Cancer Epidemiology
Volume 36, Issue 1 , Pages 11-15, February 2012

Time trends in testicular cancer in Croatia 1983–2007: Rapid increases in incidence, no declines in mortality

  • Nino Sincic

      Affiliations

    • Laboratory for Epigenetics and Molecular Medicine, Department of Medical Biology, University of Zagreb Medical School, Zagreb, Croatia
    • ,
  • Tomislav Kulis

      Affiliations

    • Department of Urology, University Hospital Centre Zagreb, Zagreb, Croatia
    • ,
  • Ariana Znaor

      Affiliations

    • Croatian National Cancer Registry, Croatian National Institute of Public Health, Zagreb, Croatia
    • Andrija Stampar School of Public Health, University of Zagreb Medical School, Zagreb, Croatia
    • Corresponding Author InformationCorresponding author at: Croatian National Cancer Registry, Rockefellerova 7, 10000 Zagreb, Croatia. Tel.: +385 1 486 32 80; fax: +385 1 486 32 71.
    • ,
  • Freddie Bray

      Affiliations

    • Section of Cancer Information, International Agency for Research on Cancer, Lyon, France

Received 14 April 2011; received in revised form 22 September 2011; accepted 27 September 2011. published online 10 October 2011.

Article Outline

Abstract 

Testicular cancer, although a rare malignancy, represents the most common cancer in young male populations of Western origin. While increasing incidence trends of testicular cancer have been reported, mortality is declining in many high-resource settings. Using national data from the Croatian National Cancer Registry for the period 1983–2007, time trends were analysed by joinpoint regression and Age–Period–Cohort models. The present study is the first to analyse the testicular cancer trends in the Croatian population. Over the 25-year period, a mean number of 89 incident cases and 13 deaths were reported annually. The observed mean annual increases in age-standardised rates were 7.0% for incidence and 1.6% for mortality, with no abrupt linear changes (joinpoints) identified. The incidence rates of testicular cancer incidence have been steeply increasing in successive cohorts born since the mid-1930s. The rapid rise in testicular cancer incidence in the Croatian population appears to be one of the highest rates of increase recorded in Europe and worldwide. The lack of decline in the mortality rates over time, while based on relatively few deaths, highlights a need for improvements in diagnostics and management of therapy in Croatia in order to improve the survival and quality-of-life of testicular cancer patients.

Abbreviations: APC, age–period–cohort, EAPC, estimated annual percent change

Keywords: Testicular cancer, Incidence, Mortality, Time trends, Croatia

 

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1. Introduction 

While testicular cancers account for less than 1% of all diagnosed cancers in men worldwide, in many high-resource settings it is the most common cancer in young men in their twenties and thirties [1], [2], [3], [4], [5]. There is a multi-fold variation in the age-standardised (World) incidence rates globally, from 12.1/100,000 in Norway to less than 0.3/100,000 in many African countries, and levels of risk diverge by race and ethnicity within homogeneous populations [1], [6], [7]. Testicular cancer incidence rates have been uniformly increasing over the second half of the 20th century in many industrialised populations, with the most steep and consistent increases described among populations with European ancestry [2], [3].

Despite progress in understanding the underlying genetics and epigenetics, the aetiology of testicular cancer remains poorly understood [3], [8], [9], [10], [11], [12], [13], [14], [15]. Nonetheless, the best-practice tumour management and advances in treatment, such as the introduction of cisplatinum-based therapies in the 1970s, have resulted in large declines in testicular cancer mortality in most European countries [3], [16], [17]. Today, testicular cancer survival can exceed 95% [18], [19], but is lower in several lower-resource European settings. In Croatia, the lack of a significant decline in mortality may be a marker of inferior survival in comparison to the European pooled average [3].

The aim of this study is to present the national trends in testicular cancer in Croatia 1983–2007 to better understand the incidence trends in comparison with other populations, and to assess the extent to which the decreasing mortality trends observed elsewhere are observed in Croatia.

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2. Materials and methods 

2.1. Data sources 

Incidence data for the period 1983–2007 were obtained from the Croatian National Cancer Registry. The Registry, founded in 1959, covers the whole Croatian population (approximately 4.4 million persons), and relies on mandatory cancer notifications from both primary and secondary health care sources, death certificates from the Croatian Bureau of Statistics, as well as hospital discharge data files (since 1999). The Registry has contributed data to the last three volumes of the Cancer Incidence in Five Continents series [20], [21], [22]. The numbers of testicular cancer deaths and population estimates were obtained from the Croatian Bureau of Statistics.

2.2. Statistical analysis 

Age-standardised rates (per 100,000 person-years at risk) of cancer incidence and mortality in Croatia were calculated by the direct standardisation method, using the World standard population as a reference [23], [24]. To describe incidence and mortality trends by calendar period, we carried out joinpoint regression analysis using the Joinpoint Regression Software [25]. The aim of the approach is to identify possible “joinpoints” where a significant change in the log-linear trend occurs. To obtain the estimated annual percent change (EAPC), a regression line was fitted to the natural logarithm of the rates using calendar year as the response [26]. Due to computational difficulties in dealing with small numbers, we restricted the analysis to the age group 15–54.

Birth cohorts were obtained on subtracting the midpoints of five-year age groups (15–19, 20–24, …, 50–54) from the corresponding five-year periods, and trends in incidence rates versus birth cohort and period by age were plotted using a semi-log scale. Age–period–cohort (APC) models were fitted and the relative contribution of each effect in the hierarchy of models [27], [28] was determined on comparing the change in the likelihood and degrees of freedom in two sequentially fitted models with the appropriate x2 statistic.

The non-identifiability inherent in APC analyses – knowledge of the values of any two of age, period and cohort implies knowledge of the third, making one of the factors redundant – was highlighted by equating the first and last effects of period to zero. While the solution is somewhat arbitrary, the substantial contribution of cohort influences in explaining testicular cancer incidence trends has been consistently demonstrated in previous reports [3], [29], [30], likely due to the changing prevalence and distribution of (largely unknown) factors that act early in life and impact on the rates in successive generations. Due to small numbers of deaths, mortality rates were not analysed using APC analysis.

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3. Results 

3.1. Overall trends in incidence and mortality 1983–2007 

In the 25-year period, 2232 cases of newly diagnosed testicular cancers were registered, thus representing 1% of the male cancer incidence in Croatia. Of all reported testicular cancers, 89.7% occurred in men aged 15–54. The significantly increasing incidence trend of 7.0% (95% CI: 5.7–8.2%) per annum in this age group was rather uniform over time since no additional joinpoints were identified (Fig. 1, Table 1). Over the analysed period, 316 men died of testicular cancer. The truncated age-standardised mortality rates varied between 0.08 per 100,000 and 1.08 per 100,000. A non-significant increase in mortality was observed with an EAPC of 1.6% (95% CI: −0.3 to 3.5), with no joinpoints identified (Fig. 1, Table 1). In terms of testicular cancer mortality, while the annual number of deaths is small relative to incidence, the number increased to an average of 10 per year during the period 2003–2007.

Table 1. Testicular cancer incidence and mortality in Croatia, ages 15–54 (1983–1987 and 2003–2007).
PeriodPerson–yearsaIncidenceMortality
CasesbASRcEAPC 1983–2007DeathsdASRcEAPC 1983–2007
1983–19871.35443.1 80.5
2003–20071.2513411.27.0%100.81.6%

aMean annual male population in age group 15–54 expressed in million person-years at risk.

bMean annual number of incidence cases in age group 15–54.

cTruncated (ages 15–54) age-standardised rate (using World standard) per 100,000 person-years at risk.

dMean annual number of deaths in age group 15–54.

3.2. Incidence trends by birth cohort 1933–1988 

The results are presented using the full APC model, which provided the best fit to the incidence data (Table 2). When the age-specific incidence trends were graphically examined, steep increases of testicular cancer incidence rates were observed in successive generations born since the mid-1930s in all age-groups (Fig. 2). This birth cohort effect was confirmed by the estimated cohort parameters from the full APC model. The incidence rate ratios estimated for each birth cohort are shown in Fig. 3. The lowest risk was observed for the birth cohort 1938, after which the cohort-specific risks uniformly increased. The risk of testicular cancer occurrence in the youngest cohort (born in the decade around 1988), was almost six-fold higher than the referent cohort born around 1963.

Table 2. Goodness-of-fit statistics for best fitting APC model.
x2d.f.p-Value
Age528.832<0.01
Age–drift79.631<0.01
Age–period53.628<0.01
Age–cohort51.721<0.01
Age–period–cohort30.0180.04

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4. Discussion 

The present study is the first to systematically analyse the testicular cancer incidence and mortality trends in the Croatian population. We chose to present the results restricted to the age group 15–54 since for testicular germ cell cancer, most incident cases occur in this age range, and an analysis that focuses the investigation on such a restricted age group has been proposed [31]. A joinpoint analysis of age-standardised rates for all ages, yielded similar results: a 6.1% annual increase in incidence, and 1.3% annual increase in mortality over the analysed period.

According to GLOBOCAN 2008, Croatian males now have a relatively high incidence rate compared to other European countries. The age-adjusted rates were comparable with those estimated in Northern Europe, which, alongside several countries in Western Europe, retain the highest testicular cancer incidence rates in Europe and worldwide.

The incidence rate in Croatia of around 7/100,000 for all ages is lower than that of Slovenia (10/100,000), though higher than in several neighbouring countries e.g., Bosnia and Herzegovina, Serbia and Montenegro (rates of around 2–5/100,000). In the region around the Adriatic Sea only in adjacent Italy is the incidence rate similar (6/100,000) [1]. Regardless of common ancestry and societal factors between countries, differences in the population structure, specific lifestyle, environmental and socioeconomic determinants likely contribute to the variations in the rates via differentials in the prevalence and distribution of the specific factors involved in testicular cancer development in the region.

There are evidently caveats in interpreting this descriptive data; estimates for most countries surrounding Croatia are not based on population-based cancer registry data, and should therefore be interpreted with caution. To enable more accurate comparisons, a selective expansion of coverage by high quality registration together with more extensive epidemiological data on testicular cancer within the region would further elucidate the observed variations.

After a continuous increase over a several decades, data from several cancer registries in Europe and the U.S. suggest that testicular cancer incidence rates may have levelled off or even shown signs of decline in certain populations during the 1990s [2], [4], [5], [32], [33]. Our temporal data showed no such effect in the Croatian male population. Testicular cancer incidence was steadily increasing with no statistically significant change in the trend over the analysed 25-year period. The average rise in incidence per year of 7% is higher than reported for other European countries, e.g., Italy (with similar age-adjusted rates), in the Nordic countries, as well as high-resource countries outside of Europe including Australia, the U.S., Israel and Japan [3], [4], [7], [34]. The observed strong birth cohort effect is consistent with reports from other countries [3], [29], [30].

The increasing trend for testicular cancer incidence in the Croatian male population appears to be among the highest observed in Europe and worldwide [2], with only trends in neighbouring Slovenia and Spain of the same order of magnitude [3]. This prominent increase in testicular cancer incidence in Croatia is unlikely to be a consequence of misclassification with other cancers considering for this age group, testicular germ cell tumours are histologically well-characterised [7], having cardinal clinical presentation features and rapidly progress without spontaneous regression [35]. An increase in completeness of registration over time could also artificially inflate the magnitude of the incidence trend. We do not think, however, that the observed trend in Croatia was affected by such artefacts, as similar uniform increases in incidence are not observed for other urological cancers reported from within the same departments, and data quality indicators are not suggestive of systematic increases of completeness over the period of study. Some authors [2], [36] have suggested that improvements in the diagnostic approaches may have contributed to the increasing incidence rates observed. This is unlikely the case in Croatia since diagnostic practices have not changed dramatically over the study period. The trends cannot be linked to enhancement in population awareness of testicular cancer and its symptoms such as self-examination, since there are no education or prevention programmes implemented thus far in Croatia. Unfortunately, there are few epidemiological studies correlating changing environmental, socioeconomic or epigenetic associations with the increasing testicular cancer trends in Croatia, or elsewhere.

In contrast to incidence, testicular cancer mortality has been in decline in most high-resource countries [3], [16], [37]. Improvements in patient management, the development of chemotherapy regimens based on cisplatinum, and advances in surgical techniques of retroperitoneal lymph node dissection have lead to curative rates of testicular cancer above 95% [18]. Even in lower-resource settings, the mortality rates, being based on few deaths, are relatively low (e.g., 0.6/100,000 for Central and Eastern Europe) [1], which limits the analysis of mortality trends in small populations, such as that of Croatia. In their report on testicular cancer incidence and mortality trends in 22 European countries, Bray et al. [3] observed declines in testicular cancer mortality of 3–6% per annum in the 1980s and 1990s for most of the countries studied. In the same study, Croatia and Portugal were identified as the only two countries with non-significant increases in testicular cancer mortality. The reported estimated EAPC for Croatia for 1986–2000 in the age group 15–54 was 4.4% (95% CI: −0.3 to 10.0%) [3]. In the present analysis, including ten additional years of mortality data, the observed EAPC was lower, although the relatively small number of deaths increased to an average of 10 per year circa 2005. Marked increases in testicular cancer incidence, accompanied by modest non-significant increases in mortality, and a widening gap between incidence and mortality suggest a continuous but modest improvement in testicular cancer survival in Croatia. With ongoing changes to testicular cancer management – including adjustments to the patient referral system and increased organization of multidisciplinary specialist treatment centres – it is possible to expect declines in testicular cancer mortality in Croatia in subsequent years [38], [39].

Insight into the current testicular cancer burden and trends over time are noteworthy from the perspective of scientific research, health planning and clinical practice, but should be recognized also in a socioeconomic context. Testicular cancers are a cause of morbidity in adolescent and young adult males, a group that represent a highly active population in terms of their contribution to the workforce and to reproduction. In this study we report that Croatian male population has one of the highest testicular cancer incidence rates in the region and possibly the steepest increase in incidence reported to date. An improvement in diagnostics and management of therapy in Croatia would almost certainly contribute to improving survival and quality-of-life of testicular cancer patients. Ideally, future epidemiological studies would be able to contribute both to the understanding of increases in incidence and testicular carcinogenesis, but also serve as a platform for the establishment of prevention strategies to alleviate the increasing testicular cancer burden in Croatia, as in many other countries where rates have historically been rather low.

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Conflict of interest statement 

None declared.

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Acknowledgments 

We wish to thank the Croatian National Cancer Registry staff for their work in producing cancer incidence data. The study was partly supported by the Croatian Ministry of Science, Education and Sports grant no. 005-1080315-0294.

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References 

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008, cancer incidence and mortality worldwide: IARC CancerBase no. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010;Available from: http://globocaniarcfr
  2. Purdue MP, Devesa SS, Sigurdson AJ, McGlynn KA. International patterns and trends in testis cancer incidence. Int J Cancer. 2005;115(5):822–827
  3. Bray F, Richiardi L, Ekbom A, Pukkala E, Cuninkova M, Moller H. Trends in testicular cancer incidence and mortality in 22 European countries: continuing increases in incidence and declines in mortality. Int J Cancer. 2006;118(12):3099–3111
  4. Holmes L, Escalante C, Garrison O, Foldi BX, Ogungbade GO, Essien EJ, et al. Testicular cancer incidence trends in the USA (1975–2004): plateau or shifting racial paradigm?. Public Health. 2008;122(9):862–872
  5. McGlynn KA, Devesa SS, Sigurdson AJ, Brown LM, Tsao L, Tarone RE. Trends in the incidence of testicular germ cell tumors in the United States. Cancer. 2003;97(1):63–70
  6. Matsuda T, Saika K. Comparison of time trends in testicular cancer incidence (1973–97) in East Asia, Europe and USA, from cancer incidence in five continents, vols. IV–VIII. Jpn J Clin Oncol. 2008;38(8):578–579
  7. Baade P, Carriere P, Fritschi L. Trends in testicular germ cell cancer incidence in Australia. Cancer Causes Control. 2008;19(10):1043–1049
  8. Garner MJ, Turner MC, Ghadirian P, Krewski D. Epidemiology of testicular cancer: an overview. Int J Cancer. 2005;116(3):331–339
  9. Lind GE, Skotheim RI, Lothe RA. The epigenome of testicular germ cell tumors. APMIS. 2007;115(10):1147–1160
  10. Schulz WA, Hoffmann MJ. Transcription factor networks in embryonic stem cells and testicular cancer and the definition of epigenetics. Epigenetics. 2007;2(1):37–42
  11. Korkola JE, Heck S, Olshen AB, Reuter VE, Bosl GJ, Houldsworth J, et al. In vivo differentiation and genomic evolution in adult male germ cell tumors. Genes Chromosomes Cancer. 2008;47(1):43–55
  12. Walsh TJ, Croughan MS, Schembri M, Chan JM, Turek PJ. Increased risk of testicular germ cell cancer among infertile men. Arch Intern Med. 2009;169(4):351–356
  13. Weir HK, Marrett LD, Kreiger N, Darlington GA, Sugar L. Pre-natal and peri-natal exposures and risk of testicular germ-cell cancer. Int J Cancer. 2000;87(3):438–443
  14. Cook MB, Akre O, Forman D, Madigan MP, Richiardi L, McGlynn KA. A systematic review and meta-analysis of perinatal variables in relation to the risk of testicular cancer – experiences of the mother. Int J Epidemiol. 2009;38(6):1532–1542
  15. Cook MB, Akre O, Forman D, Madigan MP, Richiardi L, McGlynn KA. A systematic review and meta-analysis of perinatal variables in relation to the risk of testicular cancer – experiences of the son. Int J Epidemiol. 2010;39(6):1605–1618
  16. Huddart RA. Survival from testicular cancer in England and Wales up to 2001. Br J Cancer. 2008;99(Suppl. 1):S83–S85
  17. Einhorn LH, Donohue J. Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med. 1977;87(3):293–298
  18. Dearnaley D, Huddart R, Horwich A. Regular review: managing testicular cancer. BMJ. 2001;322(7302):1583–1588
  19. Sant M, Allemani C, Santaquilani M, Knijn A, Marchesi F, Capocaccia R. EUROCARE-4. Survival of cancer patients diagnosed in 1995–1999 Results and commentary. Eur J Cancer. 2009;45(6):931–991
  20. In:  Curado MP,  Edwards B,  Shin HR,  Storm H,  Ferlay J,  Heanue M, et al. editor. Cancer incidence in five continents, vol. IX. Lyon: IARC; 2007;[IARC Scientific Publications No. 160]
  21. In:  Parkin DM,  Whelan SL,  Ferlay J,  Raymond L,  Young J editor. Cancer incidence in five continents, vol. VII. Lyon: IARC; 1997;[IARC Scientific Publications No. 143]
  22. In:  Parkin DM,  Whelan SL,  Ferlay J,  Teppo L,  Thomas DB editor. Cancer incidence in five continents, vol. VIII. Lyon: IARC; 2002;[IARC Scientific Publications No. 155]
  23. Doll R, Payne P, Waterhouse J. Cancer incidence in five continents: a technical report. New York: Springer; 1966;
  24. In:  Segi M,  Kurihara M editor. Cancer mortality for selected sites in 24 countries (1950–1957). 2nd ed.. Sendai: Tohoku University of Medicine; 1960;
  25. National Cancer Institute . Joinpoint regression program. 3.4.2 ed.. Bethesda: Statistical Research and Applications Branch, National Cancer Institute; 2009;
  26. Kim HJ, Fay MP, Feuer EJ, Midthune DN. Permutation tests for joinpoint regression with applications to cancer rates. Stat Med. 2000;19(3):335–351
  27. Clayton D, Schifflers E. Models for temporal variation in cancer rates. II. Age–period–cohort models. Stat Med. 1987;6(4):469–481
  28. Clayton D, Schifflers E. Models for temporal variation in cancer rates. I. Age–period and age–cohort models. Stat Med. 1987;6(4):449–467
  29. Bergstrom R, Adami HO, Mohner M, Zatonski W, Storm H, Ekbom A, et al. Increase in testicular cancer incidence in six European countries: a birth cohort phenomenon. J Natl Cancer Inst. 1996;88(11):727–733
  30. Bray F, Ferlay J, Devesa SS, McGlynn KA, Moller H. Interpreting the international trends in testicular seminoma and nonseminoma incidence. Nat Clin Pract Urol. 2006;3(10):532–543
  31. Pike MC, Chilvers CE, Bobrow LG. Classification of testicular cancer in incidence and mortality statistics. Br J Cancer. 1987;56(1):83–85
  32. Richiardi L, Bellocco R, Adami HO, Torrang A, Barlow L, Hakulinen T, et al. Testicular cancer incidence in eight northern European countries: secular and recent trends. Cancer Epidemiol Biomarkers Prev. 2004;13(12):2157–2166
  33. Jacobsen R, Moller H, Thoresen SO, Pukkala E, Kjaer SK, Johansen C. Trends in testicular cancer incidence in the Nordic countries, focusing on the recent decrease in Denmark. Int J Androl. 2006;29(1):199–204
  34. Chia VM, Quraishi SM, Devesa SS, Purdue MP, Cook MB, McGlynn KA. International Trends in the Incidence of Testicular Cancer, 1973–2002. Cancer Epidemiol Biomarkers Prev. 2010;19(5):1151–1159
  35. Oosterhuis JW, Looijenga LH. Testicular germ-cell tumours in a broader perspective. Nat Rev Cancer. 2005;5(3):210–222
  36. Bray F, Richiardi L, Ekbom A, Forman D, Pukkala E, Cuninkova M, et al. Do testicular seminoma and nonseminoma share the same etiology? Evidence from an age–period–cohort analysis of incidence trends in eight European countries. Cancer Epidemiol Biomarkers Prev. 2006;15(4):652–658
  37. Bertuccio P, Malvezzi M, Chatenoud L, Bosetti C, Negri E, Levi F, et al. Testicular cancer mortality in the Americas, 1980–2003. Cancer. 2007;109(4):776–779
  38. Boyle P. Testicular cancer: the challenge for cancer control. Lancet Oncol. 2004;5(1):56–61
  39. Harding MJ, Paul J, Gillis CR, Kaye SB. Management of malignant teratoma: does referral to a specialist unit matter?. Lancet. 1993;341(8851):999–1002

PII: S1877-7821(11)00151-2

doi:10.1016/j.canep.2011.09.010

Cancer Epidemiology
Volume 36, Issue 1 , Pages 11-15, February 2012

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