Results: Morbidity prevalence recorded before cancer diagnosis was almost threefold greater using the primary care (75%) vs secondary care-derived measure (28%). After adjustment, there was limited variation in the primary care interval and the number of pre-referral consultations by either definition of morbidity. Patients with more severe morbidities were less likely to have had a primary care-led investigation before cancer diagnosis compared with those without any morbidity (adjusted odds ratio, OR [95% confidence interval]: 0.72 [0.60–0.86] for Charlson score 3+ vs 0; joint P 1.00–1.41], respectively), and more likely to receive an emergency referral (aOR: 1.60 [1.26–2.02] and 1.61 [1.26–2.06], respectively). / Conclusion: Among cancer cases with up to 2 morbidities, there was no evidence of differences in diagnostic processes and intervals in primary care but higher morbidity burden was associated with longer time to diagnosis and higher likelihood of emergency referral

The relative length of the patient and the primary care interval in patients with 28 common and rarer cancers

This is the final version. Available from the publisher via the DOI in this record.BACKGROUND: Appreciating variation in the length of pre- or post-presentation diagnostic intervals can help prioritise early diagnosis interventions with either a community or a primary care focus.METHODS: We analysed data from the first English National Audit of Cancer Diagnosis in Primary Care on 10 953 patients with any of 28 cancers. We calculated summary statistics for the length of the patient and the primary care interval and their ratio, by cancer site.RESULTS: Interval lengths varied greatly by cancer. Laryngeal and oropharyngeal cancers had the longest median patient intervals, whereas renal and bladder cancer had the shortest (34.5 and 30 compared with 3 and 2 days, respectively). Multiple myeloma and gallbladder cancer had the longest median primary care intervals, and melanoma and breast cancer had the shortest (20.5 and 20 compared with 0 and 0 days, respectively). Mean patient intervals were longer than primary care intervals for most (18 of 28) cancers, and notably so (two- to five-fold greater) for 10 cancers (breast, melanoma, testicular, vulval, cervical, endometrial, oropharyngeal, laryngeal, ovarian and thyroid).CONCLUSIONS: The findings support the continuing development and evaluation of public health interventions aimed at shortening patient intervals, particularly for cancers with long patient interval and/or high patient interval over primary care interval ratio.National Institute for Health Research (NIHR)Cancer Research UKPublic Health WalesBetsi Cadwaladr University Health Boar

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

This is the final version. Available from Elsevier via the DOI in this record. 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.Cancer Research UKUK Department of Health’s Policy Research Unit in Cancer Awareness, Screening and Early Diagnosi

Variation in promptness of presentation among 10,297 patients subsequently diagnosed with one of 18 cancers: Evidence from a National Audit of Cancer Diagnosis in Primary Care

This is the final published version. Available from Wiley via the DOI in this record.Cancer awareness public campaigns aim to shorten the interval between symptom onset and presentation to a doctor (the 'patient interval'). Appreciating variation in promptness of presentation can help to better target awareness campaigns. We explored variation in patient intervals recorded in consultations with general practitioners among 10,297 English patients subsequently diagnosed with one of 18 cancers (bladder, brain, breast, colorectal, endometrial, leukaemia, lung, lymphoma, melanoma, multiple myeloma, oesophageal, oro-pharyngeal, ovarian, pancreatic, prostate, renal, stomach, and unknown primary) using data from of the National Audit of Cancer Diagnosis in Primary Care (2009-2010). Proportions of patients with 'prompt'/'non-prompt' presentation (0-14 or 15+ days from symptom onset, respectively) were described and respective odds ratios were calculated by multivariable logistic regression. The overall median recorded patient interval was 10 days (IQR 0-38). Of all patients, 56% presented promptly. Prompt presentation was more frequent among older or housebound patients (p < 0.001). Prompt presentation was most frequent for bladder and renal cancer (74% and 70%, respectively); and least frequent for oro-pharyngeal and oesophageal cancer (34% and 39%, respectively, p <.001). Using lung cancer as reference, the adjusted odds ratios of non-prompt presentation were 2.26 (95% confidence interval 1.57-3.25) and 0.42 (0.34-0.52) for oro-pharyngeal and bladder cancer, respectively. Sensitivity analyses produced similar findings. Routinely recorded patient interval data reveal considerable variation in the promptness of presentation. These findings can help to prioritise public awareness initiatives and research focusing on symptoms of cancers associated with greater risk of non-prompt presentation, such as oro-pharyngeal and oesophageal cancer. What's new? A critical aspect of cancer diagnosis is how promptly patients consult a doctor after they first notice initial symptoms. Here, the authors examine differences in this so-called patient interval in English patients subsequently diagnosed with one of 18 cancers. On average, patients with bladder and renal cancer as well as older and housebound patients consulted a doctor relatively promptly while patients with oro-pharyngeal and oesophageal cancer took the longest until first presenting to a general practitioner. The authors point out that cancer awareness campaigns should encompass symptoms of oro-pharyngeal and oesophageal cancer aiming to shorten the patient interval for these cancers. © 2014 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.National Institute for Health Research (NIHR)NHS Public Health Training Schem