Inverse Association between Cancer Risks and Age in Schizophrenia
Patients: a 12-year Nationwide Cohort Study
Short title: Age, Schizophrenia and Cancer Risk
Chun-Yuan Lina,b,c Hsien-Yuan Lanea,d Tsi-Ting Chene Yu-HsinWuc Chun-Ying Wue,f,g,h and Vivian Y. Wui
a Institute of Clinical Medical Science, Medical College, China Medical University, Taichung, Taiwan
b Department of Psychiatry, Changhua Hospital, Changhua, Taiwan c National Changhua University of Education, Changhua, Taiwan
dDepartment of Psychiatry, China Medical University Hospital, Taichung, Taiwan e Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
f Division of Gastroenterology, Taichung Veterans General Hospital, Taichung, Taiwan
gDepartment of Public Health, College of Public Health, China Medical University, Taichung, Taiwan
hDepartment of Life Sciences, National Chung-Hsing University, Taichung, Taiwan
iSol Price School of Public Policy, University of Southern California ** Correspondence:
Chun-Ying Wu, MD, MPH, PhD
Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
155, Sec. 2, Linong Street, Taipei 112, Taiwan E-mail: chun@vghtc.gov.tw
Tel: +886-4-23592525 ext. 3304; Fax: +886-4-23741331 Vivian Y. Wu, PhD
Sol Price School of Public Policy, Schaeffer Center of Health Policy and Economics. University of Southern California, USA 3335 S Figueroa St, Gateway Unit A
Los Angeles, CA 90089-0626, USA E-mail:vivianwu@usc.edu
Word count (excluding references): 4194 Word count of summary: 247
Number of tables: 2 Number of figures: 2
Summary
The association between schizophrenia and cancer risks is controversial in the clinical and epidemiological literature. Studies from different populations, tumor sites, or health care systems have provided inconsistent findings. In the present study, we examine a less well-investigated hypothesis that age plays a crucial role in cancer risks in schizophrenia. We conduct a nationwide cohort study using Taiwan’s National Health Insurance Research Database (NHIRD) between 1995 and 2007. Overall, gender-, and age-stratified standardized incidence ratios (SIR) were used to investigate the pattern of cancer risks by age. Among the 102,202 schizophrenia patients, 1,738 developed cancers after diagnosis of schizophrenia (SIR=0.92, 95% CI: 0.90-0.96). However, the age-stratified SIRs declined with age (for example, age 20-29, SIR=1.97, 95% CI: 1.85-2.33; age 60-69, SIR=0.68, 95% CI: 0.65-0.78; age70, SIR=0.36, 95% CI: 0.34-0.45) in both genders and for major cancers. Cancer risks in schizophrenia patients were lower in the cancers that are more likely to develop at older age in the general population, such as stomach cancer (SIR=0.62, 95% CI: 0.57-0.80), pancreas cancer (SIR=0.49, 95% CI: 0.39-0.84) and prostate cancer (SIR=0.35, 95% CI: 0.29-0.58). By contrast, cancer risks were higher in the cancers that have a younger onset age, such as cancers of nasopharynx (SIR=1.18, 95% CI: 1.08-1.49), breast (SIR=1.50, 95% CI: 1.44-1.66) and uterine corpus
(SIR=2.15, 95% CI: 1.98-2.74). Schizophrenia populations’ unique age structures and early aging potential might contribute to the observed inverse relationship between age and cancer risks. Higher cancer comorbidity in young schizophrenia patients deserves more attention.
Introduction
Schizophrenia, a devastating brain disorder with high morbidity and mortality, is affecting about 1% of the population worldwide.(1) In addition to suicide and
accidents, cardiovascular, respiratory and metabolic diseases are frequently comorbid with schizophrenia.(2,3) However, whether schizophrenia patients have higher risks of cancers remains controversial. While some studies found that cancer risk in patients with schizophrenia was higher relative to the general population,(4) others found that cancer risk is lower.(5-8) Yet still others indicate there is no difference.(9) In general, findings vary greatly in regards to the direction and size of difference by tumor sites, (10) study sites, races/ethnic groups and populations.(11)
Several hypotheses have been proposed to explain the differential cancer risk in the schizophrenia population. Patients with schizophrenia may appear to have lower risk because they are less likely to be screened for cancer, due to their more limited access to health care.(3,12) It is also possible that prolonged hospitalization where smoking is prohibited and diets are controlled can protect patients from developing cancer.(5) Others suggest that genetic factors may play a protective role. (13,14) In contrast, some patients’ characteristics, such as unhealthy life style, poor self-care ability, drug abuse, smoking and heavy drinking, can elevate the risk for cancer. (15,16) For example, Lichtermann et al found that patients with schizophrenia have higher risk of lung cancer in psychiatric care settings where smoking was allowed.(4)
Our study examines the effect of age on cancer risk among patients with
schizophrenia, which is an important yet less well-studied issue. It is well established that cancer is a disease of aging. However, age may affect the pattern of cancer risks in the schizophrenic population in several ways. For example, schizophrenia
population has a relative low proportion of old people because of its high mortality at early age.(17) The average age at death (57.3-65.5 years old)(18) was lower and the life-expectancy was shorter by 16.3-18.7 years(19) in schizophrenia patients as compared to the general population. Therefore it is possible that cancer risks may be lower among the older schizophrenia patients due to competitive mortality, because schizophrenia patients may decease early due to other diseases/conditions such as accidents or suicide. That is, few patients live to the older age when cancers begin to develop. It is also possible that younger schizophrenia patients may experience earlier aging. Kirkpatrick et al posit that physiological changes associated with aging occur at an earlier age in people with schizophrenia than in the general population.(20) This early-aging hypothesis is supported by the fact that early-adulthood onset schizophrenia patients have different clinical manifestations and pathophysiology from those who develop schizophrenia after middle age.(1,21,22) These factors may contribute to a different age-related cancer risks between schizophrenia and general population. Specifically, the unique age structure and the early-aging hypothesis of schizophrenia may lead to a pattern of decreasing cancer risks with age. In our study, we seek to document these important relationships between age and cancer risk among patients with schizophrenia.
Material and Methods
Data sourcesThe National Health Insurance Research Database (NHIRD) is a comprehensive dataset on more than 99% of the 23.74 million people in Taiwan enrolled in the National Health Insurance (NHI) program.(23) The NHIRD offer a rich set of patient
and clinical information, such as demographics, diagnostic codes, dates and types of procedures, prescription drugs, and expenditures.(24,25) Our study data came from a subset of the NHIRD – the Registry for Catastrophic Illness Patient Database (RCIPD). Patients with a qualified “catastrophic illness” – including schizophrenia and cancer – are waived their copayments for services. The diagnosis and enrollment of schizophrenia patients into RCIPD are pretty accurate due to the incentive of the patients to obtain benefits and care and the rigorous regulatory review and verification of the clinical information.
Study subjects
To be enrolled in RCIPD, patients with schizophrenia must have been admitted to acute psychiatric wards for at least 1 month or being regularly followed by board certified psychiatrists in the outpatient settings for at least 6 months. The study subjects were identified as patients who were diagnosed and registered with
schizophrenia (ICD-9 CM code 295) between March 1, 1995 and December 31, 2007, excluding schizophreniform disorders (ICD-9 CM code 295.8), which doesn’t meet the qualifying criteria for RCIPD. Patients younger than 20 years and those with previous cancers were excluded. These identified schizophrenia cases were then tracked until the occurrence of the first cancer, death, or the end of the study,
whichever first. The diagnoses of cancers should also be reliable, because specialists must supply ICD codes with pathological and imaging results for RCIPD
verifications. Cancers were identified by ICD-9 CM codes 140 to 208. Metastatic malignancies were excluded because the stability of these diseases is relatively low. This study was approved by the Institutional Review Board of China Medical University Hospital.
Statistical analysis
Analysis of the age structure. We provide two sets of statistics to investigate the relationship between age and cancer risks in patients with schizophrenia. First, we illustrated the difference in underlying age distributions between schizophrenia and general populations during the study period, 1995-2007. We graphed the proportion of total person-years contributed by each age group in schizophrenia and in general populations separately. The proportion of total person-years by age was calculated as the total person-years observed in each age strata divided by the total person-years contributed by all patients in the respective populations.
Analysis of cancer risk. We calculated overall and age-specific standardized
incidence ratios (SIR) to investigate overall cancer risk and the pattern of cancer risks by age among patients with schizophrenia. SIR was calculated by dividing the actual observed number of cancer cases that emerged among schizophrenia patients by the expected number of cancer cases. The expected number of cancer cases was derived by multiplying the age, gender, and follow-up year specific group population in schizophrenia by cancer incidence of the corresponding group in the general
population. The population of each age and sex strata and the corresponding stratum-specific incidence rates of cancers for the entire population were based on the Taiwan population census and National Cancer Registry cancer registry data, respectively. 95% confidence interval (CI) of SIR and trend analysis were calculated assuming a Poisson distribution.(26) Cancers with less than 10 observed cases in schizophrenia were excluded from the SIR analysis. These cancer sites include eye, nasal cavities, middle ear and accessory sinuses, salivary gland, larynx, small intestine, duodenum, gallbladder, extrahepatic bile ducts, retroperitoneum, peritoneum, pleura, thymus,
heart, mediastinum, malignant melanoma, other nervous system, bone, Hodgkin's disease, connective and other soft tissue, other endocrine glands and related structures, male breast, penis, and testis. Stratified SIR was not calculated if the gender/age stratum had less than10 observed cases. SAS statistical package (SAS System for Windows, version 9.1; SAS Institute, Cary, NC, USA) was used to perform statistical analysis in the study.
Results
Age distribution in schizophrenia versus general population
A total of 102,202 schizophrenia patients were identified where 55,755 (54.55%) were males and 46,447 (45.45%) were females. The mean follow-up years were 7.58 years and the total person-years were 774,691. The 12-year prevalence of
schizophrenia was 4.6 per 1000 in the current study. Figure 1 shows the age distribution in schizophrenia and general populations, respectively. Clearly, schizophrenia population had a much higher percentage of younger people and quickly shrinking percentage of older people, relative to the distribution of the general population. The proportion of total person-years contributed by the 50-59 year-old, 60-69 year-old, and 70 years and older in the general population was 28.6%, 15.94% and 5.38%, respectively, compared to 14.58%, 5.82%, and 1.52% in the schizophrenia population, respectively whereas schizophrenia group has higher percentage in younger age groups.
Onset age of cancer in general Taiwan population
Consistent with the rest of the world, cancer is a disease of old age in Taiwan as well. Table S1 presents cancer incidence by onset age and cancer sites in the general Taiwan population. Prostate, pancreas, liver, stomach, lung, and colorectum cancers
have onset at an older age (
60 years old), while cancers of nasopharynx, breast and uterine corpus have onset at a much younger age (40-59 years old).Overall, site-specific, and gender-specific SIR in schizophrenia
Among patients with schizophrenia, 1,738 were diagnosed with cancer during the study period. The mean age of schizophrenia patients at the time of RCIPD registration was 39.03 years old (SD12.81) and the mean age of schizophrenia patients at cancer diagnosis was 52.94 years old (SD12.53). Compared to the general population, Table 1 shows that schizophrenia patients had a statistically significant lower relative risk of cancer (SIR=0.92, 95% CI: 0.90-0.96) overall. In stratified analysis according to tumor sites, SIR values varied greatly. SIR values were greater than one in cancers of nasopharynx, brain, breast, uterine cervix (invasive), uterine corpus, ovary and other uterine adnexa, while SIR values were lower than one in cancers of lip, oral cavity and pharynax, stomach, colorectum, liver, pancreas, lung, thyroid, other skin and prostate.
Stratifying cancer risks by gender, Table 1 also provides that female
schizophrenia patients had higher overall cancer risk (SIR=1.20, 95% CI: 1.18-1.28), while male schizophrenia patients had lower overall cancer risk (SIR=0.67, 95% CI: 0.66-0.72) relative to the general population. After excluding women’s specific cancers, cancer risk of female schizophrenia patients became similar to that of general population (SIR=0.95, 95% CI: 0.92-1.04). Thus, the higher relative risk of cancer among female patients with schizophrenia overall appeared to be primarily driven by greater risks of breast, uterine cervix (invasive), uterine corpus, and ovary cancers. Higher cancer risks in younger schizophrenia patients
values by age group. Relative risk of cancer in schizophrenia is highest among those aged 20 to 29, which declines steadily as age increases. For example, younger schizophrenia patients aged 20 to 29 and 30 to 39 had SIR values of 1.97 (95% CI: 1.85-2.33) and 1.42 (95% CI: 1.38-1.57), respectively. However, SIR for the age 60-69 group was 0.68 (95% CI: 0.65-0.78) and for those age 70 and older was 0.36 (95% CI=0.34-0.45).Moreover, the results of higher cancer risk in younger patients with schizophrenia were observed in both genders, even with the exclusion of female specific cancers. The SIR values for cancer of both genders were highest in younger age and declined with age significantly (test of trend p-value < 0.0001).
We further examine the above age pattern by the major cancers in Taiwan to examine whether the age pattern is consistent across cancers. Table 2 provides age-specific SIR values by cancer. Essentially, the same age-pattern for overall cancer risk in Figure 2 was observed in Table 2 for most of major cancers we examined in Table 2. Specifically, patients with schizophrenia in the young onset age group (those between 20 and 39 years old) presented the highest SIR, then SIR declines as age increases. This pattern exists across the common cancers in Taiwan, including cancers of lip, oral cavity and pharynax, stomach, colorectum, liver, lung, breast and uterine corpus. Therefore, the pattern of declining risk by age is not cancer-specific and is likely to be driven by common factor(s) that exists in the schizophrenia population.
Discussion
Our12-year nationwide cohort study on cancer risks by age in patients with schizophrenia in Taiwan has two important findings. First, among schizophrenia patients, cancer risk appears to be decreasing by age, which is in contrast to the general population whose cancer risk increases by age. In particular, relative risk of
cancer was highest among those at the age of 20-29, and declines there after by age. This pattern was observed in both genders and across the common type of cancers.
Second, comparing to the general populations, younger schizophrenia patients (age 20
to 39 years old) have higher cancer risk relative to their corresponding groups in the general population. In contrast, older patients (age 50 and older) have lower relative cancer risks. We think that a significant shift in the age distribution toward younger age and potential early-aging occurring among early-adulthood onset schizophrenia patients might contribute to these observed patterns.
As Shiels et al discussed in the comparison of HIV/AIDS vs. general
populations,(27) fundamental difference in age composition between populations could lead to biases in estimated cancer risks. Schizophrenia, as the HIV/AIDS population, has a relatively high mortality in younger age, resulting only 14.58 percent of the population survives to age 50 and older. The sharply decreasing older schizophrenia population is likely contribute to a pattern of declining cancer risk as age increases, because of competing mortality that patients may have deceased due to other reasons before they are detected cancer. The very small older population can also lead to unstable estimate of SIRs. Because we find this pattern consistent across the cancer types and gender, it is more likely a common underlying factor, such as the age-structure we hypothesized, that affects the observed pattern rather than cancer- or gender-specific factor(s). While other studies have documented declining cancer risks by age in schizophrenia and offer several hypotheses,(28,29) our study is the first one examining the role of age structure. Due to different age compositions, the age structure hypothesis can also explain why some studies using different schizophrenia study samples in different time, location, or countries showed higher cancer risk in
schizophrenia, while others show lower.
Another important finding consistent with the age-structure shift is that SIR will be driven by cancer’s onset age. Because SIR weights general population’s cancer incidence with study population’s age distribution, overall SIR will be under-estimated if the study population has very thin proportion of people where cancer incidence is high and vice versa. The age structure hypothesis is consistent with our finding that schizophrenia patients’ SIR is smaller than 1 for cancers with old onset age (>60 years old) in the general population, such as stomach cancer (SIR=0.62), pancreas cancer (SIR=0.49) and prostate cancer (SIR=0.35). For the same reason, SIRs were greater than 1 for cancers with younger onset age (onset age <50 years old) such as cancers of nasopharynx (SIR=1.18), breast (SIR=1.50) and uterine corpus (SIR=2.15).
Female appears to have higher cancer risks than male schizophrenia in almost all the cancers we examined, which is in line with many previous studies that performed analysis by gender.(5,30) Female schizophrenia patients carried elevated risks for cancers of breast, ovary, uterine corpus and uterine cervix compared to the general female population in Taiwan, consistent with other studies that showed that breast cancer is the leading cause in all cancers among women with schizophrenia in other countries(5,7,30). It is interesting to find that women with schizophrenia had higher risks in both cancer of uterine corpus (usually endometrial cancer (31)) and invasive cervical cancer (Table 1) even though the two cancers have different pathogeneses.
Endometrial cancer, along with breast and ovary cancers, are found to be related to hormone factors.(31) It has been suggested that prolactin-releasing side effect of some antipsychoticsmay be related with galactorrhea, menstrual irregularities, sexual
dysfunction, infertility, decreased bone mineral density,(32) and higher risks for
endometrial and breast cancer.(33,34) Other risk factors such as obesity, tobacco use and sedentary lifestyle may also partly explain the higher overall risks of breast,
endometrial, and ovary cancers observed in women with schizophrenia.(35) In contrast, cervical cancer is related with human papillomavirus (HPV) infection(36) and the invasive progression could be prevented by early detection of cervical dysplasia.(31) Cervical cancer screening (papanicolaou test) program has been found to significantly reduce the invasive cervical cancer incidence rate (reduction of 48.0% from 1995 to 2006) more so than other cancers for general population in Taiwan.(37) However, women with schizophrenia were less likely to have a papanicolaou (Pap) test to get the benefit.(38) The current result of an increased risk of invasive cervix cancer in women with schizophrenia than the corresponding general population may be due to the screening gap (Table 1 and Table 2). More studies are needed to examine the trend of cervix cancer risk related with Pap test in women with schizophrenia.
In the current study, our finding of different cancer risks by gender is likely driven by the underlying difference in age structure by gender as well. Female lives longer, and therefore has a higher proportion of older patients, which will likely lead to a higher overall SIR relative to men. In addition, female-specific cancers tend to occur at younger age. For example, it was shown that breast cancer is a cancer of younger age for Asia women.(39) This, too, will lead to higher overall SIR for women. Indeed, when we excluded women specific cancers including , breast, uterine cervix, uterine corpus, ovary and other uterine adnexa, SIR for female schizophrenia patients became smaller than one, further supporting our age-structure hypothesis.
The second major finding in our study is that, compared to the general
population, schizophrenia patients seem to have higher risks of cancer in young age groups and lower risks of cancer in old age groups using SIR. This trend again is very consistent whether we look at overall cancer risk, by cancer type, or by gender for major cancers we examined. While the age distribution in schizophrenia suggests a decreasing trend of cancer risk among older age, it does not necessarily indicate elevated cancer risks relative to the general population among younger people. Therefore, the hypothesis that schizophrenia is a disease of accelerated aging(20) appears to better describe the higher risks of cancers among younger schizophrenia patients observed here. It was demonstrated that individuals with schizophrenia are associated with more abnormalities,(40) less responsive to medications, and more impaired functioning, and poorer quality of life, particularly among early-adulthood onset schizophrenia patients.(41) Because neuropsychiatric and physical degenerations may occur at a younger age, cancer screenings should probably begin at younger age for schizophrenia patients to avoid excessive mortality.(18,42)
It may be concerned that patients with schizophrenia are more likely to suffer from risk factors for cancer development, including cigrrate smoking,(16) alcohol and drug use, poor dietary habits,(43) obesity,(44) less physical activity and exercise.(45) However these risk behaviors need time to cumulate the carcinogenic effect and tend to affect older patients, therfore the factors can not explain the increased cancer risk in younger patients with schizophrenia in our study. Another issue is genetic factor. Tumor suppressor gene was hypothesized to be a candidate susceptibility gene in schizophrenia(13) based on the observation of decreased cancer risks in patients with schizophrenia(5) and their parents and siblings.(4) However this hypothesis was
regarded as premature(46) and was not supported by other research(28) and the current study, which showed an increased risk for cancer in younger patients with
schizophrenia.
Our study has the highest number of person-year observations among existing studies, which allowed us to conduct analyses by gender and cancer type and produced consistent results as in the literature (5,7,30). However, our study has several limitations. First, there had no personal information such as lifestyle and family history in NHIRD. However our finding of age effect could not be interact with these factors. Second, the current study only analyzed the patients with schizophrenia who had purchased National Health Insurance. However, the insurance rate reached 99% and our 12-year prevalence of treated schizophrenia was 4.6 per 1000 that was close to other countries.(47) It revealed that not only the accuracy of diagnosis but also the enrollment of schizophrenia were good in this study with 12-year statistics. Third, some patients might not be diagnosed immediately at the early stage of schizophrenia, and therefore cause the lag of the schizophrenia database. The limitation might cause the lower SIR values of schizophrenia patients because the younger schizophrenia patients were categorized into elder age group. However this would not change the trend of younger schizophrenia has higher cancer risk. Fourth, following most previous research, our study only included those patients who have firstly been diagnosed as schizophrenia, then cancer. The selection bias might ignore those subjects who have been diagnosed cancer before diagnosed schizophrenia and caused competitive mortality due to cancer; the overall SIR values of cancer might be
undervalued. Fifth, the overall sample size of this study is relatively large, but we have limited power to analyze SIR by cancer type and/or by gender for some cancers
with low prevalence. While SIR is supposed to produce less bias for rare diseases and we eliminate analyses for cancers with less than 10 cases, some of the results may still be unstable when the number of observed cases is small. Sixth, the subjects of our study were Taiwanese, mainly Han Chinese. Though the clinical manifestations of schizophrenia are similar across races, cancer risks in younger schizophrenia among races deserve further investigation.
In conclusion, our study presents a hypothesis that the particular age structure in schizophrenia may affect their estimated cancer risks and find several supports for this hypothesis. Findings that cancer risks decrease by age, are higher among cancers with early onset age, and are higher among females can all be consistently explained by the significant shift in the distribution of schizophrenia population toward younger age. In addition, comparing the relative risks of cancer in schizophrenia relative to the
general population in Taiwan, younger schizophrenia patients presented higher cancer risks for nearly all major cancers we examined. Early-aging occurring in younger onset schizophrenia patients may be a potential explanation. For schizophrenia patients, both neuropsychiatric and physical degenerations may occur at younger age than general population. More attention on higher physical comorbidity including cancers in young schizophrenia patients is warranted.
Acknowledgements
The present study is based in part on data from the NHIRD provided by the Bureau of National Health Insurance, Department of Health and managed by the National Health Research Institute. This study is supported in part by Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH101-TD-B-111-004, PH-100-PP-54, PH-101-PP-23).
Disclosure Statement
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Figure legends
Figure 1. Age structure in schizophrenia and general populations in Taiwan
The age structure in schizophrenia and general population is presented as the follow-up time at risk for cancer in both the schizophrenia and general populations during this cohort study (1995 to 2007), by age.
Figure 2. Overall and gender specific SIR values by age group in schizophrenia CI, confidence interval; SIR, standardized incidence ratios
† Age of schizophrenia registration
‡ Specific cancer sites of females, breast, uterine cervix, uterine corpus, ovary and other uterine adnexa, were excluded.
List of Supporting Information
Supplemental TableTable S1. Cancer incidence by onset age and cancer sites in the general Taiwan population
