Main findings and comparison with other studies
The main finding of our study was that patients with schizophrenia have a higher risk of mortality from common site-specific cancers was validated, particularly by a significantly high risk of mortality from breast, lung, and colon cancer. However, the pooled result for prostate cancer was not statistically significant. A previous meta-analysis showed no significant relationships between schizophrenia and breast and lung cancer prevalence; it also revealed that patients with schizophrenia have low incidence risk of colorectal and prostate cancer [
25].
These paradoxical findings have directed our attention to the association between schizophrenia and cancer incidence versus mortality risk. A meta-analysis published in 2017 revealed that patients with schizophrenia have a slightly decreased risk of overall cancer incidence compared with the general population [
25]. Another meta-analysis based on 16 cohort studies showed a high risk of cancer mortality in individuals with schizophrenia [
12]. Zhuo et al. described that female schizophrenia faced a higher incidence of breast cancer than the general population in a meta-analysis [
26], whereas Li et al. found a decreased incidence of breast cancer in patients with schizophrenia [
25]. Therefore, the association between cancer incidence and mortality risk in patients with schizophrenia remains vague on account of several potential confounding factors, such as gender, ethnicity, genetic background, cancer site, antipsychotic medication use, and cancer care [
27,
28].
Evidence supports the possible increased risk of breast cancer in women with schizophrenia due partly to the use of antipsychotic medications [
29], some of which may cause hyperprolactinaemia, which, in turn, may contribute to mammary development and breast carcinogenesis in animal and cell experiments [
30,
31]. Johnston et al. found that two hyperprolactinemia-inducing antipsychotics, risperidone and pimozide, incite precancerous cells to progress to cancer by activating JAK-STAT5 signaling [
31]. Patients with schizophrenia show decreased incidence of prostate cancer [
25,
32], which is theoretically related to low testosterone levels suppressed by high prolactin levels on account of antipsychotic drug use [
33]. A case–control study revealed that the reduced risk of prostate cancer among patients with schizophrenia is likely associated with long-term treatment of high-dose phenothiazines (primarily chlorpromazine) [
34].
Considerable research evidence suggests that genetic factors have been advocated to explain the decreased risk of several types of solid tumors among patients with schizophrenia. P53 and adenomatous polyposis coli polymorphisms may be associated with increased schizophrenia susceptibility and reduced vulnerability to lung and colon cancer in schizophrenia respectively [
35‐
37]. The interaction of tumor suppressor genes TXNIP and AF1q may also contribute to risk for schizophrenia [
38]. Wang et al. found that the reduced incidence of prostate cancer in schizophrenia patients may be related to JAZF1 gene mutation [
39]. Some of tumor related-genes may be risk factors for the incidence of schizophrenia, and in the meanwhile they may act as protective factors for the development of cancer.
The mortality of different cancers is influenced not only by cancer incidence but also by increased risk of suicide, unhealthy lifestyle, late-stage diagnosis, poor survival after diagnosis, inadequate cancer treatment (e.g., surgery, chemotherapy, radiotherapy, endocrine therapy, and palliative care) [
40‐
42]. Mitchell et al. demonstrated that individuals with schizophrenia are at a high risk of metabolic syndrome (MetS), which is a significant influence upon mortality. Screening for MetS risk factors and taking effective intervention measures, such as exercise, dietary changes and antipsychotic medication management, should be considered [
43]. Due to the higher mortality from smoking-related illnesses than the general population, patients with schizophrenia are encouraged to receive pharmacotherapy and behavioral treatments to give up smoking [
44]. Moreover, disruptions in the diagnosis and treatment of breast cancer are noticeable for patients with schizophrenia and result in adverse outcomes, including cancer recurrence [
45]. Poor diagnostic evaluation and belated stage-appropriate treatment in lung cancer care are common among patients with schizophrenia and lead to poor outcomes [
46]. Considering the disparities existent in cancer screening, diagnosis, treatment, and end-of-life care, collaboration between oncologists, psychiatrists, nurses, and other members of the multidisciplinary team is needed to provide high-quality care for patients with schizophrenia.
Advantages and limitations
Meta-analysis is an important tool to combine the results of included studies that may otherwise be uncertain or imprecise in a single study. The current meta-analysis presents a number of advantages. First, the study population was substantial, which means it has high statistical power. Second, our quantitative assessment was based on cohort studies to better understand the association between schizophrenia and mortality risk of site-specific cancers. Third, no publication biases was detected, which indicates that the pooled results may be stable.
Some limitations must be noted in our meta-analysis. First, on account of the low prevalence of schizophrenia and low cancer mortality in patients with schizophrenia, we ignored imparities in the measures of mortality rate and then calculated pooled RRs, which may produce negligible but inevitable statistical errors [
17]. Second, all of the data used for meta-analysis were based on observational studies, and differences in unadjusted covariates are a potential source of bias. Moreover, some of the unrecorded factors may make a difference to the relationship between schizophrenia and mortality risk of site-specific cancers. Third, some data on the mortality risk of the four different cancers surveyed in this meta-analysis were lacking and could not be extracted from the included studies, resulting in outcome selection bias. Finally, although we used a random-effects model to meta-analyze RRs and performed sensitivity analyses to explore uncertainties in the included studies, considerable heterogeneity was still observed in some of our pooled results. Moreover, no adequate baseline information or adjusted confounding factors were available in most of the studies. We therefore cannot carry out meta-regression analyses to further explore the source of heterogeneity in these works.