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Frontiers in Cancer Control and Society ·

Volume 3 - 2026 | https://doi.org/10.3389/fcacs.2025.1676661

Sixty years of population-based survival monitoring in childhood and adolescent cancer: evidence from Slovenia

  • Tina Žagar1*corresponding author
  • Mojca Birk1
  • Ana Mihor1
  • Maja Jurtela1
  • Urška Tomšič1,1
  • Katarina Lokar1
  • Teja Oblak1
  • Nika Bric1
  • Sonja Tomšič1
  • Miran Mlakar1
  • Vesna Zadnik1
  1. Slovenian Cancer Registry, Institute of Oncology Ljubljana, Ljubljana, Slovenia
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Abstract

Long-term survival of children and adolescents (CA) diagnosed with cancer has hardly been researched in Slovenia. Our aim was to present the survival trend at the population level over a period of 60 years with an additional comparison between observed and net survival. From the Slovenian Cancer Registry, we obtained data on malignant cancer cases (excluding cases of non-melanoma skin cancer) in CA aged 0–19 years diagnosed in Slovenia in 1964–2023. Survival estimates were calculated using the Kaplan-Meier estimator for observed survival and the non-parametric Pohar-Perme estimator for net survival by age, period and ICCC groups. Of the total 4,067 cancer cases, 3,935 first primary cancers were included in the survival analysis. A steady increase in the crude incidence rate was observed over the 60-year period, from 10.9 per 100,000 in the period 1964–1973 to 17.7 per 100,000 in the period 2014–2023, largely on account of increases in ICCC groups I, II, IV, X and XI. For ICCC cancer groups I, II, IV, V, VI and X, the change in the 10-year net survival was more than 50 percentage points, while at the same time for groups V and VI the 10-year net survival for patients diagnosed in the period 2004–2013 was 100%. The observed 5-year survival 30.8% (27.3–34.8%) in the period 1964–1973 steadily increased to 87.8% (85.3–90.3%) in the period 2014–2023. The 5-year observed survival in the period 2014–2023 was worst for children diagnosed at the age of 1–4 years (83.6%, 77.8–89.9%) and best for adolescents diagnosed at the age of 15–19 years (90.2%, 86.3–94.2%). The differences between the observed and net survival were very small, with a difference exceeding 1 percentage point for survival of 30 years or more. Increasing survival among Slovenian children and adolescents indicates significant progress in cancer diagnosis and treatment. The need for systematic surveillance of the late effects of cancer treatment is increasing with the growing number of survivors (resulted from decreasing mortality and increasing survival) in order to maintain their health and quality of life as they age.

Keywords

1 Introduction

Epidemiological indicators consistently show that cancer is one of the most pressing public health problems in high-income countries, including Slovenia, a Central European country with a population of two million. While the incidence of some childhood and adolescent cancer types had increased, survival has improved considerably, and mortality has decreased in countries with advanced healthcare systems (1, 2). Namely, due to improvements in diagnosis and treatment childhood and adolescent cancer have become a highly curable disease. Still, there is considerable variability in survival of cancer patients among different cancer sites and populations (3). The population-based survival of cancer patients depends on a multitude of factors, including those pertinent to the patient themselves (and their disease) as well as the performance of the healthcare system where the patient is treated. According to the researchers within the EUROCARE project, the European cooperative for studying population-based survival in cancer patients, important social determinants related to the healthcare system are healthcare workforce numbers along with diagnostic and treatment facilities (4).

The Slovenian Cancer Registry provides data on cancer patients to many international projects comparing cancer patient survival (1, 3, 5) and has been publishing its own detailed data on cancer patient survival in Slovenia for more than 25 years (6, 7). The most recent monograph, covering patients diagnosed over the twenty-year period from 1997 to 2016 (8), includes a dedicated chapter on childhood and adolescent cancer. The net survival of patients with childhood cancer has been gradually improving in both sexes. The 5-year net survival was similar in both age groups 0–14 and 15–19 years in all the observed periods; in the last observed period, from 2012 to 2016, it reached 84–91% (8). However, after the publication of this monograph, the need arose for more extensive reporting on the survival of patients diagnosed with childhood and adolescent cancers, with a focus on international comparability (the monograph uses the ICD-10 classification of cancers) and longer follow-up. The long-term survival of Slovenian children and adolescents diagnosed with cancer according to the International Classification of Childhood Cancer (ICCC), 3rd edition (9) has not been studied to date.

Population-based cancer survival is a key measure of the overall effectiveness of health systems in management of cancer (10). For groups of patients, survival represents probability to be alive after selected time period. There are several options and methods for calculating survival (11, 12). The most basic and simple survival measure is the so-called observed survival, where all deaths are included in the calculation, including those not caused by cancer. Among the various methods for calculating observed survival, the nonparametric Kaplan-Meier method (13) is the most commonly used today because it provides a high degree of accuracy and the calculation is simple. Observed survival reflects all-cause mortality, making it difficult to distinguish deaths attributable to cancer from those due to unrelated causes. In population-based cancer survival analysis, net survival is preferred over observed survival because it provides an estimate of survival if the only cause of death was the disease under study. The net survival is commonly calculated in relative survival framework, where expected survival is estimated from the expected mortality in the general population and the information on cause of death on the individual level is not required. Net survival (14) is average of ratios of observed and expected survival on the individual level and is calculated with Pohar-Perme estimator. Since all-cause mortality is low in children and adolescents, the observed and net survival estimates for cancer in these age groups show little difference (8). However, this may change in long-term survivors as they reach an older age, where deaths from other causes become more relevant, as well as deaths related to cancer in childhood and adolescence (15).

The main objective of this study was to estimate trends in survival among children and adolescents diagnosed with cancer in Slovenia over a 60-year period. Further, the comprehensive historical data from the population-based Slovenian Cancer Registry (SCR) also allows us, for the first time, to conduct a long-term analysis based on the ICCC cancer groups and to assess the differences between the observed and net survival estimates after an extended period of follow-up.

2 Materials and methods

From the SCR (16) we obtained data on all malignant neoplasms (also referred to as cancer cases) diagnosed in Slovenia in children and adolescents aged 0–19 years in the 60-year period from 1964 to 2023. The variables sex, cancer type, date of diagnosis, age at diagnosis, vital status and date of event (date of death or date of last follow-up) were extracted from the SCR database on February 27, 2025. The vital status was obtained through linkage to the Slovenian Central Population Registry. The last date of vital status follow-up was December 31, 2024. Patients with unknown vital status at the end of the study (December 31, 2024) were included in the analyses as ‘lost to follow-up’, using the date of their last visit to a Slovenian hospital for cancer treatment or the date of their emigration, whichever occurred later. Survival time is defined as the period between the date of cancer diagnosis and the date of death or censoring. Population size by sex and age was obtained from the Slovenian Statistical Office.

Malignant cancer entities in children (age at diagnosis 0–14 years) and adolescents (15–19 years) were included in the analyses. Benign and borderline that are also registered in the SCR were excluded. For the purpose of this study the Slovenian Childhood Cancer Clinical Registry which is in place within SCR since 2020 (17) reviewed all paper notification forms obtained for patients diagnosed in the years 1964–1982 and coded topography, morphology and behavior according to International Classification of Diseases for Oncology, 3rd edition (18) (ICD-O-3). This endeavor was necessary to classify all cases according to the ICCC, which was not previously available. The information in the documentation was often insufficient to determine a specific ICCC group, resulting in 3.4% of cancer cases being classified in group XII in period 1964–1983, compared with 0.7% in 1984–2023. The ICCC groups (9) are listed below for the purpose of reference in this paper:

  • Group I—Leukaemias, myeloproliferative diseases, and myelodysplastic diseases;
  • Group II—Lymphomas and reticuloendothelial neoplasms;
  • Group III—Central nervous system and miscellaneous intracranial and intraspinal neoplasms;
  • Group IV—Neuroblastoma and other peripheral nervous cell tumors;
  • Group V—Retinoblastoma;
  • Group VI—Renal tumors;
  • Group VII—Hepatic tumors;
  • Group VIII—Malignant bone tumors;
  • Group IX—Soft tissue and other extraosseous sarcomas;
  • Group X—Germ cell tumors, trophoblastic tumors, and neoplasms of gonads;
  • Group XI—Other malignant epithelial neoplasms and malignant melanomas;
  • Group XII—Other and unspecified malignant neoplasms.

The data were grouped into ten consecutive calendar periods based on the year of diagnosis. Analyses were performed for all cancer types combined (excluding non-melanoma skin cancer) and separately for the three most common cancers in children and adolescents according to the ICCC, 3rd edition: Group I, Group II and Group III. For other ICCC groups the number of patients is too low to provide reliable survival estimates.

Non-melanoma skin cancer was excluded from the incidence numbers to enable international comparisons (19). Only the first primary cancer was included in the survival analysis (the number of primary cancer cases in children and adolescents and the number of patients in our cohort are not identical, as a patient may have more than one primary cancer, defined according to the European Network of Cancer Registries rules for cancer coding). Additionally, we excluded from the survival analysis cases with a survival time of zero days (where the date of diagnosis coincided with the date of death). When the date of diagnosis was not fully known, specially trained nurses reviewed the available documentation and determined the best estimate for the date of diagnosis, which was considered more accurate than imputing the date using statistical models.

Age-standardized incidence rates per 100,000 people stratified by ICCC groups, were calculated for each calendar year and for 10-year periods using the 2001 new WHO standard. Temporal changes in incidence were analyzed using Joinpoint regression analysis to estimate average annual percentage changes (AAPCs) over the entire study period, except for groups VIII and IX, for which AAPCs were calculated over the period 1984–2023 (the early trends in the incidence of malignant bone tumor and soft tissue sarcoma are not reliable due to changes in classification).

The complete approach was implemented in the calculation of survival, allowing inclusion of patients who were followed for less than the specified time and contributing to the calculation of survival only for the duration they were observed. For example, patients diagnosed with the disease 3 years before the end of the study contribute to one- and 3-year complete survival, but when calculating 5-year survival, their survival time is censored after 3 years. Short and long-term survival estimates with 95% confidence intervals were performed using the Kaplan-Meier estimator for observed survival and the nonparametric Pohar-Perme estimator for net survival using the Slovenian population life tables for information on survival in the general Slovenian population of the same age, sex and calendar year (20), freely available at [https://www.mortality.org/]. The absolute percentage point differences between observed and net survival are reported. The analyses were performed with the R software version 4.3.1 (21), Rstudio (version 2023.6.1.524) (22) using the R packages survival (version 3.5.5) (23) and relsurv (version 2.2.9) (24), and additionally dplyr (version 1.1.4) (25) for data management.

3 Results

3.1 Incidence

Of the total 4,067 childhood and adolescent cancer cases, 48 cases of non-melanoma skin cancer were excluded from the analysis, which is common in reporting the incidence for purpose of international comparisons and in cancer survival analyses due to high curability of non-melanoma skin cancer (19).

The most common cancers diagnosed in children and adolescents are leukaemias, myeloproliferative diseases, and myelodysplastic diseases (ICCC group I), with the crude incidence rate increasing from 2.9 per 100,000 in 1964–1973 to 5.0 per 100,000 in 2014–2023 (Figure 1a). The second most common are lymphomas and reticuloendothelial neoplasms (group II), with a crude incidence rate of 3.2/100,000 in 2014–2023, followed by CNS and miscellaneous intracranial and intraspinal neoplasms (group III), with a rate of 1.8/100,000 (Figure 1a).

Crude **(a)** and age standardized (2001 new WHO standard) **(b)** incidence rates per 100,000 population (non-melanoma skin cancer is excluded) with 95% confidence intervals by cancer group according to the International Classification of Childhood Cancer (ICCC) and by 10-year calendar periods of cancer diagnosis, among Slovenian children and adolescents (age at diagnosis 0–19 years), 1964–2023. In the table below the graphs, incidence (abbreviation: Inc) is given for each 10-year period, and the average annual percentage change (abbreviation: AAPC) with 95% confidence interval is provided for each ICCC group for the trend over the period 1964–2023, except for groups VIII and IX, for which AAPC was estimated over the period 1984–2023. Source: Slovenian Cancer Registry.
Figure 1. Crude (a) and age standardized (2001 new WHO standard) (b) incidence rates per 100,000 population (non-melanoma skin cancer is excluded) with 95% confidence intervals by cancer group according to the International Classification of Childhood Cancer (ICCC) and by 10-year calendar periods of cancer diagnosis, among Slovenian children and adolescents (age at diagnosis 0–19 years), 1964–2023. In the table below the graphs, incidence (abbreviation: Inc) is given for each 10-year period, and the average annual percentage change (abbreviation: AAPC) with 95% confidence interval is provided for each ICCC group for the trend over the period 1964–2023, except for groups VIII and IX, for which AAPC was estimated over the period 1984–2023. Source: Slovenian Cancer Registry.

The highest increase in cancer incidence (Figure 1a) is observed in ICCC groups I, II, IV, X and XI (AAPC 1.1%, 1.4%, 1.5%, 3.2% and 2.9% respectively). In the other groups (III, V and VI) the crude incidence rates are stable with occasional fluctuations and declining in group VII and XII (AAPC −1,2% and −3.3% respectively). The rates for groups VIII and IX are calculated over last 40 years due to changes in classification; crude incidence rates for group VIII are increasing by 5.9% annually and are stable for group IX (Figure 1a). Age standardized rates (2001 new WHO standard) show similar trends: increasing trend in groups I, II, IV, VIII, X and XI. Decreasing trend is observed in groups VII and XII and is stable in III, V, VI and IX (Figure 1b).

3.2 Case inclusion criteria for survival analysis

For 544 cancer cases, the month and year of diagnosis were known but the day was uncertain, and for another 21 cases only the year was known, with both day and month uncertain. Excluding these cases would introduce bias in the survival analyses, as incomplete diagnosis dates after 1990 are less common and the missing data are not randomly distributed. Therefore, the diagnosis date was determined as a best estimate based on available documentation, and these cases were included in the analysis. We excluded from the survival analysis 45 cases with a survival time of zero days (the date of diagnosis coincided with the date of death): 7 cases were registered in the SCR based on death certificate information only (all pre-1976), 22 cases were diagnosed at autopsy (throughout the whole time period 1964–2023), and 16 cases were diagnosed on the same day the death followed (all pre-1976). In our cohort, 37 patients aged 0–19 years were diagnosed with more than one primary cancer—in the survival analyses, the first primary cancer was included only—survival time was calculated from the date of diagnosis of the first primary cancer. Finally, of the total 4,067 cancer cases, 3,935 cancer cases (97.9%) were included in the survival analysis. By ICCC group, most excluded cancer cases were in groups XII (21.3%) and VIII (7.1%) and the fewest were in groups V and X, where none were excluded from survival analysis. The vital status of 19 patients remained unknown at the end of the study (December 31, 2024), as they were no longer listed in the Slovenian population registry, primarily due to emigration. These cases were included in the analyses as “lost-to-follow-up” with the date of their last visit to a Slovenian hospital for cancer treatment or the date of their emigration, whichever occurred later.

Of 3,935 cancer cases included in survival analyses, 15.1% were diagnosed in the first 10-year period 1964–1973 and 18.0% in the last period 2014–2023 (Table 1), corresponding to the steady increase in the crude incidence rate from 10.9 to 17.7 per 100,000 (Figure 1a). More than half of the cases were males (55.5%, 2,182 cases), and the distribution by gender in the cohorts varied only slightly over time. 5.8% of cancer cases were diagnosed in children before their first birthday, while a third of cases (32.3%) were diagnosed in adolescents (aged 15–19 years) (Table 1).

Table 1. Cancer incidence among Slovenian children and adolescents (age at diagnosis 0–19 years; non-melanoma skin cancer is excluded), number of patients excluded and included in survival analyses, Slovenia 1964–2023.

Incidence yearIncidenceExcluded casesIncluded casesIncluded cases
SexAge at cancer diagnosis
MalesFemales0 years1–4 years5–9 years10–14 years15–19 years
1964–197361724 (3.9%)593 (96.1%)313 (52.8%)280 (47.2%)39 (6.6%)149 (25.1%)112 (18.9%)116 (19.6%)177 (29.8%)
1974–19836358 (1.3%)627 (98.7%)366 (58.4%)261 (41.6%)33 (5.3%)173 (27.6%)141 (22.5%)123 (19.6%)157 (25.0%)
1984–199369113 (1.9%)678 (98.1%)394 (58.1%)284 (41.9%)32 (4.7%)178 (26.3%)128 (18.9%)131 (19.3%)209 (30.8%)
1994–200371516 (2.2%)699 (97.8%)394 (56.4%)305 (43.6%)36 (5.2%)162 (23.2%)100 (14.3%)150 (21.5%)251 (35.9%)
2004–201364111 (1.7%)630 (98.3%)328 (52.1%)302 (47.9%)34 (5.4%)145 (23.0%)96 (15.2%)115 (18.3%)240 (38.1%)
2014–202372012 (1.7%)708 (98.3%)387 (54.7%)321 (45.3%)53 (7.5%)157 (22.2%)126 (17.8%)135 (19.1%)237 (33.5%)

The number of patients included in survival analyses is further stratified by sex and by age at cancer diagnosis (with the proportion of cancer cases in parentheses). Source: Slovenian Cancer Registry.

3.3 Survival by cancer groups

Table 2 and Figure 2 show the observed and net survival for Slovenian children and adolescents diagnosed in six consecutive 10-years periods from 1964 to 2023. The observed five-year survival increased steadily from 30.8% (27.3–34.8%) in the period 1964–1973 to 87.8% (85.3–90.3%) in the period 2014–2023, with differences in the net survival of only between 0.0 and 0.2 percentage points. Even long-term survival increased substantially with the period the cancer was diagnosed in, for example, observed 35-year survival increased from 23.6% in 1964–1973 to 40.0% in 1974–1983 and 56.3% in 1984–1993, while on average the net survival is 1.5 percentage points higher. In general, the differences between the observed and net survival are very small, with a difference exceeding 1 percentage point for survival of 30 years or more. However, even at a survival of 55 years, the differences do not exceed 4 percentage points and the confidence intervals overlap, which is true also for analyses based on cancers in groups I, II and II (Supplementary Tables S1 – S3).

Observed and net survival with 95% confidence intervals by time of diagnosis for all cancers combined and for the three most common cancer groups according to the International Classification of Childhood Cancer (ICCC, 3rd edition), among Slovenian children and adolescents (age at diagnosis 0–19 years), 1964–2023. Source: Slovenian Cancer Registry.
Figure 2. Observed and net survival with 95% confidence intervals by time of diagnosis for all cancers combined and for the three most common cancer groups according to the International Classification of Childhood Cancer (ICCC, 3rd edition), among Slovenian children and adolescents (age at diagnosis 0–19 years), 1964–2023. Source: Slovenian Cancer Registry.

Table 2. Median survival time, observed and net survival with 95% confidence intervals (in parentheses), and the difference between them [expressed in percentage points (p.p.)], according to the decade in which the cancer was diagnosed, in Slovenian children and adolescents (age at diagnosis 0–19 years, and separately for age groups 0–14 and 15–19 years), 1964–2023.

Survival atAge1964–19731974–19831984–19931994–20032004–20132014–2023
Ob-servedNetDiffer-ence [p.p.]Ob-servedNetDiffer-ence [p.p.]Ob-servedNetDiffer-ence [p.p.]Ob-servedNetDiffer-ence [p.p.]Ob-servedNetDiffer-ence [p.p.]Ob-servedNetDiffer-ence [p.p.]
Median [years]0–191.2 [1.0–1.4]1.2 [1.0–1.4]0.04.3 [2.9–7.3]4.3 [2.9–7.7]0.0////////////
0–141.0 [0.8–1.2]1.0 [0.8–1.2]0.06.0 [3.5–26.8]6.0 [3.5–34.4]0.0////////////
15–192.1 [1.3–5.2]2.1 [1.3–5.2]0.02.1 [1.6–5.2]2.1 [1.6–5.2]0.0////////////
1-year [%]0–1953.4 [49.5–57.5]53.5 [49.6–57.6]0.172.3 [68.9–75.9]72.4 [69.0–76.0]0.185.8 [83.2–88.5]85.9 [83.3–88.5]0.190.1 [87.9–92.4]90.2 [88.0–92.4]0.192.4 [90.3–94.5]92.4 [90.4–94.5]0.093.5 [91.7–95.3]93.5 [91.7–95.4]0.0
0–1449.4 [44.8–54.4]49.5 [44.9–54.6]0.173.1 [69.2–77.2]73.2 [69.3–77.3]0.185.9 [82.8–89.1]86.0 [82.9–89.2]0.190.8 [88.2–93.6]90.9 [88.3–93.6]0.190.8 [87.9–93.7]90.8 [88.0–93.7]0.092.6 [90.2–95.0]92.6 [90.3–95.0]0.0
15–1962.7 [56.0–70.3]62.8 [56.1–70.3]0.170.0 [63.1–77.7]70.1 [63.2–77.7]0.185.6 [81.0–90.5]85.7 [81.1–90.6]0.188.8 [85.0–92.8]88.9 [85.1–92.9]0.195.0 [92.3–97.8]95.0 [92.3–97.8]0.095.4 [92.7–98.1]95.4 [92.8–98.1]0.0
3-year [%]0–1936.3 [32.6–40.3]36.4 [32.7–40.5]0.153.5 [49.7–57.6]53.6 [49.8–57.7]0.171.7 [68.4–75.2]71.9 [68.5–75.3]0.280.3 [77.4–83.3]80.4 [77.5–83.4]0.186.5 [83.9–89.2]86.6 [84.0–89.3]0.189.2 [86.9–91.6]89.3 [87.0–91.6]0.1
0–1432.0 [27.8–36.8]32.1 [27.9–36.9]0.156.3 [51.9–61.0]56.4 [52.1–61.1]0.171.5 [67.5–75.7]71.6 [67.6–75.8]0.181.2 [77.7–84.9]81.3 [77.8–85.0]0.185.1 [81.7–88.7]85.2 [81.7–88.8]0.188.2 [85.3–91.2]88.3 [85.4–91.3]0.1
15–1946.3 [39.5–54.3]46.5 [39.7–54.4]0.244.9 [37.7–53.6]45.0 [37.8–53.7]0.172.2 [66.4–78.6]72.5 [66.6–78.8]0.378.5 [73.6–83.7]78.7 [73.7–83.9]0.288.8 [84.8–92.8]88.9 [85.0–92.9]0.191.2 [87.6–95.0]91.3 [87.7–95.1]0.1
5-year [%]0–1930.8 [27.3–34.8]31.0 [27.5–35.0]0.249.1 [45.3–53.2]49.3 [45.5–53.4]0.267.4 [64.0–71.1]67.6 [64.2–71.3]0.277.1 [74.1–80.3]77.3 [74.2–80.5]0.284.3 [81.5–87.2]84.4 [81.6–87.3]0.187.8 [85.3–90.3]87.8 [85.4–90.4]0.0
0–1425.6 [21.8–30.2]25.8 [21.9–30.4]0.251.3 [47.0–56.1]51.5 [47.1–56.2]0.265.9 [61.7–70.3]66.0 [61.8–70.5]0.177.9 [74.2–81.8]78.0 [74.2–81.9]0.182.3 [78.6–86.2]82.4 [78.7–86.2]0.186.5 [83.4–89.8]86.6 [83.4–89.8]0.1
15–1942.9 [36.2–50.9]43.1 [36.4–51.1]0.242.3 [35.1–50.9]42.5 [35.3–51.1]0.270.8 [64.9–77.3]71.2 [65.3–77.6]0.475.7 [70.6–81.2]76.0 [70.8–81.5]0.387.5 [83.4–91.8]87.7 [83.6–92.0]0.290.2 [86.3–94.2]90.3 [86.5–94.3]0.1
10-year [%]0–1926.5 [23.2–30.3]26.8 [23.4–30.6]0.344.4 [40.6–48.5]44.6 [40.9–48.8]0.262.1 [58.5–65.8]62.4 [58.9–66.2]0.374.2 [71.1–77.6]74.6 [71.4–77.9]0.481.9 [79.0–85.0]82.1 [79.2–85.2]0.2
0–1422.2 [18.6–26.6]22.4 [18.7–26.8]0.247.2 [42.9–52.0]47.5 [43.1–52.3]0.360.7 [56.4–65.3]60.9 [56.7–65.6]0.275.0 [71.1–79.1]75.2 [71.3–79.3]0.280.3 [76.4–84.3]80.4 [76.5–84.4]0.1
15–1936.6 [30.1–44.5]37.0 [30.5–44.9]0.435.7 [28.8–44.2]36.0 [29.1–44.5]0.365.1 [58.9–71.9]65.7 [59.5–72.6]0.672.9 [67.6–78.6]73.4 [68.1–79.2]0.584.6 [80.1–89.3]84.9 [80.5–89.6]0.3
15-year [%]0–1925.8 [22.5–29.6]26.2 [22.9–30.0]0.443.9 [40.1–48.0]44.3 [40.5–48.4]0.460.6 [57.0–64.4]61.2 [57.5–65.0]0.673.0 [69.7–76.3]73.4 [70.2–76.8]0.481.4 [78.4–84.5]81.7 [78.7–84.8]0.3
0–1421.3 [17.6–25.6]21.5 [17.9–25.9]0.246.8 [42.5–51.5]47.2 [42.8–51.9]0.459.6 [55.3–64.3]60.0 [55.7–64.7]0.473.9 [69.9–78.1]74.1 [70.2–78.3]0.279.7 [75.8–83.8]79.9 [76.0–84.0]0.2
15–1936.6 [30.1–44.5]37.0 [30.5–44.9]0.435.0 [28.2–43.5]35.4 [28.5–43.9]0.462.7 [56.5–69.6]63.6 [57.3–70.6]0.971.3 [65.9–77.1]72.1 [66.6–77.9]0.884.1 [79.6–88.9]84.6 [80.1–89.4]0.5
20-year [%]0–1924.8 [21.6–28.6]25.4 [22.1–29.2]0.643.6 [39.8–47.7]44.2 [40.4–48.3]0.659.8 [56.2–63.6]60.6 [57.0–64.5]0.871.7 [68.4–75.1]72.3 [69.0–75.7]0.6
0–1420.3 [16.7–24.6]20.7 [17.1–25.1]0.446.4 [42.0–51.1]47.0 [42.6–51.8]0.658.8 [54.5–63.4]59.4 [55.0–64.1]0.673.2 [69.2–77.4]73.7 [69.7–77.9]0.5
15–1935.5 [29.1–43.3]36.3 [29.8–44.3]0.835.0 [28.2–43.5]35.4 [28.5–43.9]0.462.2 [56.0–69.1]63.2 [56.9–70.2]1.068.9 [63.4–74.9]69.8 [64.2–75.8]0.9
25-year [%]0–1924.6 [21.4–28.4]25.3 [21.9–29.1]0.742.7 [39.0–46.8]43.6 [39.8–47.8]0.959.4 [55.8–63.2]60.4 [56.8–64.3]1.071.0 [67.7–74.5]71.9 [68.6–75.4]0.9
0–1420.3 [16.7–24.6]20.7 [17.1–25.1]0.445.5 [41.2–50.3]46.4 [42.0–51.2]0.958.5 [54.2–63.2]59.2 [54.9–63.9]0.772.2 [68.1–76.5]72.8 [68.7–77.1]0.6
15–1934.9 [28.5–42.7]35.8 [29.3–43.8]0.934.4 [27.6–42.8]35.2 [28.3–43.8]0.861.2 [55.0–68.2]62.8 [56.4–69.9]1.668.9 [63.4–74.9]70.2 [64.6–76.3]1.3
30-year [%]0–1924.3 [21.1–28.0]25.3 [21.9–29.1]1.041.1 [37.4–45.2]42.3 [38.5–46.4]1.258.2 [54.6–62.0]59.5 [55.8–63.4]1.3
0–1420.0 [16.5–24.3]20.7 [17.1–25.1]0.744.2 [39.9–49.0]45.3 [40.9–50.2]1.157.5 [53.1–62.1]58.4 [54.0–63.2]0.9
15–1934.3 [28.0–42.1]35.9 [29.3–43.9]1.631.7 [25.1–40.1]32.9 [26.1–41.5]1.259.8 [53.5–66.8]61.8 [55.3–69.1]2.0
35-year [%]0–1923.6 [20.4–27.3]25.0 [21.6–28.9]1.440.0 [36.3–44.0]41.4 [37.6–45.6]1.456.3 [52.6–60.2]58.0 [54.2–62.0]1.7
0–1419.5 [16.1–23.8]20.4 [16.8–24.8]0.943.6 [39.3–48.3]44.9 [40.5–49.8]1.356.2 [51.9–61.0]57.5 [53.1–62.3]1.3
15–1933.2 [26.9–40.9]35.5 [28.8–43.8]2.329.1 [22.7–37.3]30.6 [23.9–39.2]1.556.1 [49.7–63.5]58.8 [52.0–66.4]2.7
40-year [%]0–1922.4 [19.3–26.1]24.3 [20.9–28.2]1.938.2 [34.5–42.2]39.9 [36.1–44.1]1.7
0–1418.6 [15.2–22.7]19.7 [16.1–24.1]1.141.6 [37.4–46.3]43.2 [38.8–48.1]1.6
15–1931.5 [25.3–39.1]34.8 [28.0–43.2]3.327.8 [21.5–35.9]29.5 [22.9–38.1]1.7
45-year [%]0–1921.1 [18.0–24.6]23.3 [20.0–27.3]2.236.4 [32.8–40.5]38.8 [34.9–43.1]2.4
0–1417.1 [13.8–21.2]18.5 [15.0–22.8]1.439.5 [35.3–44.3]41.6 [37.1–46.6]2.1
15–1930.3 [24.2–37.9]34.6 [27.7–43.3]4.327.1 [20.9–35.2]30.0 [23.1–39.0]2.9
50-year [%]0–1920.0 [17.0–23.5]22.7 [19.3–26.7]2.7
0–1416.6 [13.4–20.6]18.3 [14.7–22.7]1.7
15–1928.0 [22.1–35.5]32.8 [25.8–41.7]4.8
55-year [%]0–1918.1 [15.2–21.6]22.0 [18.4–26.3]3.9
0–1414.5 [11.4–18.5]16.6 [13.0–21.3]2.1
15–1926.7 [20.8–34.1]34.4 [26.8–44.2]7.7

Source: Slovenian Cancer Registry.

Group I (leukaemias, myeloproliferative disorders and myelodysplastic diseases) has lowest survival among all cancers for periods 1964–1973 and 1974–1984. However, it's survival also increased the most from 5-year survival of 6.4% (3.5–11.7%) in the period 1964–1973 to 89.0% (84.5–93.6%) in 2014–2023 (Supplementary Table S1); in all periods survival is leveled after 10 years of follow-up time, which is not so for other cancer groups. Since 1994, 5-year survival was above 80% for group II (lymphomas and reticuloendothelial neoplasms), being 98.8% (96.6–100%) in 2014–2023 (Supplementary Table S2). Survival of group III (central nervous system and miscellaneous intracranial and intraspinal neoplasms) has not improved so drastically as of children and adolescents diagnosed with other cancers, being the same for all periods 1984–1993, 1994–2003, 2004–2013, and 2014–2023; 5-year survival is around 60% (with exception of 52.9% in period 2014–2023) and 10-year survival around 55% (Supplementary Table S3).

In general, survival improved over time for all ICCC cancer groups (data not shown). Figure 3 shows one of the possible comparisons of improvement over time: 10-year net survival improved for all ICCC cancer groups except group VIII (malignant bone tumors), for which there was no change (calculated as arithmetic difference) in 10-year net survival between patients diagnosed 1964–1973 and those diagnosed in 2004–2013 (−0.1 percentage points). However, the 5-year net survival for group VIII has improved considerably in the last decade 2014–2023 (63.1% in 1964–1973; 77.2% in 2004–2013; 85.7% in 2014–2023), so we can reasonably expect an improvement in the 10-year survival rate for the last period as well. For ICCC cancer groups I, II, IV, V, VI, and X, the change in the 10-year net survival was more than 50 percentage points, while at the same time for groups V (number of patients in 2004–2013 was 15) and VI (number of patients in 2004–2013 was 21) the 10-year net survival for patients diagnosed in the period 2004–2013 was 100%. The survival for group XI (other malignant epithelial neoplasms and malignant melanomas) is also close to 100% (number of patients in 2004–2013 was 83), but the improvement from 1964 to 1973 is not as remarkable (27.3 percentage points) (Figure 3).

The 10-year net survival of Slovenian children and adolescents (age at diagnosis 0–19 years) diagnosed in 2004–2013 is plotted against the change in 10-year net survival between patients diagnosed in 1964–1973 and those diagnosed in 2004–2013 (the calculated arithmetic difference is expressed in percentage points), by cancer group according to the International Classification of Childhood Cancer (ICCC). The diameter of the outer circle is proportional to the number of cancer cases in 2004–2013. Source: Slovenian Cancer Registry.
Figure 3. The 10-year net survival of Slovenian children and adolescents (age at diagnosis 0–19 years) diagnosed in 2004–2013 is plotted against the change in 10-year net survival between patients diagnosed in 1964–1973 and those diagnosed in 2004–2013 (the calculated arithmetic difference is expressed in percentage points), by cancer group according to the International Classification of Childhood Cancer (ICCC). The diameter of the outer circle is proportional to the number of cancer cases in 2004–2013. Source: Slovenian Cancer Registry.

3.4 Survival by age groups

Figure 4 and Table 2 show the observed and net survival for Slovenian children and adolescents according to age group at the time of cancer diagnosis, with each line representing a 10-year period of cancer diagnosis. Observed and net survival are plotted together to highlight how similar the curves are, in contrast to the substantial differences in survival for adult cancers (12). The 5-year net survival in period 2014–2023 is worst for children diagnosed at the age of 1–4 years (83.6%, 95% CI is 77.8–89.9%) and best for adolescents diagnosed at the age of 15–19 years (90.2%, 95% CI is 86.3–94.2%). However, after a follow-up period of 30 years or more, the survival for those diagnosed at ages 5–19 years decreases, while the survival for ages 0 and 1–4 years remains the same. Adolescents diagnosed at ages 15–19 years in 1964–1973 and 1974–1983 have a very similar survival, which is not observed for other age groups.

Observed and net survival with 95% confidence intervals for children and adolescents diagnosed with cancer at ages 0, 1–4, 5–9, 10–14 and 15–19 years, Slovenia 1964–2023. Source: Slovenian Cancer Registry.
Figure 4. Observed and net survival with 95% confidence intervals for children and adolescents diagnosed with cancer at ages 0, 1–4, 5–9, 10–14 and 15–19 years, Slovenia 1964–2023. Source: Slovenian Cancer Registry.

4 Discussion

In the presented study, we estimated trends in survival among children and adolescents diagnosed with cancer in Slovenia over a 60-year period. For the first time, incidence and survival were analyzed based on the ICCC cancer groups.

4.1 Incidence

Over the last six decades, the incidence rates of childhood and adolescent cancers in Slovenia have increased, largely on account of increases in ICCC groups I, II, X, and XI. The early trends in the incidence of malignant bone tumor and soft tissue sarcoma are not reliable due to changes in classification between bone and soft tissue sarcomas or underreporting in the past (26). Incidence of group XII cancers has fallen to a very low level, largely due to improvements in cancer diagnostics and, to some extent, also improvements in cancer registration. The overall increase is in line with observations from other countries worldwide (27–31). While some of the increase may be due to improved registration and diagnostics, particularly for non-fatal cancers such as non-melanoma skin and thyroid cancer in group XI, a true increase in incidence is likely for other groups. The reasons behind the potential true increase are not well understood—changes in prenatal exposures, such as increased use of fertility or hormonal treatments (32, 33) or changes in patterns of childhood exposure to infections are often reported (34, 35).

4.2 Six decades of progress in survival

On the other hand, improvements in treatment have led to a significant overall improvement of survival of children and adolescents with cancer over the last 60 years. Cho et al. (36) argue that changes in survival must be interpreted in the context of incidence and mortality. In this sense, we considered the significant decrease in mortality (37) as evidence of the overwhelming progress in curing cancer in children and adolescents in Slovenia. Survival tends to be better for children aged 1–4 years compared to infants and children aged 5–9 years. Today, children aged 10–14 and adolescents aged 15–19 years have comparable survival to younger children, though some of the increase in survival for all cancers combined for this age group may be due to a larger share (and overdiagnosis) of cancer group XI, which is dominated by skin and thyroid cancers, which have a good prognosis and are highly curable. Our results are in line with other studies in which infants and older children have a lower survival for all cancers combined compared to the 1–4 year age group, primarily due to age-related differences in leukemia survival (1, 2, 38, 39).

4.3 Comparisons of survival with European data

Compared to the EUROCARE-6 pool for children, the observed 5-year survival is above average and is almost 85% in the period 2004–2013, which overlaps most with the most recent EUROCARE data (1). Looking at the three most common ICCC groups, the largest increase in observed 5-year survival is for leukaemias, at over 80 percentage points increase, meaning that a once fatal disease has become curable in the vast majority of cases and Slovenia compares favorably with other EUROCARE countries (40). The survival for lymphoma is almost 100%. Survival for malignant tumors of the central nervous system are generally among the worst of all ICCC groups, although survival vary across European countries, at least in part due to differences in registration practices that influence the distinction between malignant and non-malignant cases and the recording of both (41). In the last 40 years, the survival for malignant tumors of the central nervous system in Slovenia has not improved significantly and is around 60%, though it is above the pooled European average (1, 41). It should be noted that the results between different studies are not directly comparable, as different inclusion criteria (e.g., inclusion of benign tumors of the central nervous system in the calculation of survival) may have been used and/or different methods may have been applied, e.g., age standardization or survival calculation approach (12).

4.4 Observed vs. net survival

In this study, we were able to compare how the observed and the net survival correlate over a follow-up period of more than 50 years. The observed survival represents the probability of surviving all causes of death beyond the given follow-up time. In the real world, patients can die from any cause of death. The net survival, on the other hand, estimates the probability of survival in a hypothetical scenario in which the only cause of death is the disease under study. As cancer in children and adolescents is a rare disease (16) and mortality rates are generally low in high-income countries as well as in Slovenia (20), therefore we expected similar results for observed and net survival within a short follow-up time. However, we were able to show that even more than 30 years after cancer diagnosis, the differences between observed and net survival are very small and the confidence intervals overlap, suggesting that cancer and cancer-related late effects are the leading cause of death well into adulthood. Only after 30 years after diagnosis does the observed survival become a less reliable proxy for net survival in Slovenia. Based on this study, we conclude that in Slovenia the more difficult calculations of net survival in childhood and adolescent cancer are not necessary unless very long-term survival analyses are required.

4.5 Estimation of cure based on survival curves

In all age groups and all ICCC groups, the greatest decline in survival is observed in the first 3 years after diagnosis. Thereafter, the survival then decreases further up to 10 years after diagnosis and then levels off over a longer period of time. This suggests that mortality directly related to the cancer is no longer observed after this period and those affected can be considered cured of the cancer. For infants under 1 year of age and for group I cancers, the leveling off occurs even earlier, namely 5 years after diagnosis. For group III cancers, the plateau occurs later, around 15 years after diagnosis, which is due to the longer period during which the primary cancer affects mortality.

The plateau in observed and net survival ends after some time, particularly for certain cancers and age groups, generally around 30–35 years after diagnosis. This decline reflects premature mortality at older ages due to the late effects of cancer treatment. This does not appear to be the case with ICCC group I (leukaemias, myeloproliferative disorders and myelodysplastic diseases). This observation means that survivors of childhood and adolescent cancer do not (yet) have the same life expectancy compared to the general population, although they are cured of cancer in the strict sense according to the definition of cure in the Erice statement (42). Since this observation refers to earlier diagnosis periods when there was sufficient follow-up time to determine it, we do not know whether it also applies to the most recent periods. Standardized mortality ratios and cumulative mortality are also needed to quantify excess mortality in survivors. The large PanCareSurfUp study has shown that cumulative mortality has decreased substantially over time. Although excess mortality decreased over time since diagnosis due to a decline in deaths from the primary cancer, the standardized mortality ratio 60–69 years after diagnosis was still over two, mainly due to deaths from secondary malignancies and cardiovascular disease (43).

4.6 Implications for follow-up of survivors

Given that survival has improved significantly, the prevalence of survivors is increasing and with it the number of patients requiring follow-up treatment for late effects in adulthood (44). Even when the cancer itself is cured, the long-term net survival shows the burden of premature mortality due to late effects of cancer treatment in patients diagnosed several decades ago, confirming the need for lifelong surveillance. Long-term follow-up may indeed be a factor that, together with improvements in diagnostics, treatment regimes and overall health care, contributes to an ever-decreasing excess risk of death in survivors (2, 45).

However, in many parts of the world, the transition from pediatric to adult treatment is not systematically managed, resulting in adult survivors of childhood cancer not receiving the most appropriate treatment or being lost to follow-up (46, 47). The Late Effects Unit of the Institute of Oncology Ljubljana has been in operation since 1986 and follows all Slovenian survivors of childhood or adolescent cancer (17, 48). According to the data from the studies conducted so far, the majority of patients visiting the Late Effects Unit have at least one somatic late effect, while the risk of a second primary cancer is significantly higher among survivors compared to the general population (49–55). Although the long-term activity of the Late Effects Unit has undoubtedly contributed to improving the survival and quality of life of Slovenian cancer survivors (56), continuous research efforts are needed, as new therapies may lead to new (possibly previously unknown) late effects, which also need to be monitored (43).

4.7 Strengths and limitations

The main strength of this study lies in the long-term availability of high-quality, complete population-based cancer data. This allowed us to analyse survival trends over several decades, assess excess mortality up to 40 years after diagnosis, and compare observed survival with net survival estimates.

One limitation is that we did not include information on stage (for solid cancers) and treatment. Over the long time period, the stage migration could be an important source of bias (57). For many childhood malignancies, TNM-based systems that document the extent of disease at diagnosis are either inadequate or do not exist (58). Consensus guidelines for use by population cancer registries for staging childhood cancers (the Toronto Childhood Cancer Stage Guidelines) have been developed to facilitate the collection of internationally consistent and comparable information on childhood cancer stage at diagnosis (58) and were adopted by the SCR in 2020, meaning this information was not available for this study. Treatments for the period before 2019 are only recorded in the SCR as yes/no statements for the main modalities and are of limited use for survival analysis. Another limitation is the possibility of misclassification for very old cases. The ICD-O histology (18) required for ICCC grouping was unavailable for cases prior to 1983; therefore, we determined it retrospectively using cancer notification forms and other available patient documentation. This approach is prone to classification errors, as the current ICD-O system is much more detailed than the WHO codes used in the SCR prior to the introduction of ICD-O. However, apart from a possible misclassification between soft tissue and bone sarcomas in early cases, we are confident that the grouping into the main ICCC categories was accurate.

5 Conclusion

Population-based cancer survival in Slovenia has improved substantially over the past 60 years. Five-year survival among children and adolescents increased from approximately 30% in the earliest period to nearly 90% in recent years, matching outcomes reported in other high-income countries. This upward trend was observed across time periods, age groups, and most major ICCC diagnostic categories.

In all periods, the largest decline in survival occurred within the first five years after diagnosis, regardless of age or cancer group, indicating that early post-diagnosis mortality remains the most critical period. Beyond 10 years after diagnosis, survival curves for the most common childhood and adolescent cancers showed a marked plateau, suggesting that long-term survivors may be considered cured.

Despite this plateau, long-term follow-up of our cohort demonstrated that childhood and adolescent cancer survivors still experience excess late mortality compared with the general population. The data show increased risks of secondary malignancies and cardiovascular disease, consistent with known late effects of cancer treatment. As survival improves and more individuals reach long-term survivorship, these late-effect burdens become increasingly evident in population-level estimates.

These findings underscore the clinical importance of structured lifelong surveillance, particularly given the growing survivor population. The data also highlight the essential role of the Late Effects Unit in Slovenia in managing the long-term health of survivors, as well as the value of the Slovenian Cancer Registry in providing comprehensive and reliable longitudinal data that enable detailed survival and late-effect analyses.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcacs.2025.1676661/full#supplementary-material

Supplementary material Supplementary material at the source

Footnotes

Edited by: Petar Ozretić, Rudjer Boskovic Institute, Croatia

Reviewed by: Angelica Castro-Rios, Mexican Social Security Institute, Mexico

Fabienne Van Aelst, Scientific Institute of Public Health (Sciensano), Belgium

Statements

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author VZ declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This research was partially funded by the Slovenian research program for comprehensive cancer control – SLORApro by Slovenian Research and Innovation Agency (grant number ARIS P3-0429).

Data availability

The datasets presented in this article are not readily available because of data protection laws. Please address requests for additional explanations on the data sets to the corresponding author. Requests to access the datasets should be directed to Tina Žagar, tzagar@onko-i.si.

Author contributions

TŽ: Writing – original draft, Supervision, Validation, Conceptualization, Methodology, Writing – review & editing, Investigation. MB: Writing – original draft, Software, Formal analysis, Methodology. AM: Investigation, Writing – review & editing, Writing – original draft, Conceptualization. MJ: Software, Validation, Writing – original draft, Data curation. UT: Writing – review & editing, Resources. KL: Writing – review & editing, Conceptualization, Investigation, Resources. TO: Resources, Investigation, Conceptualization, Writing – review & editing. NB: Writing – review & editing, Visualization. ST: Writing – review & editing, Conceptualization. MM: Writing – review & editing, Data curation. VZ: Conceptualization, Supervision, Methodology, Writing – review & editing.

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Citation

Žagar, T., et al. (2026). Sixty years of population-based survival monitoring in childhood and adolescent cancer: evidence from Slovenia. Frontiers in Cancer Control and Society, Volume 3. https://doi.org/
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3 - 2026

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Copyright © 2026 Žagar, Birk, Mihor, Jurtela, Tomšič, Lokar, Oblak, Bric, Tomšič, Mlakar and Zadnik.

License: https://creativecommons.org/licenses/by/4.0/

*Correspondence: Tina Žagar

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