Worldwide trends in population-based survival for children, adolescents, and young adults diagnosed with leukaemia, by subtype, during 2000-14 (CONCORD-3): analysis of individual data from 258 cancer registries in 61 countries.

BACKGROUND: Leukaemias comprise a heterogenous group of haematological malignancies. In CONCORD-3, we analysed data for children (aged 0-14 years) and adults (aged 15-99 years) diagnosed with a haematological malignancy during 2000-14 in 61 countries. Here, we aimed to examine worldwide trends in survival from leukaemia, by age and morphology, in young patients (aged 0-24 years). METHODS: We analysed data from 258 population-based cancer registries in 61 countries participating in CONCORD-3 that submitted data on patients diagnosed with leukaemia. We grouped patients by age as children (0-14 years), adolescents (15-19 years), and young adults (20-24 years). We categorised leukaemia subtypes according to the International Classification of Childhood Cancer (ICCC-3), updated with International Classification of Diseases for Oncology, third edition (ICD-O-3) codes. We estimated 5-year net survival by age and morphology, with 95% CIs, using the non-parametric Pohar-Perme estimator. To control for background mortality, we used life tables by country or region, single year of age, single calendar year and sex, and, where possible, by race or ethnicity. All-age survival estimates were standardised to the marginal distribution of young people with leukaemia included in the analysis. FINDINGS: 164 563 young people were included in this analysis: 121 328 (73·7%) children, 22 963 (14·0%) adolescents, and 20 272 (12·3%) young adults. In 2010-14, the most common subtypes were lymphoid leukaemia (28 205 [68·2%] patients) and acute myeloid leukaemia (7863 [19·0%] patients). Age-standardised 5-year net survival in children, adolescents, and young adults for all leukaemias combined during 2010-14 varied widely, ranging from 46% in Mexico to more than 85% in Canada, Cyprus, Belgium, Denmark, Finland, and Australia. Individuals with lymphoid leukaemia had better age-standardised survival (from 43% in Ecuador to ≥80% in parts of Europe, North America, Oceania, and Asia) than those with acute myeloid leukaemia (from 32% in Peru to ≥70% in most high-income countries in Europe, North America, and Oceania). Throughout 2000-14, survival from all leukaemias combined remained consistently higher for children than adolescents and young adults, and minimal improvement was seen for adolescents and young adults in most countries. INTERPRETATION: This study offers the first worldwide picture of population-based survival from leukaemia in children, adolescents, and young adults. Adolescents and young adults diagnosed with leukaemia continue to have lower survival than children. Trends in survival from leukaemia for adolescents and young adults are important indicators of the quality of cancer management in this age group. FUNDING: Children with Cancer UK, the Institut National du Cancer, La Ligue Contre le Cancer, Centers for Disease Control and Prevention, Swiss Re, Swiss Cancer Research foundation, Swiss Cancer League, Rossy Family Foundation, US National Cancer Institute, and the American Cancer Society.

Largely varying patterns and trends of primary cancer-directed resection for gastric carcinoma with synchronous distant metastasis in Europe and the US: a population-based study calling for further standardization of care.

AIMS: The role of resection remains debated in cases of metastatic gastric carcinoma (mGC). Some mGCs are technically resectable. At the population level, the real-world application of resection for mGC remains largely unclear in most Western countries. This large, population-based international investigation aimed to reveal the resection patterns and trends for mGC and the treatment-associated factors in Europe and the US. METHODS: Data on cases with microscopically-confirmed primary invasive stomach carcinoma with distant metastasis were obtained from the nationwide cancer registries of the Netherlands, Belgium, Norway, Sweden, Estonia, and Slovenia and the US Surveillance, Epidemiology, and End Results-18 database. We calculated age-standardized rates of primary cancer-directed resection and assessed resection trends using linear regression. We investigated associations of treatment with patient and cancer factors using multivariable-adjusted log-binomial regression. RESULTS: Among 133,321 patients with gastric cancer, overall, 40,215 cases with mGC diagnosed between 2003-2017 were investigated. Age-standardized resection rates significantly declined over time in the US, Belgium, Sweden, and Norway (by 5-14%). Resection rates greatly differed from 5% to 16% in 2013-2014. Cases with older ages, cardia tumors, or tumors involving adjacent structures were significantly less often operated across most countries. Sex was not significantly associated with resection. Across countries the association patterns and strengths differed largely. With multivariable adjustment, resection rates decreased significantly in all countries except Slovenia and Estonia (prevalence ratio per year = 0.90-0.98), and the decreasing trends were consistently observed in various stratifications by age and location. CONCLUSION: In Europe and the US, resection patterns and trends largely varied across countries for mGCs, which were mostly less often resected in the early 21st century. Various resection-associated factors were shown, with greatly varying association patterns and strengths. Our report could aid to identify discrepancies in clinical practice and highlight the great need for further clarifying the role of resection in mGCs to enhance standardization of care.

Colorectal cancer incidence, mortality, and stage distribution in European countries in the colorectal cancer screening era: an international population-based study.

BACKGROUND: Colorectal cancer screening programmes and uptake vary substantially across Europe. We aimed to compare changes over time in colorectal cancer incidence, mortality, and stage distribution in relation to colorectal cancer screening implementation in European countries. METHODS: Data from nearly 3·1 million patients with colorectal cancer diagnosed from 2000 onwards (up to 2016 for most countries) were obtained from 21 European countries, and were used to analyse changes over time in age-standardised colorectal cancer incidence and stage distribution. The WHO mortality database was used to analyse changes over time in age-standardised colorectal cancer mortality over the same period for the 16 countries with nationwide data. Incidence rates were calculated for all sites of the colon and rectum combined, as well as the subsites proximal colon, distal colon, and rectum. Average annual percentage changes (AAPCs) in incidence and mortality were estimated and relevant patterns were descriptively analysed. FINDINGS: In countries with long-standing programmes of screening colonoscopy and faecal tests (ie, Austria, the Czech Republic, and Germany), colorectal cancer incidence decreased substantially over time, with AAPCs ranging from -2·5% (95% CI -2·8 to -2·2) to -1·6% (-2·0 to -1·2) in men and from -2·4% (-2·7 to -2·1) to -1·3% (-1·7 to -0·9) in women. In countries where screening programmes were implemented during the study period, age-standardised colorectal cancer incidence either remained stable or increased up to the year screening was implemented. AAPCs for these countries ranged from -0·2% (95% CI -1·4 to 1·0) to 1·5% (1·1 to 1·8) in men and from -0·5% (-1·7 to 0·6) to 1·2% (0·8 to 1·5) in women. Where high screening coverage and uptake were rapidly achieved (ie, Denmark, the Netherlands, and Slovenia), age-standardised incidence rates initially increased but then subsequently decreased. Conversely, colorectal cancer incidence increased in most countries where no large-scale screening programmes were available (eg, Bulgaria, Estonia, Norway, and Ukraine), with AAPCs ranging from 0·3% (95% CI 0·1 to 0·5) to 1·9% (1·2 to 2·6) in men and from 0·6% (0·4 to 0·8) to 1·1% (0·8 to 1·4) in women. The largest decreases in colorectal cancer mortality were seen in countries with long-standing screening programmes. INTERPRETATION: We observed divergent trends in colorectal cancer incidence, mortality, and stage distribution across European countries, which appear to be largely explained by different levels of colorectal cancer screening implementation. FUNDING: German Cancer Aid (Deutsche Krebshilfe) and the German Federal Ministry of Education and Research.

Decreasing resection rates for nonmetastatic gastric cancer in Europe and the United States.

BACKGROUND: Resection is the cornerstone of curative treatment for many nonmetastatic gastric cancers (GCs), but the population treatment patterns remains largely unknown. This large international population-based study aimed at investigating the treatment patterns and trends for nonmetastatic GC in Europe and the United States and at exploring factors associated with resection. METHODS: Data of patients with microscopically confirmed primary invasive GC without distant metastasis from the national cancer registries of the Netherlands, Belgium, Sweden, Norway, Slovenia, and Estonia and the US Surveillance, Epidemiology, and End Results (SEER)-18 Program were retrieved. Age-standardized treatment rates were computed and trends were evaluated using linear regression. Associations of resection with patient and tumor characteristics were analyzed using multivariable-adjusted log-binomial regression. Analysis was performed in each country respectively without pooling. RESULTS: Together 65 707 nonmetastatic GC patients diagnosed in 2003-2016 were analyzed. Age-standardized resection rates significantly decreased over years in all countries (by 4-24%). In 2013-2014, rates varied greatly from 54 to 75%. Patients with increasing ages, cardia cancers, or cancers invading adjacent structure were significantly less frequently resected. Resection was further associated with sex, performance status, comorbidities, tumor histology, tumor size, hospital type, and hospital volume. Association patterns and strengths varied across countries. After multivariable adjustment, resection rates remained decreasing (prevalence ratio = 0.97-0.995 per year), with decreasing trends consistently seen in various subgroups. CONCLUSIONS: Nonmetastatic GCs were less frequently resected in Europe and the United States in the early 21st century. Resection rates varied greatly across countries and appeared not to be optimal. Various factors associated with resection were revealed. Our findings can help to identify differences and possibly modifiable places in clinical practice and provide important novel references for designing effective population-based GC management strategies. In Europe and the United States, nonmetastatic gastric cancers were less frequently resected in the early 21st century. Resection rates varied greatly across countries and appeared not optimal. Various factors associated with resection were revealed. Our findings identify differences and possibly modifiable places in clinical practice and provide important novel references for designing effective population-based management strategies.

The fall and rise of cancer registration in Estonia: The dangers of overzealous application of data protection.

BACKGROUND: The population-based Estonian Cancer Registry (ECR) has maintained a database of cancer cases since 1968. Between 2001 and 2007 the ECR was prohibited from linking cancer records to death certificates. In January 2008, the prohibition was lifted, and two years later the ECR was able to begin tracing back unmatched deaths. This paper estimates the effect of the linkage ban on reported cancer incidence and survival. METHODS: Incident cancers in 2001-2007 were extracted from the ECR database in May 2018 to allow for late registrations. Two datasets were created: one with all incident cases and another without death-certificate-initiated (DCI) cases. Using both datasets, age-standardised incidence rates (ASIR) and their ratios; age-standardised five-year relative survival ratios (ARSR) and excess mortality rate ratios were calculated. RESULTS: In 2001-2007, 46,535 incident cancers were registered in the ECR. Of them, 2299 (4.9 %) were DCI cases. The inclusion of DCI cases increased the ASIR for overall cancer by 6 % in men and 3 % in women. An increase ≥10 % in ASIR for lung, liver and pancreatic cancer was observed. The effect of accrued DCI cases to the ARSR was minor. Excess mortality in the dataset without DCI cases was 4 % underestimated in men and 3 % in women. CONCLUSION: Biases in cancer incidence and survival measures generated by the temporary record linkage ban were largely correctable by using trace-back procedures when this became possible. Nevertheless, this type of ban and the arguments put forward to justify it, harm disease registration and register-based research.

Childhood cancer incidence and survival trends in Estonia (1970-2016): a nationwide population-based study.

BACKGROUND: Childhood cancers represent a small proportion of all cancers but are still a major public health problem. The study analysed long-term trends in childhood cancer incidence and survival in Estonia in relation to societal and health care transition. METHODS: Data on all malignant tumours, diagnosed in children aged 0-14 during 1970-2016, were derived from the Estonian Cancer Registry. Age-standardised (World standard) incidence rates were calculated by ICCC-3 site groups and joinpoint regression was used to estimate annual percentage change (APC) for incidence trends. Cohort and period approach were used to estimate 5-year survival. Internal age standardisation was applied. RESULTS: A total of 1628 incident cancer cases were diagnosed during the study period and overall incidence increased significantly at a rate of 0.5% per year. Significant increases were seen for neuroblastoma and germ cell tumours, for lymphoid leukemias and some CNS sub-sites. At the same time, decline in incidence was seen in almost all subgroups of unspecified neoplasms. The overall 5-year survival improved from 24% in 1970-1979 to 73% in 2010-2016, with the largest changes occurring in the 1990s and 2000s. For many sites, survival increase thereafter has been marginal. CONCLUSION: In this first comprehensive population-based study of childhood cancer incidence and survival in Estonia, long-term trends are shown in the context of societal and health care changes. Even though the increasing incidence of some sites may, at least partially, be explained by improved diagnostics reflected in the decreased incidence of unspecified neoplasms, the overall cancer incidence in children seems to be rising. Rapid progress in diagnosis and care have improved childhood cancer survival immensely, but deficit in Estonia persists compared to other European countries. Results of the study accentuate the need for a more in-depth analysis of clinical data, but also for the prioritization of childhood cancer in Estonia, to ensure access to standard care and innovative treatments.

Development and validation of a prognostic model to predict the prognosis of patients who underwent chemotherapy and resection of pancreatic adenocarcinoma: a large international population-based cohort study.

BACKGROUND: Pancreatic cancer (PaC) remains extremely lethal worldwide even after resection. PaC resection rates are low, making prognostic studies in resected PaC difficult. This large international population-based study aimed at exploring factors associated with survival in patients with resected TNM stage I-II PaC receiving chemotherapy and at developing and internationally validating a survival-predicting model. METHODS: Data of stage I-II PaC patients resected and receiving chemotherapy in 2003-2014 were obtained from the national cancer registries of Belgium, the Netherlands, Slovenia, and Norway, and the US Surveillance, Epidemiology, and End Results (SEER)-18 Program. Multivariable Cox proportional hazards models were constructed to investigate the associations of patient and tumor characteristics with overall survival, and analysis was performed in each country respectively without pooling. Prognostic factors remaining after backward selection in SEER-18 were used to build a nomogram, which was subjected to bootstrap internal validation and external validation using the European datasets. RESULTS: A total of 11,837 resected PaC patients were analyzed, with median survival time of 18-23 months and 3-year survival rates of 21-31%. In the main analysis, patient age, tumor T stage, N stage, and differentiation were associated with survival across most countries, with country-specific association patterns and strengths. However, tumor location was mostly not significantly associated with survival. Resection margin, hospital type, tumor size, positive and harvested lymph node number, lymph node ratio, and comorbidity number were associated with survival in certain countries where the information was available. A median survival time- and 1-, 2-, 3-, and 5-year survival probability-predictive nomogram incorporating the backward-selected variables in the main analysis was established. It fits each European national cohort similarly well. Calibration curves showed very good agreement between nomogram-prediction and actual observation. The concordance index of the nomogram (0.60) was significantly higher than that of the T and N stage-based model (0.56) for predicting survival. CONCLUSIONS: In these large international population-based cohorts, patients with resected PaC receiving chemotherapy have distinct characteristics independently associated with survival, with country-specific patterns and strengths. A robust benchmark population-based survival-predicting model is established and internationally validated. Like previous models predicting survival in resected PaC, our nomogram performs modestly.

Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations.

OBJECTIVE: Resection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation. DESIGN: Data from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003-2016 were analysed. Age-standardised resection rates for overall and stage I-II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models. RESULTS: A total of 153 698 records were analysed. In population-based registries in 2012-2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I-II tumours, with great international variations. During 2003-2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I-II tumours: 0.05-0.18 and 0.01-0.06 across countries) and increasing age (ORs for patients 70-79 and ≥80 versus those <60 years: 0.37-0.63 and 0.03-0.16 across countries). Patients with advanced-stage tumours (stage III-IV: 63.8%-81.2%) and at older ages (≥70 years: 52.6%-59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application. CONCLUSION: Rates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations.

Nonsurgical therapies for resected and unresected pancreatic cancer in Europe and USA in 2003-2014: a large international population-based study.

The role of chemotherapy in the treatment of pancreatic cancer (PaC) has been well-established, while radiation plays ambiguous roles. This international large-scale population-based study aimed to investigate the real-world application of chemotherapy and radiotherapy for resected and unresected PaC in Europe and USA. Population-based data from multiple European national cancer registries and the US Surveillance, Epidemiology and End Results (SEER)-18 database during 2003-2014 were analyzed. Temporal trends and geographical variations in the application rates of chemotherapy and radiotherapy were quantified using age standardization. Associations of treatment with demographic and clinical characteristics were assessed using multivariable logistic regression. A total of 141,533 PaC patients were analyzed. From 2003-2005 to 2012-2014, chemotherapy administration rates increased in most countries and more strongly among resected patients, while radiation rates were generally low with a slight decline or no obvious trend. In 2012-2014, 12.5% (Estonia) to 61.7% (Belgium) of resected and 17.1% (Slovenia) to 56.9% (Belgium) of unresected patients received chemotherapy. Radiation was administered in 2.6% (Netherlands) to 32.6% (USA) of resected and 1.0% (USA) to 6.0% (Belgium) of unresected patients. Strong temporal and geographical variations were observed. Patterns and strengths of associations of treatment administration with various demographic and clinical factors differed substantially between resected and unresected cancers and varied greatly across countries. Conclusively, administration of chemotherapy but not radiotherapy for PaC increased during the last decade in Europe and USA. Treatment rates were low and the uptake strongly varied across countries, highlighting the need for standardization in PaC treatment to improve patient care.

The impact of under-reporting of cases on the estimates of childhood cancer incidence and survival in Estonia.

About 35 new childhood cancer cases are diagnosed in Estonia (population 1.3 million in 2011) every year. Despite continuous improvements in the healthcare system and available cancer treatment options, the survival rates for childhood cancers have appeared to remain lower than the European average. These observations and the accompanying decrease in incidence led us to hypothesize that some nonfatal cases might be missing from the Estonian Cancer Registry (ECR). The aim of this study was to evaluate the completeness of reporting of childhood cancer cases to the ECR and its impact on the estimates of cancer incidence and survival. All cases of benign and malignant tumours, diagnosed in 2000-2011 among children aged 0-17 years and eligible for registration in the ECR, were included in the study. Completeness of reporting was evaluated for cases aged 0-17 years, and incidence and survival were analysed for cases aged 0-14 for international comparisons. The total number of new cancer cases increased from 459 to 515. Overall completeness of case ascertainment was estimated to be 89.5%. After adding the missing cases, the overall incidence rate increased from 12.9 to 14.9/100 000 (from 3.4 to 4.7 for leukaemias). The 2010-2014 period estimate of the 5-year survival increased from 70 to 76% for all sites combined and from 71 to 82% for leukaemias. In conclusion, the under-reporting of nonfatal childhood cancer cases to the ECR had an important impact on incidence and survival rates, causing a considerable underestimation of both.

Trends in cervical cancer incidence and mortality in the Baltic countries, Bulgaria and Romania.

The burden of cervical cancer varies considerably in the European Union (EU). In this article, we describe trends in incidence of and mortality from this cancer in the two most affected areas: the Baltic countries (Estonia, Latvia and Lithuania) and Southeast Europe (Bulgaria and Romania). Incidence data were obtained from the national cancer registries. Data on population and number of deaths from uterine cancers were extracted from the World Health Organization mortality database. Mortality rates were corrected for inaccuracies in the death certification of not otherwise specified uterine cancer. Joinpoint regression was used to study the annual variation of corrected and standardized incidence and mortality rates. Changes were assessed by calendar period and age group, whereas the evolution by birth cohort was synthesized by computing standardized cohort incidence/mortality ratios. Joinpoint regression revealed rising trends of incidence (in Lithuania, Bulgaria and Romania) and of mortality (in Latvia, Lithuania, Bulgaria and Romania). In Estonia, rates were rather stable. Women born between 1940 and 1960 were at continuously increasing risk of both incidence of and mortality from cervical cancer. Although some quality issues in the registration of cancer and causes of death cannot be ignored, the trends indicate increased exposure to human papillomavirus infection and absence of effective screening programs. Rising trends of cervical cancer in the most affected EU member states reveal a worrying pattern that warrants urgent preventive actions.

Testicular cancer survival in Estonia: improving but still relatively low.

BACKGROUND: international comparisons have pointed to very low survival of patients diagnosed with testicular cancer (TC) in Estonia. METHODS: using population based data from the Estonian Cancer Registry and period analysis, we examined trends in TC survival between 1985 and 2004. Additional results from a review of clinical records to ascertain patterns of disease management (1990-2003) were used to explain the changes and identify the areas for potential improvement. RESULTS: age-adjusted 5-year period relative survival increased from 47.9% in 1985-1989 to 74.5% in 2000-2004 (p for trend <0.01). A marked improvement was seen for the patients younger than 30, with the 5-year survival reaching 93.3%, while the improvement remained modest among patients aged 30 and above. Although substantial advances occurred in staging and treatment techniques since 1990, deficiencies remained evident in disease management, including not referring patients to an oncologist after their orchiectomy and less careful diagnostic workup for patients above 30 years of age. Low use of radiotherapy suggests poor access to contemporary equipment. Delays in seeking medical consultation, but also in starting adjuvant therapy, could have contributed to poorer outcomes. CONCLUSIONS: survival in TC increased markedly in Estonia by the 21(st) century, but is still notably lower than in the more developed countries. Multidisciplinary efforts may help to achieve further improvement. The provision of TC care should be coordinated by specialised cancer centres.

Place of residence predicts breast cancer stage at diagnosis in Estonia.

BACKGROUND: Stage at diagnosis is one of the most important predictors of breast cancer survival. The objective of this population-based study was to examine the impact of age, period of diagnosis and place of residence on breast cancer stage at diagnosis in Estonia. METHODS: Female breast cancer cases reported to the Estonian Cancer Registry in 1995-2006 with a known extent of disease were included. Logistic regression was used to estimate the risk of advanced stage (non-localized) disease. RESULTS: Overall, 56% of the 6936 women included in the analysis were diagnosed at advanced stage. The risk of advanced disease at diagnosis decreased over the study period in all age groups, but the change was much larger among women aged 50-69 years than among women in younger and older age groups. Multivariate analysis indicated that the strongest predictor of advanced stage disease was the place of residence. Compared with Tallinn (the capital of Estonia), living in Tartu (a small town with a university hospital) was associated with a significant 36% reduction in risk while the odds ratio associated with living in a marginal industrial county (Ida-Viru) was 1.52 (95% confidence interval 1.29-1.79). CONCLUSIONS: The observed regional variations are most likely due to differences in education, unemployment and health care access. Younger and elderly women, those living in remote areas and of lower socio-economic status should be addressed with specific measures to promote earlier detection of breast cancer, particularly in view of current economic difficulties and a sharply rising unemployment rate.

Trends in cervical cancer incidence and mortality in Bulgaria, Estonia, Latvia, Lithuania and Romania.

OBJECTIVE: The burden of cervical cancer varies considerably in the European Union. In this paper, we describe trends in incidence of and mortality from this cancer in the five most affected member states. METHODS: Data on number of deaths from uterine cancers and the size of the female population of Estonia, Latvia, Lithuania, Bulgaria and Romania were extracted from the WHO mortality database. Mortality rates were corrected for inaccuracies in the death certification of not otherwise specified uterine cancer. Incidence data were obtained from the national cancer registries. Joinpoint regression was used to study the annual variation of corrected and standardized incidence and mortality rates. Changes by birth cohort were assessed for specific age groups and subsequently synthesized by computing standardized cohort incidence/mortality ratios. RESULTS: Joinpoint regression revealed rising trends of incidence (in Lithuania, Bulgaria and Romania) and of mortality (in Latvia, Lithuania, Bulgaria and Romania). In Estonia, rates were rather stable. Women born between 1940 and 1960 were at continuously increasing risk of both incidence of and mortality from cervical cancer. CONCLUSIONS: Rising trends of cervical cancer in the most affected EU member states reveal a worrying pattern that warrants urgent introduction of effective preventive actions as described in the European guidelines.