Annals of Oncology Advance Access originally published online on August 25, 2008
Annals of Oncology 2009 20(2):365-373; doi:10.1093/annonc/mdn588
epidemiology |
Cancer in adolescents and young adults in north Netherlands (1989–2003): increased incidence, stable survival and high incidence of second primary tumours
1 Department of Medical Oncology
2 Department of Paediatric Oncology, University Medical Center Groningen, University of Groningen
3 Comprehensive Cancer Center North Netherlands
4 Department of Haematology, University Medical Center Groningen, University of Groningen, Groningen
5 Department of Medical Oncology, Radboud University Nijmegen, Medical Centre Nijmegen, Nijmegen, The Netherlands
* Correspondence to: Prof. W. T. A. van der Graaf, Department of Medical Oncology, Radboud University Nijmegen, Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31-(0)24-3610353; Fax: +31-(0)24-3540788; E-mail: w.vandergraaf{at}onco.umcn.nl
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abstract |
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Background: Lack of survival improvement in adolescents and young adults (AYA) with cancer has led to increased awareness of this young population.
Design: We carried out a population-based study of incidence and survival of primary tumours and second primary tumours in patients aged 12–24 in north Netherlands. Age-specific incidence rates per 100 000 and 3-year moving means were calculated. Factors associated with incidence and survival were assessed using a Poisson model, log-rank test and multivariate Cox proportional hazards analysis.
Results: From 1989 to 2003 a total of 1118 patients were diagnosed. The total age-specific incidence rates per 100 000 were as follows: males: 13.4 (12–15 years), 26.9 (16–19 years) and 27.5 (20–24 years) and females: 13.9, 20.7 and 20.7. Male : female ratio was 1.32. The overall estimated annual percentage change (EAPC) in incidence was 2.15% (P < 0.01). Five-year survival was 80.8% and did not improve during the study period. With median follow-up of 5.5 years (range 0.0–16.0) in our cohort the standardized incidence ratio (SIR) of second primary tumours was 30.55 (95% confidence interval = 19.96–44.76, P < 0.05).
Conclusions: The total incidence of cancer in AYA increased (EAPC = 2.15%). Survival was unchanged. The SIR of a second primary tumour in this young cohort increased 31-fold. Further research is needed to study this increasing incidence and optimise treatment outcome in these young patients.
Key words: adolescents, cancer, epidemiology, second primary, young adults
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introduction |
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Malignancies in the young age group 15–24 years are uncommon, with an estimated incidence of 291 per million per year in the year 2000 in the United States [1]. Within the total burden of cancer incidence (4203 per million in Europe 2003 [2] and 4723 per million in the United States during 1996–2000 [3]) the adolescent cancer patient population forms a minority, whereas malignancies in children (0–14 years) are even more uncommon (153 per million per year in the United States in 2000 [1] and 130.9 per million per year in Europe [4]).
Although the number of adolescent and young adult (AYA) cancer patients remains low, reports have shown a marked increase in incidence. Over the past three decades, the cancer incidence among AYA (15–24 years) in the United States increased by 0.85% per year, and European studies report an increase as well [1, 5, 6].
Survival has improved considerably during the past three decades for young children treated by paediatric oncology groups in Western countries, probably as a result of large-scale enrolment into international cooperative multicentre clinical trials investigating new treatment strategies including multi-agent chemotherapy. In contrast, AYA had a less favourable improvement in clinical outcome [5, 7]. Surveillance Epidemiology and End Results (SEER) data showed an annual increase in 5-year relative survival of only 0.75% in adolescents (15–24 years), compared with 1.53% in children (0–14 years) from 1975 to 1997 [1]. Notably, due to the relatively low incidence of cancer in this age group, patients are getting dispersed between large numbers of patients at oncology departments.
Although improvement in survival in AYA lags behind, the number of cancer survivors in this group has increased consistently over time. With the increasing age of survivors and more intensive treatment of cancer, awareness of an increased risk for developing second and treatment related secondary tumours in young cancer patients is important [8].
We assessed recent trends in incidence and outcome of cancer, with special attention to second primary tumours, among AYA cancer patients in a population-based cohort of 12–24 year olds diagnosed from 1989 to 2003 in the north Netherlands.
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methods |
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patients
Patients diagnosed from 1989 to 2003 in the northern part of The Netherlands [covered by the cancer registry of the Comprehensive Cancer Centre North Netherlands (CCCN)] aged 12–24 years were included in this study. Patients were classified by cancer type, age group (12–15, 16–19 and 20–24 years) and gender for the periods 1989–1993, 1994–1998 and 1999–2003. These age groups were constructed because 12- to 15-year olds are generally treated at a paediatric oncology unit and most 20- to 24-year olds are treated at a medical oncology unit, whereas 16- to 19-year-old patients form an intermediate group. Age group therefore can be used as a proxy for treatment by a paediatric or adult medical oncology unit. Cancer type was defined using the International Classification of Diseases for Oncology (ICD-O-3) classification [9] and classified by the classification scheme for cancer in 15- to 24-year olds (version 5) according to Birch et al. [10]. Carcinoids of the appendix (mostly incidental findings) with malignant properties (ICD 8240-8245, ICD-O-3) were excluded from the analysis.
data collection by the cancer registries
Data were collected by the regional cancer registry of the CCCN, covering the northern Netherlands, a predominantly rural area with a population of 
2.2 million. The nationwide Dutch network and registry of histopathology and cytopathology regularly submits reports of all diagnosed malignancies to the cancer registries. The national hospital discharge databank, which receives discharge diagnoses of admitted patients from all Dutch hospitals, completes case ascertainment. After notification, trained registry personnel collect data on diagnosis, staging and treatment from the medical records, including pathology and surgery reports, using the registration and coding manual of the Dutch Association of Comprehensive Cancer Centres. Vital status was established either directly from the patient's medical record or through linkage of cancer registry data with the municipal population registries, which record information on their inhabitant's vital status. There were no death certificates only in the cohort. The closing date of the study was 31 December 2004, resulting in follow-up <5 years in 17.4% of the patients. A second primary tumour was defined as a new primary tumour registered in the regional cancer registry, as reported by the clinician or pathologist. Furthermore, when a second primary tumour was suspect to be a relapse (same histology) we checked medical files of the patients. A melanoma was considered a second primary only when its location was obviously different from the first tumour. Furthermore, a contralateral testicular tumour was considered to be a second primary tumour [11].
statistical analysis
The population at risk for each year was retrieved from Statistics Netherlands (http://statline.cbs.nl/StatWeb). The annual age-specific incidence rates for each tumour type were calculated per 100 000 according to gender and period of diagnosis. In addition, 3-year moving means of the incidence were calculated for patients aged 12–15, 16–19 and 20–24 years. Trends in incidence rates were estimated based on a linear regression of the log-transformed incidence rates with year of diagnosis as the regressor variable. The regression coefficient for year of diagnosis was used to estimate the annual percentage change. The association of age, year and sex with incidence was carried out using a multivariate Poisson model. Survival rates at 3, 5 and 10 years were calculated for all ages together by the life table method. Differences in survival rates were analysed using the log-rank test. Multivariate Cox proportional hazards analysis was carried out to determine factors associated with survival for this age group. To assess the risk of second primary tumours a standardized incidence ratio (SIR) was calculated, which compares the observed number of secondary tumours with the expected number of tumours. The expected number of second tumours was calculated using age-, year- and gender-specific incidence rates in the general population derived from the cancer registry. Cumulative incidence of second primary tumours over the study period and confidence intervals (CIs) were estimated, with death as competing risks [12, 13].
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results |
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patients
A total of 1118 patients aged 12–24 years were diagnosed with cancer in the period 1989–2003 in northern Netherlands. In this cohort, 203 patients (18.2%) were 12–15 years of age, 385 (34.4%) were 16–19 years of age and 530 (47.4%) were 20–24 years of age at diagnosis, with a male : female ratio of 1.32. Of these patients, 1055 were diagnosed and treated in northern Netherlands and the remaining 63 were treated in regions covered by other cancer registries.
incidence
Figure 1A shows the distribution of the tumour types by age group and gender. Table 1 shows the age-specific incidence rates for the main tumour types, by age group, gender and time period. The annual cancer incidence (rate per 100 000) was lowest among 12–15 year olds: 13.4 (males) and 13.9 (females). This incidence increased to 27.3 (males) and 20.9 (females) in 16–19 year olds and 27.9 (males) and 20.8 (females) in 20–24 year olds.
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The highest incidence in males was seen for germ cell tumours with the highest incidence in 20–24 year olds (9.3). Non-seminomatous testicular cancer (ICD-9065, ICD-O-3) was the predominant morphological subtype (79.6%). Lymphomas were the second most frequent tumour type in males with the highest incidence in 16–19 year olds (7.4). In females, lymphomas represented the most frequent cancer type with a highest incidence of 7.2 for 16–19 year olds.
Cancer incidence increased markedly over time with an estimated annual percentage change (EAPC) of 2.15% (P = 0.001, unadjusted for age group and sex). The age-specific incidence (3-year moving means) of all cancer types in both sexes from 1989 to 2003 is shown in Figure 1B. We observed an increase in incidence in the age groups of 16–19 and 20–24 years for males. In females, the incidence increased for all age groups, especially after 2000 for the age group 16–19 years.
Table 2 explores the association of age, gender and year of diagnosis with incidence in a multivariate regression analysis. Increasing age was associated with increasing incidence in lymphoma (P < 0.001), germ cell tumours (P < 0.001), melanomas (P = 0.001) and carcinomas (P < 0.001). While the incidence of leukaemia did not differ significantly by age group, it should be mentioned that with increasing age the contribution of acute lymphoblastic leukaemia (ALL) to the total of cases of leukaemia declined, whereas the contribution of acute myeloblastic leukaemia increased. For central nervous system (CNS) tumours, incidence decreased significantly with increasing age (P = 0.03). Later year of diagnosis was associated with an increase in incidence for lymphomas (P = 0.008), germ cell tumours (P < 0.001) and carcinomas (P = 0.002). A remarkably high lymphoma incidence was found during the period 1999–2003 (11.7 and 9.9 among males and females, respectively), due to a high incidence of Hodgkin's lymphoma in 16–19 year olds in the period 1999–2003. Germ cell tumour incidence was significantly lower for females (incidence rates ratio = 0.33; P < 0.001), and incidence of melanoma and carcinoma was higher in females than among males (P < 0.001 for both). This is largely due to the high incidence of thyroid cancer in females.
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survival
Survival (3, 5 and 10 years) of the most prevalent tumour types is shown by age group in Table 3. The median follow-up time in the cohort was 5.5 years (range 0.0–16.0). The 5-year survival was 80.8% (95% CI = 78.1–83.1).
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High survival rates were found for germ cell tumours and melanoma with 5-year survival rates exceeding 90%. Intermediate survival was found for carcinomas (87.1%) and lymphomas (87.0%). The 5-year survival rates were rather low for CNS tumours, leukaemia, bone tumours and soft tissue sarcomas (STSs), not exceeding 70%. The numbers at risk for bone tumours and STSs were, however, small.
Multivariate survival analysis adjusting for age group and gender did not show any increase in survival over time for the whole group (hazards ratio = 0.96; 95% CI = 0.93–1.0; P = 0.33) or for the different tumour types (Table 4).
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second primary tumours
With a median follow-up time of 5.5 years (range 0.0–16.0), 26 patients developed a second tumour (Table 5). This corresponds with a SIR of 30.55 (95% CI = 19.96–44.76, P < 0.05). The cumulative incidence of second primary tumours at 10 years was 2.83% (95% CI = 1.7–4.3, cumulated over 1989–2003; Figure 2). The median interval between first and second primary malignancy was 6.19 years (range 0.02–12.9). Of the patients with a second malignancy, 21 patients are alive with a median follow-up after the second tumour of 8.69 years (range 1.5–15.7).
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Two patients developed a secondary tumour in the radiation field after treatment for Hodgkin's lymphoma. Five patients with melanoma developed a localized second melanoma at a distinct place. Only one patient with multiple melanomas was known with familial atypical multiple mole melanoma (FAMMM) syndrome. Four patients with a primary testicular tumour in adolescence developed a contralateral testicular tumour during follow-up.
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discussion |
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Interest in oncology in the AYA group is emerging [14–16]. In order to better define the current magnitude of the cancer problem for this age group, we started an inventory study on the incidence and survival of 12–24 year olds, with emphasis not only on the primary tumour but also on the second primary tumours.
The incidence of cancer in AYA (20.5 per 100 000 per year 1989–2003) was particularly low when compared with the overall cancer incidence, with a reported annual incidence of 415.8/100 000 (European Standardized Rate [17]) in 2002 in the same district.
Within the AYA group the incidence increases with increasing age from 13.7 in 12–15 year olds to 24.1 and 24.4 in 16–19 and 20–24 year olds, respectively. These age groups were constructed to be used as a proxy for treating unit. All 12–15 year olds are generally treated at a paediatric oncology unit, 20–24 year olds at a medical oncology unit, whereas 16–19 year olds will be seen at both departments. Most studies, however, routinely utilize 5-year increments for their analyses, considering patients up to 14 years as children and those 15 years and older into the adolescent and younger adult group [1, 5, 18].
When comparing our data with those from other countries, the total incidence of cancer in 12–15 year olds greatly resembles SEER (United States) [1] (10–14 year olds) and British data [18] (10–14 year olds), but the incidence in our 16- to 19-year-old population is slightly higher than that reported in the United States as well as in Europe (24.1 compared with 20.3 in the United States 1975–2000 [1] and 18.6 in Europe 1988–1997 in 15–19 year olds [19]). This might be due to the difference in age group or study period. The incidence we showed in 20–24 year olds (24.4) is lower than that in the United States (35.2 per 100 000 per year, 1975–2000 [1]) and comparable to British data (22.6 per 100 000 per year, 1979–1997 [18]).
We found a significant increase in incidence of all malignancies over time in 12- to 24-year olds. When corrected for age group and gender, an increase in germ cell malignancies, lymphomas and carcinomas was found, confirming the findings from other recent reports in the Western countries [1, 5–7, 10, 18, 20] lymphomas and carcinomas was found. Increasing incidence for germ cell malignancies in males (e.g. testicular cancer) seems to be a worldwide phenomenon [1, 21] and is not fully understood thus far. An increase in incidence for lymphomas was observed in both sexes. This increase in incidence was caused mainly by an increase in Hodgkin's lymphoma in 16–19 year olds, which was previously reported by Reedijk et al. [5] and Clavel et al. [22]. Interestingly, in England, Birch et al. [10] observed a decrease for both Hodgkin's lymphoma and non-Hodgkin's lymphoma in 15–24 year olds in the same period. Moreover, SEER data show an EAPC of 3.6% for non-Hodgkin's lymphoma, compared with only 0.2% for Hodgkin's lymphoma in 20–24 year olds and a decrease in 10–19 year olds during 1975–2000 [1]. The variation in reported trends for lymphomas over time might be due to improvement of the quality of data collection, uniformity in classification and homogeneity in international coding and classification practices, as suggested by Clavel et al. [22].
We found no improvement in survival from 1989 to 2003. When compared with children, AYA benefited less from the general survival improvement during the past decades as shown by several large studies in Western countries. As stated before, from 1975 to 2000, SEER data (United States) reported a twice higher annual increase of 5-year relative survival in children in comparison to adolescents [1]. In contrast, Reedijk et al. [5] reported equal 5-year survival increases in adolescents as well as in children (adolescents: 64%–82%, children: 56%–75%, 1973–1999). We carried out our study on data from 1989 up to date, which might indicate that following the large improvements made in the seventies and eighties with the introduction of chemotherapy, the increase in survival of AYA has come to a steady state during the last 10 years.
The cooperation of experts in developing large comprehensive children's cancer studies in the United States as well as in Europe has lead to worldwide improvement in children's cancer care. Whereas 90% of children under the age of 15 are entered in a clinical trial, only 10% of adolescents (15–19 years) and 2% of young adults (20–24 years) in the United States are entered in clinical trials of the paediatric or adult cooperative groups [23]. Survival rates for specific tumour types in AYA are still <70%. These malignancies include non-Hodgkin's lymphoma, STSs and bone sarcomas, CNS tumours and leukaemias. Treatment optimization, especially for these malignancies, is of great importance. Because of the rarity of these tumours, international cooperation and inclusion in clinical trials is warranted for these patients.
Importantly, adolescents may access oncologic care from paediatric or adult medical centres. In adolescent patients with leukaemia, especially ALL, childhood protocols improve survival [24–27]. Furthermore, a recent study from Utah investigated the site of oncologic specialty care for older adolescents (15–19 years), concluding that 66% of these patients were never seen by a paediatric oncologist, and there was a trend to worse survival for adolescents not treated by a paediatric oncologist for all malignancies except non-Hodgkin's lymphoma, germ cell tumours and carcinomas [28]. Unfortunately we were not able to assess the treatment unit for the patients in our cohort, as data concerning inclusion in clinical trials were incomplete in the cancer registry.
Apart from these treatment variables, other factors such as patient and/or doctor's delay in referral and/or diagnosis may play a role in the final outcome of the patients, presuming that AYA patients are diagnosed at a relatively higher stage of disease than children. A very recent study from the Canadian Childhood Cancer Surveillance and Control Program also confirms this idea and shows a longer delay in both referral and diagnosis in 10–19 year olds when compared with children <10 years, due to both patients and physicians [29]. Furthermore, more aggressive tumour biology is also suggested to play a role in a disadvantage in outcome for adolescents [30].
Remarkably, we observed an unexpectedly high risk of second malignancies in our cohort (SIR = 30.55) which has not been reported previously. Because the median time from first to second malignancy was longer (6.19 years) than the median follow-up (5.5 years), we might have missed the bulk of second malignancies in our study. This means that the observed SIR in our study might even be an underestimation of the actual risk. Since more young people survive cancer nowadays, the potential risk of late effects after primary cancer treatment has increasingly become a major topic of interest over time [31–33].
A reasonable origin of these second tumours could be both intrinsic (genetic susceptibility) and/or extrinsic (environmental exposure, treatment induced). For example, melanoma of skin shows association not only with sun exposure but also with total and dysplastic nevi and genetic predisposition and this may lead to an increased risk of developing second or even third melanomas [34]. In general, the younger sequential tumours become overt, the higher chance that intrinsic (genetic) factors play an important etiological role. The occurrence of second tumours of the same histology in eight patients (melanoma and non-seminomatous testicular cancer), with only one patient known with a familiar predisposition for melanoma (FAMM syndrome), confirms the hypothesis that extrinsic factors as well as unknown genetic predisposition play an important role in carcinogenesis in these young patients and should be further investigated.
Despite the growing interest in AYA oncology in general, population-based studies with an overview of all second primary tumours in this group are scarce. The only reported data found an SIR of 12.4 in 15–24 year olds and a peak incidence in 15–19 year olds [35]. In contrast to the scarcity of data on AYA, data on second primary malignancies in childhood cancer survivors (up to 18–20 years of age) are widely available, reporting a five- to six-fold increased risk for second primary malignancies [8, 36–38].
In conclusion, we found an increase in incidence of malignancies in AYA, with no survival improvement during 1989–2003. Large-scale enrolment and treatment of AYA in international cooperative multi-centric clinical trials could be the solution in optimising care in this neglected group of young patients worldwide. The prevalence of survivors of adolescent cancer is increasing. In our cohort we showed that these survivors are at high risk for developing second primary malignancies. Further research is needed to study the increasing incidence of cancer in AYA and the incidence of second malignancies to optimise care for these young patients.
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Both authors contributed equally. 
Received for publication January 29, 2008. Revision received July 20, 2008. Accepted for publication July 25, 2008.
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