Radiol Oncol 2021; 55(1): 42-49. doi:10.2478/raon-2021-0003 42 research article Trends in population-based cancer survival in Slovenia Vesna Zadnik1, Tina Zagar1, Katarina Lokar1, Sonja Tomsic1, Amela Duratovic Konjevic2, Branko Zakotnik1 1 Epidemiology and Cancer Registry, Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Institute of Oncology Ljubljana, Ljubljana, Slovenia Radiol Oncol 2021; 55(1): 42-49. Received 2 January 2021 Accepted 10 January 2021 Correspondence to: Prof. Vesna Zadnik, M.D., Ph.D., Zaloška 2, SI-1000 Ljubljana, Slovenia. E-mail: vzadnik@onko-i.si Disclosure: No potential conflicts of interest were disclosed. Background. The aim of our study was to describe the survival of Slovenian cancer patients diagnosed in the last twenty years. An insight is given into the improvement made in different cancer types, population groups and prog- nostic factors. Materials and methods. The principal data source was the population-based Slovenian Cancer Registry. The survival analysis included patients diagnosed with cancer in twenty years period from 1997 to 2016, which has been divided into four consecutive five-year periods. In addition, the analysis was stratified by cancer type, gender, age and stage. The survival was estimated using net survival calculated by the Pohar-Perme method and the complete approach has been applied. Results. The survival of Slovenian cancer patients has been increasing over time. During the 20 years observed, five- year net survival increased by 11 percentage points. Significantly higher growth was observed in men. Age and stage at diagnosis are still crucial for the survival of cancer patients. Five-year net survival is lowest in those over 75 years of age at diagnosis but has also improved by seven percentage points over the past 20 years. The five-year net survival of patients in the localized stage increased by ten percentage points over the 20 years under observation. Survival of patients in the distant stage has not been improving. In both sexes, survival for melanoma, colorectal and lung cancers have increased significantly over the last 20 years. Progress has also been made in the two most common gender specific cancers: breast cancer in women and prostate cancer in men. Still, the significant progress in prostate cancer is probably mostly due to lead-time bias as during the study period, Slovenia used indiscriminate PSA testing, which probably artificially prolonged survival. Conclusions. The survival of Slovenian cancer patients has been increasing over time, which gives us a basis and an incentive for future improvements. To monitor the effectiveness of managing the cancer epidemic, the cancer burden needs to be monitored also in the future, using quality data and scientifically justified methodological ap- proaches. In this process a well organised population-based cancer registries should play a key role. Key words: cancer burden; cancer survival; time trend; Slovenian Cancer Registry Introduction Global health indicators show that cancer is an epidemic of modern times. Epidemiological in- dicators from Slovenian Cancer Registry confirm similar situation also in Slovenia. Among all causes of death, it ranks 1st in men and 2nd in women. In recent years, 15,000 Slovenes per year have devel- oped cancer, and slightly over 6,000 have died of cancer. There are more than 120,000 people living in Slovenia who had ever been diagnosed with can- cer. Since cancer is more common among the el- derly (only a third of patients are younger than 65 years at the time of diagnosis), and the Slovenian Radiol Oncol 2021; 55(1): 42-49. Zadnik V et al. / Trends in population-based cancer survival in Slovenia 43 population is ageing, it is expected that the burden of this disease will increase, even if the level of risk factors remains the same as today.1,2 Continuous and systematic collection, storage and analysis of data on all cancer patients in a de- fined population is the basis for controlling this major public health problem – a key role is played by population-based cancer registries. One of their main purpose is to collect accurate and complete cancer data that can be used to plan and evaluate the National Cancer Control Programmes, specifi- cally in the fields of primary and secondary pre- vention, diagnostics, treatment and rehabilitation and palliative care, to plan the capacities and re- sources needed to manage cancer (staff, medical equipment, hospital and rehabilitation facilities).3 Incidence, mortality and survival are the main cancer burden indicators that are reported by the population-based cancer registries. Cancer mortal- ity is the primary indicator of the cancer burden worldwide, since it is available for the largest num- ber of countries. Mortality depends on the number of new patients (incidence) on one hand and on their survival on the other. Survival itself does not depend on the incidence, as it considers only those who have already fallen ill, so it indirectly indi- cates the success of diagnosis and treatment (in pa- tients with earlier diagnosed disease and prompt treatment according to guidelines, a better survival is expected) and is considered as the most power- ful indicator. The population survival of cancer pa- tients, as shown by cancer registries is, therefore, a composite indicator. It reflects the characteristics of patients as well as the organization, accessibil- ity, quality, and efficiency of the healthcare system. Clinical studies usually present the results of sur- vival of groups of patients with a specific disease and for specific well-defined treatment, where strict entry criteria for the study group are defined, such as stage, performance status 0 or 1, normal organ function, age under 70 years etc. Population data on survival significantly differs from that. Population survival is affected, for example, by the disease stage at diagnosis, which depends on the time length from the first signs to the visit of gen- eral practitioner and further to the time of diagno- sis. This time may be reduced through informing the population about when to visit a physician in case of health problems and the ability of general practitioners to consider the possibility of a serious disease, through increasing the availability of di- agnostic tests, and minimising waiting times. The availability of screening programmes with proved benefit further increases the chances of cure or at least better survival, as they detect precancerous le- sions or early-stage of the disease. Once diagnosed, the success of treatment depends on the type of cancer, the patient’s characteristics (age, comorbid- ities, general physical performance, etc.) and also on the availability of multidisciplinary treatment and the qualifications of the medical team. All of these diverse factors that determine population survival must be considered by the researcher or clinician who interprets the results of population survival studies, and even more so when compar- ing survival between countries.4 In this study we are presenting the survival of Slovenian cancer patients diagnosed in the last twenty years. An insight is given into the improve- ment that was made in different cancer types, dif- ferent population groups (gender and age) and stage at diagnosis. The survival improvements support reported ongoing progress achieved by Slovenian oncology and Slovenian healthcare sys- tem. The results of survival analysis are further discussed in the comprehensive report, which con- tains also insights from clinical experts who are in- volved in specific treatment of cancer patients in Slovenia.5 Materials and methods The principal data source for the analysis is the population-based Slovenian Cancer Registry (SCR). Thus, the data refer to all cancer patients, residents of Republic of Slovenia at the time of di- agnosis, irrespective of where they have been diag- nosed, treated or where they have died. The SCR’s quality and completeness indices prove that can- cer registration in Slovenia adequately covers the entire population.6 To assure completeness and to obtain additional information on registered cancer cases, SCR is linked with several governmental and health databases. Synchronisation of data between different sources is based on unique personal iden- tification number, which is assigned to every resi- dent in Slovenia and recorded in every state regis- try including SCR. Using unique personal identifi- cation number guaranties data integrity, data qual- ity and prevents duplication. SCR is linked with the Central Register of Population through secure on-line connection (24/7 availability) and daily up- dates information on vital status and address for each person registered by SCR. The electronic link- age to the national Mortality Database and to the breast, colorectal and cervical screening registries is performed at least once per year.6,7 Radiol Oncol 2021; 55(1): 42-49. Zadnik V et al. / Trends in population-based cancer survival in Slovenia44 The data on gender, date of diagnosis, age at diagnosis, code of primary site according to the International classification of Diseases (10th edi- tion), stage at diagnosis (general categorization into localized, regional or distant stage) and vital status with the date of end of follow-up (date of death, date of lost to follow-up or date of the end of study) were extracted from the SCR’s database for all cancer cases. The survival analysis included pa- tients who were diagnosed with cancer in the years from 1997 to 2016. The entire observed period has been divided into four consecutive five-year peri- ods. The patients older than 95 years of age were excluded from survival analysis. Separate analyses were made for children (0–14 years), adolescents (15–19 years) and adults (20–94 years). All analyses were performed on data registered in the SCR database on 1st September 2019 and 234,827 cases of cancer were extracted from the database. Among them, there were 37,917 non- melanoma skin cancer patients. Because this is a frequent but almost completely curable disease, we excluded these patients from the analysis. Further, we excluded 1,711 cases of cancer being registered by death certificate only, since the date of diag- nosis is unknown, 4,470 cases in which the date of registration was the same as the date of death (mostly they are diagnosed at autopsy), and 668 cases in which the person was 95 years of age or older. The vital status of patients was last checked on 31st August 2019. At the end of the observation period, the person can be alive, dead or lost from the vital statistics records. Between 1997 and 2001, 26 persons with no follow-up data in the Central Register of Population were registered in the SCR (0.06% of 45,390 new cancer cases during this pe- riod) and only 3 persons with no follow-up data between 2002 and 2016 (0.002% of 189,437). In the group of patients, the survival is interpret- ed as the proportion of patients who are still alive after a certain time from the diagnosis. Survival time is defined as the time between the date of can- cer diagnosis and the date of the end of follow-up. The survival was estimated using net survival cal- culated by the Pohar-Perme method. Net survival is the survival that would be observed if the only cause of death was the disease we are studying, i.e. causal specific survival. For example, a net survival of 30% over five years tells us that in a hypotheti- cal case where patients would die only from cancer and no other causes, 70% of those patients would die within five years from diagnosis.8,9 Because all the included patients were not followed-up for five years we have applied the complete approach in the survival calculation.10 For the calculation, we used the relsurv library for the R software environment.11 Results and discussion There were 191,154 patients aged 20 to 94 years di- agnosed between 1997 and 2016 with any cancer (non-melanoma skin cancer excluded). Throughout the observed period, slightly more men than wom- en were diagnosed, of which most were aged from 50 to 74 years. In solid tumours, the disease was mostly detected in the localized stage. The five most frequent cancers in Slovenia – non-melanoma skin, prostate, colorectal, breast and lung cancer – account for 60% of all new cancer cases.1 Survival of cancer gradually increased in rela- tion to the year of diagnosis. Over the 20-year peri- od, five-year net survival increased by slightly less than 11 percentage points (Figure 1). The rise is in concordance to observed in our last three reports on survival of Slovenian cancer patients diagnosed with cancer between 1963–1990, 1983–1997 and 1995–2005.12,13,14 According to the CONCORD-3 study which compared the five-year net survivals of adult patients with 15 different cancers between 2010 and 2014 in 26 European countries, in most cases the survivals of Slovenian cancer patients are below the European average.14 As presented in Table 1, in the first observed period, between 1997 and 2001, the net five-year survival for all cancers combined was much bet- ter for women than for men, with a difference of 16 percentage points. In the 20-year period signifi- cantly higher growth was observed in men, where five-year net survival increased by 17 percentage points (from 38% to 56%). In women, five-year net survival increased by six percentage points (from 54% to 60%). At a first glance, it seems that men have started to take better care of their health and that the ‘macho’ male population (refusing to see a doctor) is disappearing. Undoubtedly, breast and prostate cancer, which represent as many as a fifth of all cancer patients in men and women, contrib- ute the most to reducing the gap between the gen- ders. A large proportion of the increase in survival in men can be attributed to the survival of patients with prostate cancer, where it rose by as much as 21 percentage points (Table 1). However, this significant progress in prostate cancer survival is probably mostly artificial (lead time bias), since we used indiscriminate PSA testing in Slovenia quite uncritically during the study period, with which we also detected those prostate cancers that devel- Radiol Oncol 2021; 55(1): 42-49. Zadnik V et al. / Trends in population-based cancer survival in Slovenia 45 FIGURE 1. Five-year net survival (with a 95% confidence interval) of adult patients (20–94 years) with selected cancers, Slovenia 1997–2001 and 2012–2016. Radiol Oncol 2021; 55(1): 42-49. Zadnik V et al. / Trends in population-based cancer survival in Slovenia46 op slowly and would not cause health problems for men during their lifetime. This artificially prolongs survival, as the disease is detected earlier, but the course of the disease is not changed.15 However, the most common cancer in women, breast cancer, has not seen such a large improvement in survival (Table 1). The breast cancer screening programme was introduced across the whole country only in 2018, so it could not make a significant contribu- tion to the results of our current analysis.16 In both sexes, survival for other three common cancers have increased significantly over the last 20 years: colorectal cancer (by 14 percentage points, from 48% to 62%), cutaneous melanoma (by 11 percentage points, from 79% to 90%), and lung cancer (by 8 percentage points, from 10% to 18%) (Figure 1). These results reflect earlier diagnostics and advances in systemic treatment. Despite treat- ment progress, the survival of lung cancer patients remains low. There are some other cancers where almost no progress over time was observed and in which survival remains low including pancreatic, oesophageal, gallbladder and bile duct, liver and brain cancers. TABLE 1. Five-year net survival (with a 95% confidence interval) of adult patients (20–94 years) with selected cancers by sex, Slovenia 1997–2001 and 2012–2016 Cancer type Male Female 1997–2001 2012–2016 1997–2001 2012–2016 Five- year net survival 95% confidence interval Five- year net survival 95% confidence interval Five- year net survival 95% confidence interval Five- year net survival 95% confidence interval C00-C14 Mouth and pharynx 34.4 31.6-37.3 43.6 40.6-46.8 61.1 53.8-69.4 65.2 58.5-72.8 C32 Larynx 59.4 54.4-64.9 62.1 56.3-68.4 67.9 55.2-83.5 51.5 38.6-68.5 C15 Oesophagus 5.1 3.2-8.1 10.5 7.5-14.9 8.2 3.7-18.3 14.2 8.0-25.1 C16 Stomach 20.7 18.4-23.4 31.6 28.8-34.7 25.4 22.4-28.9 30.7 27.3-34.7 C18-C20 Colon and rectum 47.1 44.9-49.5 63.1 61.1-65.2 48.7 46.3-51.2 59.7 57.4-62.1 C22 Liver and intrahepatic bile ducts 2.9 1.3-6.4 12.3 9.5-15.9 3.4 1.0-11.6 9.1 4.8-17.1 C23-C24 Gallbladder and billiary tract 11.9 8.0-17.5 14.7 11.2-19.3 6.5 4.3-9.9 13.7 10.6-17.8 C25 Pancreas 4.3 2.7-4.8 4.7 3.4-6.6 2.8 1.7-4.8 6.0 4.5-8.0 C33-C34 Trachea, bronchus and lung 9.6 8.6-10.7 15.5 14.3-16.8 11.4 9.5-13.6 22.1 20.2-24.1 C38.0, C47-C49 Connective and soft tissue 61.3 51.1-73.7 58.0 48.9-68.7 55.0 45.1-67.0 52.0 44.8-60.3 C40-C41 Bone 66.7 52.3-85.1 65.7 48.9-88.3 66.0 50.7-86.1 51.8 36.5-73.3 C43 Malignant melanoma of skin 75.4 70.9-80.3 90.0 87.0-93.2 81.8 77.9-85.8 90.8 88.0-93.7 C50 Breast - - - - 77.5 76.0-79.0 87.6 86.3-88.9 C53 Cervix uteri - - - - 73.1 70.2-76 69.0 64.7-73.7 C54 Corpus uteri - - - - 79.8 77.1-82.6 80.6 78.0-83.3 C56 Ovary - - - - 47.9 44.5-51.6 40.4 36.7-44.5 C61 Prostate 71.1 68.4-73.8 92.3 91.0-93.7 - - - - C62 Testis 96.4 94.2-98.7 97.6 95.9-99.3 - - - - C64-C65 Kidney with renal pelvis 56.5 52.1-61.3 64.6 61.1-68.3 61.4 56-67.4 69.3 64.8-74.1 C67 Bladder 48.5 44.1-53.2 55.3 51.3-59.6 50.5 42.9-59.4 44.4 38.4-51.3 C70-C72 Central and autonomic nervous system 13.2 9.8-17.9 15.8 12.4-20.1 18.7 14.2-24.7 15.0 11.4-19.7 C73 Thyroid gland 88.1 79.5-97.7 90.6 85.1-96.4 86.6 82.1-91.4 95.3 92.7-97.9 C81 Hodgkin's lymphoma 78.3 69.3-88.5 78.3 69.2-88.5 79.0 69.5-89.7 85.7 77.3-95.1 C82-C85 non-Hodgkin's lymphoma 55.1 49.8-60.9 65.7 61.9-69.8 54.7 49.8-60.1 61.3 57.6-65.2 C90 Multiple myeloma and malignant plasma cell neoplasms 36.8 28.9-46.9 38.9 32.6-46.4 32.8 26.4-40.7 44.0 37.5-51.5 C91-C95 Leukaemias 49.8 44.7-55.4 46.0 41.8-50.6 41.6 36.2-47.9 47.2 41.9-53.0 C00-C96 (but C44) All sites, but skin 38.4 37.6-39.2 55.8 55.0-56.5 54.3 53.4-55.1 59.9 59.1-60.6 Radiol Oncol 2021; 55(1): 42-49. Zadnik V et al. / Trends in population-based cancer survival in Slovenia 47 Age and stage at diagnosis are prognostic fac- tors for disease development and treatment out- come and also for the survival of cancer patients. The survival of persons aged 20 to 49 was better in the last two periods compared to other age groups and improved by 15 percentage points in period 2012 to 2016 compared to the period 1997 to 2001 (Figure 2). Five-year net survival is lowest in those over 75 years of age but also in this age group has improved by seven percentage points over the last 20 years. The number of older patients with cancer is increasing in Slovenia, for example, the number of patients aged over 75 has more than doubled in the analysed period.17 It is precisely these patients who most frequently have comorbidities that can severely limit attainability of specific oncological treatment, which explains why the proportion of patients without specific oncological treatment re- mained roughly the same through time despite the increasingly complex treatments available - around 20% according to the last SCR’s report on cancer patient’s survival.5 We can conclude that doctors equally often decide to treat elderly patients, al- though more complex treatments are often accom- panied by many more side effects. Consequently, as seen from our analysis in the last three time pe- riods, the five-year net survival of the oldest group of patients still remained almost the same, while in the younger groups it increases steadily and signif- icantly. Apparently, the age and concomitant dis- eases are a wall that we cannot scale with today’s treatments. The importance of the stage at diagnosis can- not be overemphasised. The five-year net survival of patients diagnosed with solid tumours in local- ized stage increased by 10 percentage points over the 20 years of observation and reached 85% in the last period. Five-year net survival of patients di- agnosed with cancer in regional stage approaches 55%, whereas in patients diagnosed with cancer in distant stage it is only slightly below 25% and does not improve statistically significantly through time (Figure 3). Despite a number of new insights into prognostic and predictive factors and with the advancement of molecular biology which enabled more effective treatments, the classical stage of TNM remains the basic predictor of disease pro- gression and survival (together with the age of can- cer patient). Reporting the stage in cancer registries is historically simplified into three groups: local- ized, regional, and distant disease. Results show, that nowadays the disease is more frequently diag- nosed in the localized stage and less often in the re- gional stage; the percentage of patients with distant disease remains the same. This is partly due to more accurate and accessible diagnostic methods that al- low detecting more and smaller distant lesions de- spite on a whole the diagnostic is done earlier. From our analysis, we can conclude that the im- provement in survival can be explained by the dis- ease being diagnosed at an earlier stage and is not just the consequence of the stage-shift described above. This is certainly the case for the last period for colorectal and breast cancers. For all patients who respond to the screening invitation, the five- year risk of death is four to five times lower than for those who do not respond to the invitation, due to the disease being diagnosed at a lower stage.18 Of course, survival is not a measure of the success of a screening programme (it’s biased due to time advantage), but treatment of the disease at an ear- lier stage undoubtedly affects recovery and conse- quently cause specific mortality. Successful screen- ing programmes and high population responsive- ness are therefore improving survival. Although rarely, cancer is diagnosed in children as well. In the present survival analysis, we included FIGURE 2. Five-year net survival of patients with cancer (all sites but non-melanoma skin cancer) by age group, Slovenia 1997–2016. FIGURE 3. Five-year net survival of patients with cancer (all solid tumours but non- melanoma skin cancer) by stage at diagnosis, Slovenia 1997–2016. Radiol Oncol 2021; 55(1): 42-49. Zadnik V et al. / Trends in population-based cancer survival in Slovenia48 1,379 children and adolescents (aged 0 to 19 years) diagnosed in Slovenia in the target period 1997 to 2016. The net survival has been gradually increasing with respect to the year of diagnosis. For example, the five-year net survival for all childhood cancers combined increased by almost 8 percentage points and exceeded 85% in the last period 2012–2016 com- pared to the first period 1997–2001 and being less than 30% fifty years ago.12,19 There is a significant difference in the survival among patients with dif- ferent cancer sites: patients with malignant brain tu- mours survived five years in 70%, those diagnosed with leukaemia in 88%, but all of those diagnosed with lymphomas survived five years in 98%. The 20-year improvement was the highest in lympho- mas – for 12 percentage points. Clearly, the malig- nant diseases in children are heterogeneous group and a retrospective analysis of factors contributing to the observed improvement in survival is difficult. In Slovenia, all children suspected of having cancer undergo a diagnostic workup and treatment in a single national paediatric centre, which positively affects their survival along with developments in diagnostics and treatment.19,20 Similarly, as in adults, boys achieve slightly lower survivals than girls, but the gap between the sexes has been narrowing over time (Table 2). Five-year net survival was similar in children and in adolescents in all observed periods (Figure 2, Table 2). In the first two observed periods, be- tween 1997 and 2006, it was slightly better in the 0 to 14 years age group, and in the last two peri- ods, between 2007 and 2016, it was reversed being better in the 15–19 age group. In the last observed period, from 2012 to 2016, it reached 85 and 91% for children and adolescents, respectively. The five-year net survival of children and adolescents with solid tumours with localized and regional stage disease exceeds 85% in the last ten years. In children and adolescents with distant disease at diagnosis, the five-year net survival approaches 70% (Table 2). Conclusions Population-based cancer survival is a composite indicator reflecting the characteristics of patients as well as the organisation, accessibility, quality, and efficiency of the healthcare system. This analysis is the starting point of our fourth comprehensive re- port on the survival of Slovenian cancer patients5 and shows the progress of Slovenian oncology and healthcare, as well as Slovenian general attitude to- wards cancer over the last twenty-year period. As we determined, the survival of Slovenian cancer patients has been increasing over time, which gives us a basis and an incentive for future improve- ments. In addition, the lag in survival of Slovenian cancer patients in comparison with the patients from other European health systems identified in some cancers in the CONCORD-3 study14 and in the last EUROCARE study21provides us with a le- gitimate basis for considering improvements in the future. The National Cancer Control Programme deliv- ers a comprehensive set of activities in the fields of primary and secondary prevention, diagnostics, treatment and rehabilitation, as well as palliative care. Therefore, in order to reduce the cancer bur- den and improve the quality of life and economic sustainability, all evidence-based primary and secondary prevention programmes must be estab- lished and used, and evidence-based treatment im- plemented in scientifically acceptable time frames. The development of medical science, oncology and molecular biology in the last 20 years has brought many revolutionary insights into the field of on- cology, which undoubtedly have had an impact and will have an even more significant impact on the survival of cancer patients in the future. To monitor the effectiveness of managing the cancer epidemic of today, also in the future the burden of cancer will need to be monitored based on qual- ity data and scientifically justified methodological approaches both provided by established cancer TABLE 2. Five-year net survival of children (0–14 years) and adolescences (15–19 years) with cancer by period of diagnosis, sex, age group and stage at diagnosis for solid tumours, Slovenia 1997–2016 Period of diagnosis Gender Age at diagnosis Stage (C00-C80) All Male Female 0–4 year 5–9 year 10–14 year 15–19 year Localized Regional Distant 1997 – 2001 205 146 93 48 78 132 116 59 20 351 2002 – 2006 180 149 96 49 51 133 114 52 21 329 2007 – 2011 170 161 89 53 69 120 126 33 18 331 2012 – 2016 200 168 104 74 56 134 144 53 27 368 Radiol Oncol 2021; 55(1): 42-49. Zadnik V et al. / Trends in population-based cancer survival in Slovenia 49 registries. Further on, cooperation between onco- logical epidemiologists and clinical specialists is crucial for a comprehensive review and prepara- tion of proposals for improvement. Acknowledgements The authors thank the staff of the Slovenian Cancer Registry whose endless efforts to collect accurate and complete data have made this report possible. 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