Cholangiocarcinoma across England: Temporal changes in incidence, survival and routes to diagnosis by region and level of socioeconomic deprivation.

Background & Aims: While cholangiocarcinoma (CCA) incidence and mortality rates are increasing globally, whether there are regional/temporal variations in these rates for different biliary tract cancer (BTC) subtypes, or whether they differ by sex, socioeconomic status, or route to diagnosis (RtD) remains unknown. In this work, we aimed to perform an in-depth analysis of data on the incidence, mortality, survival and RtD of CCA and other BTCs. Methods: Data on all BTCs diagnosed in England between 2001 and 2018 were extracted from NHS Digital's National Cancer Registration Dataset. Age-standardised incidence rates (ASRs), mortality rates (ASMRs) and net survival rates were calculated, and Kaplan-Meier overall survival estimates and RtD trends were analysed. Analyses were stratified by sex, socioeconomic deprivation, tumour subtype and region. Results: The ASR for CCA rose from 2.9 in 2001-2003 to 4.6 in 2016-2018 and from 1.0 to 1.8 for gallbladder cancers (GBCs). ASMR trends mirror those of incidence, with most deaths due to iCCA. Over 20% of patients with CCA were under 65 years old. The ASRs and ASMRs were consistently higher in the most socioeconomically deprived group for CCA and GBC. The most common RtD was the emergency route (CCA 49.6%, GBC 46.2% and ampulla of Vater cancer 43.0%). The least deprived patients with CCA and ampulla of Vater cancer had better overall survival (p <0.001). Net survival rates rose for all BTCs, with 3-year net survival for CCA increasing from 9.2% in 2001 to 12.6% in 2016-2018. There was notable geographical variation in ASRs, ASMRs and net survival for all BTCs. Conclusions: BTC incidence and mortality rates are increasing, with differences observed between tumour types, socioeconomic deprivation groups, RtDs and geographical regions. This highlights the need for targeted interventions, earlier diagnosis and better awareness of this condition amongst the public and healthcare professionals. Impact and implications: Cholangiocarcinoma (CCA) incidence and mortality rates are rising globally, particularly for intrahepatic CCA. However, it has not previously been reported if, within a single country, there are temporal and regional differences in incidence, mortality and survival rates for different biliary tract subtypes, and whether these differ by sex, socioeconomic status, or route of diagnosis. In this study we show that mortality rates for patients with CCA continue to rise and are almost 40% higher in the most socioeconomically deprived compared to the least; additionally, we observed regional variation within England in incidence, mortality and survival. This study is relevant to researchers and policy makers as it highlights regional variation and inequality, as well as emphasising the need for earlier diagnosis and better awareness of this condition amongst the public and healthcare professionals.

Regional variation in routes to diagnosis of cholangiocarcinoma in England from 2006 to 2017.

BACKGROUND: Incidence of cholangiocarcinoma (CCA) is rising, with overall prognosis re-maining very poor. Reasons for the high mortality of CCA include its late presentation in most patients, when curative options are no longer feasible, and poor response to systemic therapies for advanced disease. Late presentation presents a large barrier to improving outcomes and is often associated with diagnosis via mergency presentation (EP). Earlier diagnoses may be made by Two Week Wait (TWW) referrals through General practitioner (GP). We hypothesise that TWW referrals and EP routes to diagnosis differ across regions in England. AIM: To investigate routes to diagnosis of CCA over time, regional variation and influencing factors. METHODS: We linked patient records from the National Cancer Registration Dataset to Hospital Episode Statistics, Cancer Waiting Times and Cancer Screening Programme datasets to define routes to diagnosis and certain patient characteristics for patients diagnosed 2006-2017 in England. We used linear probability models to investigate geographic variation by assessing the proportions of patients diagnosed via TWW referral or EP across Cancer Alliances in England, adjusting for potential confounders. Correlation between the proportion of people diagnosed by TWW referral and EP was investigated with Spearman's correlation coefficient. RESULTS: Of 23632 patients diagnosed between 2006-2017 in England, the most common route to diagnosis was EP (49.6%). Non-TWW GP referrals accounted for 20.5% of diagnosis routes, 13.8% were diagnosed by TWW referral, and the remainder 16.2% were diagnosed via an 'other' or Unknown route. The proportion diagnosed via a TWW referral doubled between 2006-2017 rising from 9.9% to 19.8%, conversely EP diagnosis route declined, falling from 51.3% to 46.0%. Statistically significant variation in both the TWW referral and EP proportions was found across Cancer Alliances. Age, presence of comorbidity and underlying liver disease were independently associated with both a lower proportion of patients diagnosed via TWW referral, and a higher proportion diagnosed by EP after adjusting for other potential confounders. CONCLUSION: There is significant geographic and socio-demographic variation in routes to diagnosis of CCA in England. Knowledge sharing of best practice may improve diagnostic pathways and reduce unwarranted variation.

Cost of hepatocellular carcinoma to the national health service in England: a registry-based analysis.

OBJECTIVE: Hepatocellular carcinoma (HCC) incidence in the UK trebled between 1997 and 2017. With increasing numbers requiring treatment, understanding the likely impact on healthcare budgets can inform service planning and commissioning. The aim of this analysis was to use existing registry data to describe the direct healthcare costs of current treatments for HCC and estimate the impact on National Health Service (NHS) budgets. DESIGN: A retrospective data analysis based on the National Cancer Registration and Analysis Service cancer registry informed a decision-analytic model for England comparing patients by cirrhosis compensation status and those on palliative or curative treatment pathways. Potential cost drivers were investigated by undertaking a series of one-way sensitivity analyses. RESULTS: Between 1 January 2010 and 31 December 2016, 15 684 patients were diagnosed with HCC. The median cost per patient over 2 years was £9065 (IQR: £1965 to £20 491), 66% did not receive active therapy. The cost of HCC treatment for England over 5 years was estimated to be £245 million. CONCLUSION: The National Cancer Registration Dataset and linked data sets have enabled a comprehensive analysis of the resource use and costs of secondary and tertiary healthcare for HCC, providing an overview of the economic impact to the NHS England of treating HCC.

Cohort study to assess geographical variation in cholangiocarcinoma treatment in England.

BACKGROUND: Outcomes for cholangiocarcinoma (CCA) are extremely poor owing to the complexities in diagnosing and managing a rare disease with heterogenous sub-types. Beyond curative surgery, which is only an option for a minority of patients diagnosed at an early stage, few systemic therapy options are currently recommended to relieve symptoms and prolong life. Stent insertion to manage disease complications requires highly specialised expertise. Evidence is lacking as to how CCA patients are managed in a real-world setting and whether there is any variation in treatments received by CCA patients. AIM: To assess geographic variation in treatments received amongst CCA patients in England. METHODS: Data used in this cohort study were drawn from the National Cancer Registration Dataset (NCRD), Hospital Episode Statistics and the Systemic Anti-Cancer Therapy Dataset. A cohort of 8853 CCA patients diagnosed between 2014-2017 in the National Health Service in England was identified from the NCRD. Potentially curative surgery for all patients and systemic therapy and stent insertion for 7751 individuals who did not receive surgery were identified as three end-points of interest. Linear probability models assessed variation in each of the three treatment modalities according to Cancer Alliance of residence at diagnosis, and for socio-demographic and clinical characteristics at diagnosis. RESULTS: Of 8853 CCA patients, 1102 (12.4%) received potentially curative surgery. The mean [95% confidence interval (CI)] percentage-point difference from the population average ranged from -3.96 (-6.34 to -1.59)% to 3.77 (0.54 to 6.99)% across Cancer Alliances in England after adjustment for patient sociodemographic and clinical characteristics, showing statistically significant variation. Amongst 7751 who did not receive surgery, 1542 (19.9%) received systemic therapy, with mean [95%CI] percentage-point difference from the population average between -3.84 (-8.04 to 0.35)% to 9.28 (1.76 to 16.80)% across Cancer Alliances after adjustment, again showing the presence of statistically significant variation for some regions. Stent insertion was received by 2156 (27.8%), with mean [95%CI] percentage-point difference from the population average between -10.54 (-12.88 to -8.20)% to 13.64 (9.22 to 18.06)% across Cancer Alliances after adjustment, showing wide and statistically significant variation from the population average. Half of 8853 patients (n = 4468) received no treatment with either surgery, systemic therapy or stent insertion. CONCLUSION: Substantial regional variation in treatments received by CCA patients was observed in England. Such variation could be due to differences in case-mix, clinical practice or access to specialist expertise.

Regional variations in hepatocellular carcinoma incidence, routes to diagnosis, treatment and survival in England.

BACKGROUND: Hepatocellular carcinoma (HCC) incidence, management and survival across England were examined to determine if geographical inequalities exist. METHOD: 15,468 HCC cases diagnosed 2010-2016 were included. Age-standardised incidence rates, net survival and proportions receiving potentially curative treatment and presenting through each route to diagnosis adjusted for age at diagnosis, sex and area-based deprivation quintile, were calculated overall and by Cancer Alliance. RESULTS: HCC incidence rates increased in men from 6.2 per 100,000 in 2010 to 8.8 in 2016, and in women from 1.5 to 2.2. The highest incidence rates, found in parts of the North of England and London, were nearly double the lowest. The adjusted proportion presenting as an emergency ranged 27-41% across Cancer Alliances. Odds increased with increasing deprivation quintile and age. Only one in five patients received potentially curative treatment (range 15-28%) and odds decreased with increasing deprivation and age. One-year survival in 2013-2016 ranged 38-53%. CONCLUSION: This population-based, nationwide analysis demonstrates clear differences in HCC incidence, management and survival across England. It highlights socioeconomic-associated variation and the need for improvement in early diagnosis and curative treatment of HCC. This research should assist policymakers, service providers and clinicians to identify regions where additional training, services and resources would be best directed.

Primary liver cancer in the UK: Incidence, incidence-based mortality, and survival by subtype, sex, and nation.

BACKGROUND & AIMS: The incidence of primary liver cancer (PLC) is increasing in Western Europe. To understand trends over time and the current burden in the UK, a detailed analysis of the epidemiology of PLC and its subtypes was conducted. METHODS: Data on PLCs diagnosed during 1997-2017 were obtained from population-based, nationwide registries in the UK. European age-standardised incidence (ASR) and incidence-based mortality rates (ASMR) per 100,000 person-years were calculated overall and by sex and UK-nation. Annual percentage change in rates was estimated using Joinpoint regression. One-, 2-, and 5-year age-standardised net survival was estimated. RESULTS: A total of 82,024 PLCs were diagnosed. Both hepatocellular carcinoma (HCC) incidence and mortality rates trebled (ASR 1.8-5.5 per 100,000, ASMR 1.3-4.0). The rate of increase appeared to plateau around 2014/2015. Scottish men consistently had the highest HCC incidence rates. PLC survival increased, driven by a substantial increase in the proportion that are HCC (as prognosis is better than other PLCs) and in HCC survival (change in 1-year survival 24-47%). Intrahepatic cholangiocarcinoma was the most common PLC in women and 1-year survival improved from 22.6% to 30.5%. CONCLUSIONS: PLC incidence has been increasing rapidly but, as most risk factors are modifiable, it is largely a preventable cancer. This rate of increase has slowed in recent years, possibly attributable to effective treatment for hepatitis C. As other risk factors such as obesity and diabetes remain prevalent in the UK, it is unlikely the considerable burden of this disease will abate. While improvements in survival have been made, over half of patients are not alive after 1 year, therefore further progress in prevention, early detection, and treatment innovation are needed. LAY SUMMARY: Many more people are getting liver cancer, particularly the subtype hepatocellular carcinoma, than 20 years ago. Men in Scotland are most likely to get liver cancer and to die from it. Survival after liver cancer diagnosis is getting longer but still less than half are alive after 1 year.

Survival from Cervical Cancer Diagnosed Aged 20-29 Years by Age at First Invitation to Screening in England: Population-Based Study.

Age at which women are first invited to attend cervical screening in England has changed twice: in 2004, women under 25 years were no longer invited; and in 2012, first invitations were sent six months earlier (at age 24.5 years). Concomitantly, a dramatic increase in screen-detected cervical cancer was observed, and their survival had not been documented. Diagnoses of invasive cervical cancer at ages 20-29 years in 2006-2016 in England were followed until the end of 2018 for deaths. We estimated 8-year overall survival (OS) by International Federation of Gynecology and Obstetrics (FIGO) stage and age at first screening invitation. Overall and relative survival for stage IA cervical cancer for women diagnosed aged 20-29 years in England (n = 1905) was excellent at 99.8% (95% confidence intervals (CI): 99.4-99.9%) and 100% (95% CI: 99.7-100.1%), respectively. OS for stage IB cervical cancer (n = 1101) was 90.4% (95% CI: 88.3-92.2%). Survival from stage IB was worse for women diagnosed age 20-24 years compared to those diagnosed 25-29 years at diagnosis (p < 0.0001), but no difference was observed by age at first invitation for screening, p = 0.8575. OS for stage II (65.5%, 95% CI: 60.2-72.0%) and stage III+ (36.6%, 95% CI 28.4-44.7%) were poorer. Survival from stage I cervical cancer in young women in England is excellent: mortality in women with stage IA cancer is akin to that of the general population regardless of age at first invitation to screening.

Variation in geographical treatment intensity affects survival of non-small cell lung cancer patients in England.

OBJECTIVES: We aimed to determine the geographical variation in the proportion of non-small cell lung cancer (NSCLC) patients undergoing curative treatment and assess the relationship between treatment access rates and survival outcomes. METHODS: We extracted cancer registration data on 144,357 lung cancer (excluding small cell tumours) patients diagnosed between 2009 and 2013. Surgical and radiotherapy treatment intensity quintiles were based on patients' Clinical Commissioning Group (CCG) of residence. We used logistic regression to assess the effect of travel time and case-mix on treatment use and Cox regression to analyse survival in relation to treatment intensity. RESULTS: There was wide variation in the use of curative treatment across CCGs, with the proportion undergoing surgery ranging from 8.9% to 20.2%, and 0.4% to 16.4% for radical radiotherapy. The odds of undergoing surgery decreased with socioeconomic deprivation (OR 0.91, 95% CI 0.85-0.97), whereas the opposite was observed for radiotherapy (OR 1.16, 95% CI 1.08-1.25). There was an overall effect of travel time to thoracic surgery centre on the odds of undergoing surgery (OR 0.81, 95% CI 0.76-0.87 for travel time >55 min vs ≤15 min) which was amplified by the effect of deprivation. No clear association was observed for radiotherapy. Higher mortality rates were observed for the lower resection and radiotherapy quintiles (HR 1.08, 95% CI 1.04-1.12 and HR 1.06, 95% CI 1.02-1.10 for lowest vs. highest resection and radiotherapy quintile). CONCLUSION: There was wide geographical variation in the use of curative treatment and a higher frequency of treatment was associated with better survival.

Geographical variations in the use of cancer treatments are associated with survival of lung cancer patients.

INTRODUCTION: Lung cancer outcomes in England are inferior to comparable countries. Patient or disease characteristics, healthcare-seeking behaviour, diagnostic pathways, and oncology service provision may contribute. We aimed to quantify associations between geographic variations in treatment and survival of patients in England. METHODS: We retrieved detailed cancer registration data to analyse the variation in survival of 176,225 lung cancer patients, diagnosed 2010-2014. We used Kaplan-Meier analysis and Cox proportional hazards regression to investigate survival in the two-year period following diagnosis. RESULTS: Survival improved over the period studied. The use of active treatment varied between geographical areas, with inter-quintile ranges of 9%-17% for surgical resection, 4%-13% for radical radiotherapy, and 22%-35% for chemotherapy. At 2 years, there were 188 potentially avoidable deaths annually for surgical resection, and 373 for radical radiotherapy, if all treated proportions were the same as in the highest quintiles. At the 6 month time-point, 318 deaths per year could be postponed if chemotherapy use for all patients was as in the highest quintile. The results were robust to statistical adjustments for age, sex, socio-economic status, performance status and co-morbidity. CONCLUSION: The extent of use of different treatment modalities varies between geographical areas in England. These variations are not attributable to measurable patient and tumour characteristics, and more likely reflect differences in clinical management between local multi-disciplinary teams. The data suggest improvement over time, but there is potential for further survival gains if the use of active treatments in all areas could be increased towards the highest current regional rates.

Investigation of the international comparability of population-based routine hospital data set derived comorbidity scores for patients with lung cancer.

INTRODUCTION: The International Cancer Benchmarking Partnership (ICBP) identified significant international differences in lung cancer survival. Differing levels of comorbid disease across ICBP countries has been suggested as a potential explanation of this variation but, to date, no studies have quantified its impact. This study investigated whether comparable, robust comorbidity scores can be derived from the different routine population-based cancer data sets available in the ICBP jurisdictions and, if so, use them to quantify international variation in comorbidity and determine its influence on outcome. METHODS: Linked population-based lung cancer registry and hospital discharge data sets were acquired from nine ICBP jurisdictions in Australia, Canada, Norway and the UK providing a study population of 233 981 individuals. For each person in this cohort Charlson, Elixhauser and inpatient bed day Comorbidity Scores were derived relating to the 4-36 months prior to their lung cancer diagnosis. The scores were then compared to assess their validity and feasibility of use in international survival comparisons. RESULTS: It was feasible to generate the three comorbidity scores for each jurisdiction, which were found to have good content, face and concurrent validity. Predictive validity was limited and there was evidence that the reliability was questionable. CONCLUSION: The results presented here indicate that interjurisdictional comparability of recorded comorbidity was limited due to probable differences in coding and hospital admission practices in each area. Before the contribution of comorbidity on international differences in cancer survival can be investigated an internationally harmonised comorbidity index is required.

Explaining the Better Prognosis of Screening-Exposed Breast Cancers: Influence of Tumor Characteristics and Treatment.

BACKGROUND: In England, population mammographic screening has been offered to women for over 20 years. Overall decrease in breast cancer mortality rates and improvements in cancer awareness and organization of medical care over this period call for a more current evaluation of the mediators behind the better prognosis of screening-exposed breast cancers. METHODS: A case-control study was conducted within the English National Breast Screening Program. Women who died from primary breast cancer in 2008 to 2009 were matched (by year of birth, screening invitation, and area) to controls that received a diagnosis of invasive breast cancer at the time of the case diagnosis but survived the case death. Data were analyzed by unconditional logistic regression with adjustment for matching factors. RESULTS: The unadjusted OR for dying from breast cancer associated with ever having attended breast screening was 0.44 [95% confidence interval (CI), 0.33-0.58]. After adjustment for lead time, overdiagnosis, and self-selection, the OR increased to 0.69 (95% CI, 0.50-0.94). Adjusting for tumor size, lymph node status, stage, grade, histopathology, and laterality accounted for all the screening effect (OR, 1.00; 95% CI, 0.71-1.40). Further adjustment for treatment factors only had a minimal impact on the OR (OR, 1.02; 95% CI, 0.72-1.45). CONCLUSIONS: Our results suggest that earlier diagnosis, as reflected by tumor characteristics, remains the major mediator of the improvement in breast cancer survival due to participation in mammographic screening. IMPACT: Mammographic screening continues to prevent breast cancer-related deaths in the epoch of adjuvant systemic therapy.

The effect of emergency presentation on surgery and survival in lung cancer patients in England, 2006-2008.

BACKGROUND: A large proportion of lung cancer patients in England are diagnosed through an emergency route, which is associated with poorer outcomes. Here, we investigated the association between emergency presentation and the odds of undergoing surgical resection and subsequent survival among lung cancer patients undergoing surgical resection as well as those who did not. METHODS: Details of 93,783 lung cancers were extracted from the National Cancer Data Repository. For non-small cell lung cancer (NSCLC) patients we calculated odds ratios for undergoing surgical resection. Survival was assessed for resected NSCLC and for all other lung cancer patients in three different time intervals: short-term, intermediate and long-term. RESULTS: Compared with those who did not, NSCLC patients presenting through an emergency route were less likely to undergo surgical resection (adjusted OR=0.22, 95% CI: 0.20-0.24). Patients who underwent surgical resection after an emergency presentation had lower survival in the intermediate period (adjusted HR=1.27, 95% CI: 1.06-1.54) and long term (adjusted HR=1.20, 95% CI: 0.99-1.45). Among all other lung cancer patients, those diagnosed through an emergency route had lower survival, particularly in the short-term (adjusted HR=3.54, 95% CI: 3.42-3.67), but the association remained in the intermediate (adjusted HR=1.66, 95% CI: 1.63-1.69) and long term (adjusted HR=1.10, 95% CI: 1.05-1.15). CONCLUSION: The reduced access to surgical resection and lower survival among lung cancer patients who present through an emergency admission, highlights the importance of ensuring symptoms are recognised early so that presentation as an emergency can be reduced.

Predictors of early death in female patients with breast cancer in the UK: a cohort study.

Objective To identify factors predicting early death in women with breast cancer. Design Cohort study. Setting 29 trusts across seven cancer networks in the North Thames area. Participants 15 037 women with primary breast cancer diagnosed between January 1996 and December 2005. Methods Logistic regression analyses to determine predictors of early death and factors associated with lack of surgical treatment. Main exposures Age at diagnosis, mode of presentation, ethnicity, disease severity, comorbidities, treatment and period of diagnosis in relation to the Cancer Plan (the NHS's strategy in 2000 for investment in and reform of cancer services). Main outcome measures Death from any cause within 1 year of diagnosis, and receipt of surgical treatment. Results By 31 December 2006, 4765 women had died, 980 in the year after diagnosis. Older age and disease severity independently predicted early death. Women over 80 were more likely to die early than women under 50 (OR 8.05, 95% CI 5.96 to 10.88). Presence of distant metastases on diagnosis increased the odds of early death more than eightfold (OR 8.41, 95% CI 6.49 to 10.89). Two or more recorded comorbidities were associated with a nearly fourfold increase. There was a significant decrease in odds associated with surgery (OR 0.29, 95% CI 0.24 to 0.35). Independently of disease severity and comorbidities, women over 70 were less likely than those under 50 to be treated surgically and this was even more pronounced in those aged over 80 (OR 0.09, 95% CI 0.07 to 0.10). Other factors independently associated with a reduced likelihood of surgery included a non-screening presentation, non-white ethnicity and additional comorbidities. Conclusions These findings may partially explain the survival discrepancies between the UK and other European countries in female patients with breast cancer. The study identifies a group of women with a particularly poor prognosis for whom interventions aiming at early detection may be targeted.

Trends in the treatment of breast cancer in Southeast England following the introduction of national guidelines.

There is little published evidence on trends in the treatment of breast cancer in England following the publication of the Calman-Hine report in 1995. Reliable national data are available for women with screen-detected breast cancer, but data on women presenting symptomatically have been difficult to collect. Using data from both a clinical audit database and a population-based cancer register, we show that between 1996 and 2003 the rates of mastectomy and chemotherapy treatment for women with breast cancer in Southeast England have increased marginally, whereas there has been a steady decline in the use of hormone therapy and radiotherapy recorded within 6 months of diagnosis.