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Annals of Oncology Advance Access originally published online on July 28, 2007
Annals of Oncology 2007 18(9):1561-1568; doi:10.1093/annonc/mdm186
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© 2007 European Society for Medical Oncology

Up-to-date monitoring of childhood cancer long-term survival in Europe: methodology and application to all forms of cancer combined

Hermann Brenner1,*, Eva Steliarova-Foucher2 and Volker Arndt1

1 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
2 Data Analysis and Interpretation Group, International Agency for Research on Cancer, Lyon, France

* Correspondence to: Dr H. Brenner, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Bergheimer Strasse 20, D-69115 Heidelberg, Germany. Tel: +49-6221-548140; Fax: +49-6221-548142; E-mail: h.brenner{at}dkfz-heidelberg.de


   Abstract
Top
 Abstract
introduction
 methods
 results
 discussion
 Acknowledgements
 References
 
Background: The Automated Childhood Cancer Information System (ACCIS) provides a unique database for monitoring and comparing long-term prognosis of children with cancer in Europe. The ‘period’ method has been shown particularly useful for that purpose.

Patients and methods: The ACCIS database was used for comparative analyses of up-to-date long-term survival in four regions and 19 countries of Europe by period analysis. Overall, follow-up data on 49 503 children diagnosed between 1985 and the end of the 1990s were included. Period estimates of 10-year survival were derived for the 1995–99 period and compared with estimates obtained by cohort and complete analysis. In this article, the methodology is described and the approach is illustrated for all forms of childhood cancer combined.

Results: Long-term childhood cancer survival achieved in Europe by the end of the twentieth century is much higher than previous estimates indicated. The overall period estimate of 10-year survival was 71% for all countries combined, but it varied between 45% for Estonian children and 79% for Swedish and Finnish children with cancer.

Conclusion: Period analysis is the method of choice to monitor population-based survival. Despite major improvement during the past decades, tremendous variation in childhood cancer survival between European countries has persisted.

Key words: cancer registries, childhood cancer, Europe, population-based, prognosis, survival


   introduction
Top
 Abstract
 introduction
methods
 results
 discussion
 Acknowledgements
 References
 
Survival of childhood cancer patients has been improving steadily over the past decades, although large differences in the prognosis persist between European countries. In particular, lower population-based survival has been observed in the countries of Eastern Europe compared to other European countries [1–4]. Differences in survival of children with cancer were also found between Europe and the United States [5]. Socio-economic factors undoubtedly are responsible for at least part of the geographical differences observed [4]. The above studies referred to patients diagnosed up to 1989 [5], 1992 [1], 1994 [2] and 1997 [3, 4], and most often, 5-year survival estimates were compared. The ongoing progress in therapies for childhood cancers, and improving socio-economic conditions, may have resulted in further increase in survival since the publication of the most recent results. Parents of children with cancer, as well as professional communities, would certainly welcome if this extra improvement could be quantified as rapidly as possible, to deliver the good news.

It has been shown that the period method of survival analysis introduced a few years ago by Brenner and Gefeller [6] provides better up-to-date estimates of survival than the traditional cohort-based methods [7]. This has been evaluated empirically and confirmed [8] within the large database of the Automated Childhood Cancer Information System (ACCIS) [3], which contains currently the most up-dated information on childhood cancer follow-up on the European scale. In this article we describe how we have implemented the period-analysis methodology to the ACCIS database and how it may be used for up-to-date monitoring of 10-year survival of children with cancer in Europe. The approach is illustrated with survival analyses for all forms of childhood cancer combined. Our results thus supplement recent cohort-based analyses conducted within the ACCIS project [4]. Period survival for specific groups of childhood cancer is presented in subsequent articles in this journal [9–11].


   methods
Top
 Abstract
 introduction
 methods
results
 discussion
 Acknowledgements
 References
 
database
This analysis is based on the database of the Automated Childhood Cancer Information System (ACCIS), the September 2003 edition [3]. All cases of cancer diagnosed in children below age 15 years between 1985 and 1999, recorded in selected registries, were included in the analysis. Population-based cancer registries were selected only if they had submitted data with close to or entirely complete follow-up for vital status throughout a time window ranging from 1987 or earlier to 1997 or later.

The list of registries included in the analysis and the numbers of patients provided by these registries is given in Table 1. Overall, 49 503 patients contributed by 27 registries from 19 countries were included. About 44% of the patients were contributed by the nationwide German childhood cancer registry, the other patients were living in different countries from all regions of Europe. Four regions were defined for regional analyses: Eastern, Southern, Western and Northern regions. The population of the Northern region, composed in this study of Denmark, Finland, Iceland, Norway and Sweden, was covered completely. The Eastern region was represented by national registries of the Czech Republic, Estonia, Hungary and Slovakia, and a regional registry in Romania. The database for the Southern region included data from the national registries of Croatia and Slovenia, and a number of regional registries in Italy and Spain. The Western region was represented by the national paediatric cancer registry of Germany, and a number of regional registries in France, the Netherlands, Switzerland and the United Kingdom. The minimum number of patients per region was 4732 (South) and the maximum was 26 495 (West).


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  		Table 1. Registries, years of diagnosis, years of follow-up, and numbers of cases included in various analyses

 
For each case, information available included basic demographic data, description of tumour, dates of birth, diagnosis and last contact and the vital status at the date of last contact. Survival time in days was calculated centrally, based on the most exact available date of diagnosis and date of last contact for each patient. To ensure the maximum possible level of confidentiality, month and day of birth, diagnosis, last contact and death were then removed from the central data set used for analyses.

statistical methods
Period estimates of 10-year survival for the 1995–99 period were calculated from the survival experience in 1995–99 of patients diagnosed in 1985–99, as illustrated by the dashed black frame in Figure 1. With this approach, survival for the 1st year following diagnosis was estimated using data of patients diagnosed in 1994–99, conditional survival for the 2nd year following diagnosis was estimated using data of patients diagnosed in 1993–98, and so on, until conditional survival for the 10th year following diagnosis, which was estimated using data of patients diagnosed in 1985–90. These conditional survival probabilities were then multiplied to estimate 10-year cumulative survival. According to our empirical evaluation [8], this period estimate should come quite close to the actual 10-year survival experience of patients diagnosed in 1995–99, which will only be known with certainty after follow-up through the year 2009. For comparison, we also provide 10-year survival estimates obtained by traditional cohort analysis (pertaining to the survival experience in 1985–99 of patients diagnosed in 1985–89) and by traditional complete analysis (pertaining to the survival experience in 1985–99 of patients diagnosed in 1985–99), as shown in Figure 1 (solid black frame and grey frame, respectively). Regardless of the method described above, we present estimates of absolute survival rather than estimates of relative survival, as competing causes of death are rare among childhood cancer patients in Europe [12].


Figure 1
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  		Figure 1. Years of diagnosis and years of follow-up included in estimation of recent 10-year survival by cohort analysis (black solid frame), complete analysis (grey solid frame) and period analysis (black dashed frame).

 
All estimates were carried out with the SAS statistical software package, using a macro which can be employed for cohort, complete and period analysis, as previously described [13]. For period analysis, month of diagnosis, which had been removed from the central data set for confidentiality reasons, was imputed as ‘December’ for all cases, and month of end of follow-up was recalculated based on this imputed month and recorded survival time, as recommended after careful evaluation [14]. Standard errors of cumulative survival estimates were calculated according to Greenwood's method [15].

In this article, survival estimates are shown for all forms of childhood cancer combined by region, by country and by four major age groups (<1, 1–4, 5–9, 10–14 years). More detailed analyses for selected subgroups of childhood cancer using the same methodology are given in the subsequent articles in this journal.


   results
Top
 Abstract
 introduction
 methods
 results
discussion
 Acknowledgements
 References
 
Table 2 shows the numbers of patients by age and European region. Overall, 10% of children were below 1 year of age at the time of diagnosis, 37% were between 1 and 4 years of age, and about 27% of children were in each of the age groups 5–9 and 10–14 years. Although children from Eastern and Southern European countries were on average slightly older than children from other countries, the age distribution was quite similar for all four European regions, and therefore no age-adjustment was made in the region-specific survival analyses.


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  		Table 2. Numbers of patients included in various analyses by age group and regiona

 
As Figure 2 shows, 5-year and 10-year period survival estimates for the 1995–99 period, for all cancers and all countries combined, were about 75 and 71%, respectively. Both 5- and 10-year period survival estimates were approximately 4 and 8% units higher than the corresponding estimates obtained by complete analysis and cohort analysis, respectively.


Figure 2
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  		Figure 2. Survival of children with any form of cancer derived by cohort analysis for children diagnosed in 1985–89 (black solid curve), complete analysis for children diagnosed in 1985–99 (grey solid curve) and period analysis for the 1995–99 period (black dashed curve). Results are shown for all European regions and all age groups (0–14 years) combined.

 
Variation of survival by age is shown in Table 3 and Figure 3. Ten-year survival was higher in age group 1–4 than in the other age groups, irrespective of the method of the estimate. However, the differences between the age groups were most pronounced for the period estimates: 74% 10-year survival for age group 1–4 and 70% for the other age groups (5-year survival: 77 and 71–74%, respectively). In addition, the difference between the period estimate as compared to the other two estimates was larger in age group 1–4 than in the other age groups, which suggests a somewhat stronger recent improvement in survival for children diagnosed at the ages 1–4 years.


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  		Table 3. Estimates of 10-year survival with standard errors (SE) by region and age for children with any form of cancer derived by cohort analysis, complete analysis and period analysis; total numbers of children included in various analyses are shown in Table 1 and Table 2

 

Figure 3
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  		Figure 3. Survival by age of children with any form of cancer derived by cohort analysis for children diagnosed in 1985–89 (black solid curve), complete analysis for children diagnosed in 1985–99 (grey solid curve) and period analysis for the 1995–99 period (black dashed curve). Results are shown for all European regions combined.

 
The variation of survival between European regions is shown in Table 3 and Figure 4. According to period analysis, 10-year survival for all forms of childhood cancer combined was 76% in Northern Europe, 74% in Western Europe, 69% in Southern Europe and 59% in Eastern Europe (5-year survival: 79, 78, 72, and 63%, respectively). The estimates obtained by the other two methods showed the same ranking of regions, but were again substantially lower than the period estimates in all regions. The differences according to the method of survival analysis were largest for the East, followed by North, West and South. The larger this difference, the stronger improvement in the 1990s may be assumed. Standard errors (SEs) of 10-year survival estimates were similar for cohort and period analysis (between 0.6 and 1.2% for each of the four regions), and somewhat lower for complete analysis (between 0.4 and 0.8%) (Table 3).


Figure 4
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  		Figure 4. Survival by European region of children with any form of cancer derived by cohort analysis for children diagnosed in 1985–89 (black solid curve), complete analysis for children diagnosed in 1985–99 (grey solid curve) and period analysis for the 1995–99 period (black dashed curve). Results are shown for all age groups (0–14 years) combined.

 
Figure 5 shows the 1995–99 period estimates of 10-year survival by single countries, based on the data available from the registries shown in Table 1. To ensure adequate precision, only countries where the estimates were based on more than 300 children are included. Ten-year survival rates were lower in all countries from the Eastern region than in other countries, although for some countries, there was an overlap of confidence intervals with those for countries in other regions. In general, within all regions there was a considerable variability of 10-year survival between individual countries. The region-specific estimates are therefore not necessarily representative of every single country or a region within the country.


Figure 5
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  		Figure 5. Period estimates of 10-year survival for the 1995–99 period (with 95% confidence intervals as line sections) by country for children with any form of cancer. The national estimates are based on the data from the cancer registries (listed in Table 1) providing at least 300 cases for the analyses. Various factors may influence the differences in survival shown, including variable access to effective medical care, differences in the registration practices and classification of tumours [20]. Results are shown for all age groups (0–14 years) combined.

 

   discussion
Top
 Abstract
 introduction
 methods
 results
 discussion
Acknowledgements
 References
 
This is the first comprehensive period analysis of long-term survival of children with cancer on the European scale. Applying this approach to data of 27 registries from 19 European countries included in the ACCIS database, an overall estimate of 10-year survival of 71% was obtained for the 1995–99 period. This estimate was substantially higher than the most up-to-date estimates of 10-year survival that were obtained from the same database by traditional cohort or complete survival analysis. This pattern suggests that there has been ongoing improvement in long-term prognosis in the past decade, which has so far remained undisclosed by traditional methods of survival analysis. Furthermore, period analysis for the 1995–99 period suggests that major variation in survival between various European countries and regions persists despite major improvements in all parts of Europe during the past decade.

Despite being more up-to-date than traditional methods of survival analysis, even the period estimates of 10-year survival might somewhat underestimate the 10-year survival to be expected for patients diagnosed in 1995–99, as suggested by our preceding evaluation of the methodology [8]. Also, there may have been further improvement since 1999, which was not possible to disclose from the existing database even with period analysis. To overcome this limitation, more up-to-date collection of data, both on the registry level and on the European leve, should be aimed for, along with the implementation of period-analysis methodology for further investigations. Nevertheless, with the data available, the period survival estimates are substantially more up-to-date and higher than previously available survival statistics for Europe, which were mostly confined to 5-year survival of children diagnosed in the 1980s or the early or middle 1990s [1–5].

Period estimates of survival have so far been published only for selected forms of childhood cancer in Germany, the United States and Italy [16–19]. The 10-year period estimate of survival for the 1995–99 period for all forms of childhood cancer in the United States was 75.2%, which is very similar to the corresponding estimates for children from Western and Northern European regions obtained in the current study.

The European estimate of 10-year survival obtained in this analysis reflects the selection of registries for this analysis according to pre-defined criteria. Due to limited data availability, the representation of Europe as a whole, the four European regions and some countries (represented by regional cancer registries) is not ideal. With its nationwide coverage of children in Germany, the German paediatric cancer registry contributed more than 40% of the cases included in this analysis. The overall estimates of 10-year survival for Europe, and even more so for the Western region, are therefore heavily influenced by the prognosis of children from this large country (see Table 1). Our overall survival estimates cannot therefore be considered representative of Europe as a whole. However, with the relatively large European coverage, they are indicative of European patterns, while emphasizing variations among different regions and countries of Europe.

In this study, based on routinely collected data from population-based cancer registries, data are lacking on prognostic indicators and treatment. Beside treatment protocols, these may include, for example, ease and rapidity of access to diagnosis or well-designed referral system [20]. It would be desirable in the future to include prognostic factors in the data-collection protocol, such as delay between diagnosis and treatment, inclusion in clinical trials, stage at diagnosis and possibly the initial treatment. However, in large population-based cancer registries this information may be difficult to obtain systematically. Despite the absence of pertinent information, different access (or lack thereof) to effective medical care is the most plausible main determinant of the large survival differences between European regions.

These differences should be subjected to further close monitoring. Whereas the 10-year survival estimate for the 1995–99 period ranged between 68.5 and 76.0% for all other European regions, it remained under 60% for the Eastern region. On the other hand, the differences between estimates of 10-year survival obtained by period analysis and by cohort-based analyses are somewhat larger for the Eastern European region, suggesting that the improvement in survival in the last decade has been somewhat more pronounced in this than the other regions.

Differences in 10-year survival between individual countries are even more striking, with 1995–99 period estimates ranging from 45% for children in Estonia to 79% for children in Finland and Sweden. Although some of this imbalance could have been caused by differences in the registration and coding practices, as well as completeness of follow-up, the tremendous differences in survival again essentially point to the role of different access (or lack thereof) to effective medical care [20]. Our analyses add further support to the need for improved access to modern therapy in all parts of Europe. While equal access to modern therapy remains a major goal to be aimed at by the European community in the years to come, the period-analysis approach described in this paper offers a useful tool to monitor progress towards this end. The usefulness of the ACCIS database would be further enhanced by its extension, both in time and geographical coverage of Europe.


   Acknowledgements
Top
 Abstract
 introduction
 methods
 results
 discussion
 Acknowledgements
References
 
This project was funded by the European Commission from the Europe Against Cancer programme (contract SPC.2002303), jointly with the International Agency for Research on Cancer. Eva Steliarova-Foucher was partly supported by the Cancéropôle Lyon Auvergne Rhône Alpes and the Federal Ministry of Health of the Federal German Government. The authors are grateful to the following registries participating in ACCIS for their contribution to this study: Croatia: Croatian National Cancer Registry; Czech Republic: Czech Cancer Registry; Denmark: Danish Cancer Society; Estonia: Estonian Cancer Registry; Finland: Finnish Cancer Registry; France: Childhood Cancer Registry of Lorraine and the Association of Childhood Cancer Registries of the Rhone-Alps Region; Germany: German Childhood Cancer Registry; Hungary: Hungarian Paediatric Cancer Registry; Iceland: Icelandic Cancer Registry Italy: Cancer Registry of Latina Province, Lombardy Cancer Registry, Childhood Cancer Registry of Piedmont, Ragusa Cancer Registry and Tuscany Cancer Registry; Netherlands: Eindhoven Cancer Registry of Comprehensive Cancer Centre South; Norway: Cancer Registry of Norway; Romania: Territorial Cancer Registry of Bihor County; Slovakia: National Cancer Registry of Slovakia; Slovenia: Cancer Registry of Slovenia; Spain: Asturias Cancer Registry, Granada Cancer Registry and Tarragona Cancer Registry; Sweden: Swedish Cancer Registry; Switzerland: Basel Cancer Registry, Geneva Cancer Registry; United Kingdom: Scottish Cancer Registry.

Received for publication November 17, 2006. Revision received April 4, 2007. Accepted for publication April 11, 2007.


   References
Top
 Abstract
 introduction
 methods
 results
 discussion
 Acknowledgements
 References
 
1. Capocaccia R, Gatta G, Magnani C, et al. Childhood cancer survival in Europe 1978–1992: the EUROCARE study. Eur J Cancer (2001) 37:671–816.[CrossRef][Web of Science][Medline]

2. Gatta G, Corazziari I, Magnani C, et al. Childhood cancer survival in Europe. Ann Oncol (2003) 14(Suppl 5):V119–V127.[CrossRef][Medline]

3. Steliarova-Foucher E, Stiller C, Kaatsch P, et al. Geographical patterns and time trends of cancer incidence and survival among children and adolescents in Europe since the 1970s (the ACCIS project): an epidemiological study. Lancet (2004) 364:2097–2105.[CrossRef][Web of Science][Medline]

4. Steliarova-Foucher E, Coebergh JW, Kaatsch P, et al. Cancer in children and adolescents in Europe. Eur J Cancer (2006) 42:1913–2183.[CrossRef][Web of Science]

5. Gatta G, Capocaccia R, Coleman MP, et al. Childhood cancer survival in Europe and the United States. Cancer (2002) 95:1767–1772.[CrossRef][Web of Science][Medline]

6. Brenner H, Gefeller O. An alternative approach to monitoring cancer patient survival. Cancer (1996) 78:2004–2010.[CrossRef][Web of Science][Medline]

7. Brenner H. Up-to-date survival curves of children with cancer by period analysis. Brit J Cancer (2003) 88:1693–1697.[CrossRef][Web of Science][Medline]

8. Steliarova-Foucher E, Arndt V, Parkin DM, et al. Timely disclosure of progress in childhood cancer survival by period analysis: experience from the Automated Childhood Cancer Information System. Ann Oncol (2007) 18:1554–1560.[Abstract/Free Full Text]

9. Brenner H, Coebergh JW, Parkin DM, et al. Up-to-date monitoring of childhood cancer long-term survival in Europe: Leukaemias and lymphomas. Ann Oncol (2007) 18:1569–1578.[Abstract/Free Full Text]

10. Arndt V, Kaatsch P, Steliarova-Foucher E, et al. Up-to-date monitoring of childhood cancer long-term survival in Europe: Central nervous system tumours. In: Ann Oncol. (in press).

11. Arndt V, Lacour B, Steliarova-Foucher E, et al. Up-to-date monitoring of childhood cancer long-term survival in Europe: Tumours of the sympathetic nervous system, retinoblastoma, renal and bone tumours and soft tissue sarcomas. In: Ann Oncol. (in press).

12. Sankila R, Martos Jimenez MC, Miljus D, et al. Geographical comparison of cancer survival in European children (1988–1997): Report from the Automated Childhood Cancer Information System project. Eur J Cancer (2006) 42:1972–1980.[CrossRef][Web of Science][Medline]

13. Brenner H, Gefeller O, Hakulinen T. A computer program for period analysis of survival. Eur J Cancer (2002) 38:690–695.[CrossRef][Web of Science][Medline]

14. Brenner H, Arndt V. Period analysis of cancer patient survival in datasets from which month of diagnosis has been removed. Eur J Cancer (2005) 41:438–444.[CrossRef][Web of Science][Medline]

15. Greenwood M. A report on the natural duration of cancer. (1926) London: Ministry of Health, His Majesty's Stationery Office.

16. Brenner H, Kaatsch P, Burkhardt-Hammer T, et al. Long-term survival of children with leukemia achieved by the end of the second millennium. Cancer (2001) 92:1977–1983.[CrossRef][Web of Science][Medline]

17. Burkhardt-Hammer T, Spix C, Brenner H, et al. Long-term survival of children with neuroblastoma prior to the neuroblastoma screening project in Germany. Med Pediatr Oncol (2002) 39:156–162.[CrossRef][Web of Science][Medline]

18. Brenner H. Up-to-date survival curves of children with cancer by period analysis. Brit J Cancer (2003) 88:1693–1697.[CrossRef][Web of Science][Medline]

19. Zuccolo L, Dama E, Maule MM, et al. Updating long-term childhood cancer survival trend with period and mixed analysis: good news from population-based estimates in Italy. Eur J Cancer (2006) 42:1135–1142.[CrossRef][Web of Science][Medline]

20. Pritchard Jones K, Kaatsch P, Steliarova-Foucher E, et al. Cancer in children and adolescents in Europe: Developments over 20 years and future challenges. Eur J Cancer (2006) 42:2183–2190.[CrossRef][Web of Science][Medline]


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