Increasing Trends in the Prevalence of Prior Cancer in Newly Diagnosed Lung, Stomach, Colorectal, Breast, and Uterine Cancer Patients: A Population-Based Study


 Background: Cancer survivors are frequently excluded from clinical research, resulting in their omission from the development of many cancer treatment strategies. Quantifying the prevalence of prior cancer in newly diagnosed cancer patients can inform research and clinical practice. This study aimed to describe the prevalence, characteristics, and trends of prior cancer in newly diagnosed cancer patients in Japan.Methods: Using Osaka Cancer Registry data, we examined the prevalence, characteristics, and time trends of prior cancer in patients who received new diagnoses of lung, stomach, colorectal, female breast, or uterine cancer between 2004 and 2015. Site-specific prior cancers were examined for a maximum of 15 years before the new cancer was diagnosed. Time trends were evaluated using the Cochran-Armitage trend test.Results: Among 275,895 newly diagnosed cancer patients, 21,757 (7.9%) had prior cancer. The prevalence of prior cancer ranged from 3.3% (breast cancer) to 11.1% (lung cancer). In both sexes, the age-adjusted prevalence of prior cancer had increased in recent years (P values for trend < 0.001), especially in newly diagnosed lung cancer patients. The proportion of smoking-related prior cancers exceeded 50% in patients with newly diagnosed lung, stomach, colorectal, and breast cancer.Conclusions: The prevalence of prior cancer in newly diagnosed cancer patients is relatively high, and has increased in recent years. Our findings suggest that a deeper understanding of the prevalence and characteristics of prior cancer in cancer patients is needed to promote more inclusive clinical research and support the expansion of treatment options.


Introduction
Cancer survivors are at risk of developing second primary cancers, and their numbers are increasing worldwide [1][2][3][4][5]. A study from the US Surveillance, Epidemiology, and End Results Program reported that almost 20% of individuals with incident cancers between 2009 and 2013 had prior cancer [6]. The increasing incidence of second malignant cancers may be in uenced by hereditary and familial risk, antecedent cancer therapy, lifestyle-related factors (e.g., tobacco and alcohol consumption), and environmental factors [7].
Cancer survivors require unique medical and psychosocial support with proactive assessments and follow-up care [4]. Several studies have reported that prior cancer did not adversely affect survival in lung and pancreatic cancer patients [8][9][10][11]. In contrast, another study noted that poorer survival was associated with some prior cancer types (e.g., colorectum, melanoma, and breast), but not others (e.g., esophagus, stomach, and lung) [12].
Despite the growing number of measures designed to support various aspects of cancer survivorship in patients, caregivers, and clinicians, further evidencebased resources are needed to improve the quality and effectiveness of cancer care. Identifying the occurrence and type of prior cancer in each newly diagnosed cancer patient can facilitate more accurate risk assessments in various clinical settings, including clinical cancer research. In addition, the frequent exclusion of cancer survivors from clinical research can lead to blind spots in the effectiveness and safety of treatment strategies for patients with metachronous cancers [13].
Insight into the prevalence and characteristics of prior cancer can inform research and clinical practice, but few studies have used population-based cancer registry data to examine these issues. In addition, most epidemiological evidence for the association between prior cancer and newly diagnosed cancer is derived from studies conducted in the US and Europe, with little evidence from Asian populations. The aim of this study was to provide globally comparable estimates of the prevalence, characteristics, and trends of prior cancer in newly diagnosed cancer patients using a long-term Japanese cancer registry database in order to aid further research and inform healthcare strategies.

Data source and study design
Data were obtained from the Osaka Cancer Registry (OCR), a population-based cancer registry founded in 1962 for the purpose of registering and monitoring all malignant tumors and benign intracranial tumors throughout Osaka prefecture (the third largest metropolitan area in Japan). The OCR covers a population of 8.8 million people, and allows the identi cation of prior cancers in individual patients [14].
Data on all cancer patients diagnosed between 1989 and 2015 were extracted for analysis. The various cancers were identi ed using the corresponding International Classi cation of Diseases, Tenth Revision (ICD-10) codes. The data also included each patient's age at diagnosis (hereinafter referred to as diagnostic age), sex, cancer detection method, cancer stage, treatment, month of diagnosis (diagnostic month), year of diagnosis (diagnostic year), inclusion in the registry through death certi cate only, living status, and survival time.
We quanti ed the prevalence of prior cancer in patients who received new diagnoses of cancer of the following sites between 2004 and 2015: lung, stomach, colorectum, female breast (hereinafter referred to as breast), and uterus. These sites were selected as they are the target sites for cancer screening programs in Japan, and are associated with high incidence [15]. We then examined the occurrence and types of prior cancers within 15 years before the diagnostic month and year of each newly diagnosed cancer.
De nitions and study subjects Index cancers were de ned as cancers that were newly diagnosed between 2004 and 2015 in patients who met the following criteria: 1) diagnostic age of 15-99 years, 2) pathologically diagnosed cancer for any of the target sites (lung, stomach, colorectum, breast, and uterus), and 3) survived for three months or more after diagnosis. In Osaka prefecture, the percentage of cases registered from death certi cate only fell below 10% from 2004 onward [16]. Therefore, data from 2004 and later were used to identify the index cancer cases. Patients were excluded if they were registered in the OCR through death certi cate only. Cases of multiple cancers are recorded in the OCR in accordance with the guidelines of the International Agency for Research on Cancer and the International Association of Cancer Registries [17]. However, multiple cancers of the same site in an individual patient were combined as the "most common prior cancer" to avoid including the incomplete integration of multiple prior cancers or metastatic cancers [5].
Prior cancers were de ned as cancers diagnosed during the 15-year period before the index cancer diagnosis. If two or more prior cancers had the same diagnostic month and year in a patient, the sequence of these cancers was randomly determined using a previously described method [6].

Prior cancer characteristics
For patients with prior cancer, we calculated the number of prior cancers before the index cancer, as well as the diagnostic time interval between the index cancer and most recent prior cancer. In addition, we examined the stage, treatment, and site of each prior cancer. The prior cancer site was identi ed for the most recent prior cancer. We categorized the following prior cancers as smoking-related cancers based on previous studies [20][21][22][23][24]: mouth, pharynx, larynx, lung, esophagus, stomach, liver, pancreas, kidney, urinary bladder, colorectum, uterine cervix, and acute myeloid leukemia.

Statistical analysis
The main outcome measure was the prevalence of prior cancer in the study subjects. In order to account for the varying age structures of the cancer patient population over time, we examined the trends in the age-adjusted prevalence (measured every two years) of prior cancer for each index cancer site according to sex. First, we calculated the age-speci c prior cancer prevalence for each age group according to sex and cancer site. To obtain the expected number of prior cancer cases, we multiplied the age-speci c prior cancer prevalence by the number of patients for each age group according to sex in our subjects between 2004 and 2015, which we had set as the reference cancer population. We then totaled the expected number of prior cancer cases from all age groups. Finally, to calculate the age-adjusted prevalence, we divided the total expected number of prior cancer cases by the reference cancer population. We described the time trends in prior cancer prevalence from 2004 to 2015 using the Cochran-Armitage trend test [25]. The distributions of the above sitespeci c measurements were also examined according to sex.
Continuous variables were summarized as median values and interquartile ranges, and categorical variables were summarized as proportions. Proportions were compared using Pearson's chi-square test. The signi cance level was set at 5% (two-sided). All analyses were performed using STATA version 14 (Stata corporation, College Station, TX, USA).

Results
Prior cancer prevalence and patient characteristics Figure 1 shows the subject selection process. We identi ed 275,895 index cancer patients that met the inclusion and exclusion criteria. Among these, 21,757 (7.9%) had prior cancer. As shown in Fig. 2, the age-adjusted prevalence of prior cancer had signi cantly increased over the study period for all index cancers in both male and female patients (all P values < 0.001). This prevalence was notably higher in lung cancer patients in both sexes.
The characteristics of the patients according to index cancer site are summarized in Table 1. The results for cervical cancer and corpus uterine cancer are described separately in Table A1 (Additional le). Among all patients, the prevalence of prior cancer was 11.1% in lung cancer patients, 9.5% in stomach cancer patients, 7.5% in colorectal cancer patients, 3.3% in breast cancer patients, and 4.5% in uterine cancer patients (cervix: 2.7%, corpus: 6.7%). Among older patients aged 65 years or older, the prevalence of prior cancer was 12.1% in lung cancer patients, 10.5% in stomach cancer patients, 8.4% in colorectal cancer patients, 5.2% in breast cancer patients, and 6.2% in uterine cancer patients (cervix: 5.4%, corpus: 8.5%). Patients whose index cancers were incidentally detected during follow-up examination for another disease had a higher prevalence of prior cancer than other cancer detection methods for all index cancer sites. The prevalence of prior cancer was also higher in patients whose index cancer was in the localized stage. With the exception of other or unknown treatments, surgery was the most common treatment for lung cancer (16.9%), colorectal cancer (8.2%), breast cancer (4.6%), and uterine cancer (5.2%). Abbreviation: IQR, interquartile range.
Categorical variables between cancer patients with and without prior cancer were compared using Pearson's chi-square test. Signi cant differences (P ≤ 0.05) were found in all categories except for diagnostic year in uterine cancer patients. a Prior refers to newly diagnosed cancer patients with prior cancer of the speci ed site. b Incidental detection during follow-up examination for another disease.

Prior cancer characteristics
The characteristics of male and female patients with prior cancer are shown in Table 2 and   Values are expressed as the number of patients and column percentage.
a Interval between the diagnostic dates of the most recent prior cancer and index cancer.
b Most recently diagnosed prior cancer.
The most common sites of the most recent prior cancers were analyzed according to index cancer site in male patients (Table 2) and female patients ( Table 3). The results for cervical cancer and corpus uterine cancer are described separately in Table A2 (Additional le). In male patients, smoking-related cancers accounted for approximately 70% of prior cancer. In female patients, smoking-related prior cancers were more common in index breast cancer patients than patients with other index cancers. Patients with cervical cancer had a signi cantly higher proportion of smoking-related cancers than those with corpus uterine cancer in Figure A1 (Additional le). The proportions of smoking-related prior cancers in male patients were signi cantly higher than in female patients for index lung, stomach, and colorectal cancer (Fig. 3).

Discussion
In this analysis of population-based cancer registry data from a major metropolitan area in Japan, we ascertained the prevalence, characteristics, and trends of prior cancer in patients newly diagnosed with one of ve major cancer types. Even after accounting for the changes in age structure, the prevalence of prior cancer was found to have increased over time for all index cancer sites. These trends may be attributable to earlier detection (increase in localized cancer rates: 35 Among our subjects, patients with newly diagnosed lung cancer had the highest prevalence of prior cancer among the assessed index cancers. These differences in the prevalences of prior cancer may be indicative of underlying or shared risk factors (e.g., lifestyle habits such as smoking), and require further investigation.
Our analysis showed that the prevalence of prior cancer increased with age for all index cancers, with adolescents and young adults (aged 15-39 years) having a lower prevalence than older patients. However, our estimated prevalences of prior cancer in patients aged 65 years or older were lower than those reported in a previous study conducted in the US (lung: 18.7%, stomach: 17.8%, colorectum: 15.3%, breast: 7.4%, cervix: 13.6%, and corpus: 13.6%) [6]. This disparity may be in uenced by an inherent difference in the age-standardized cancer incidence rates for all sites between the US (393.2 per 100,000 population) and Japan (285.9 per 100,000 population) [28]. In addition to variations in prior cancer prevalence, this may also be indicative of differences in genetic, lifestyle-related, and/or environmental risk factors. Differences in the prevalence of prior cancers among previous studies may also be explained in part by our non-inclusion of patients with carcinoma in situ, as this condition is generally curable and would not unduly affect survival. In addition, we did not use the recorded sequence numbers that indicate the order of cancer in individual cases, which may also have resulted in a lower apparent prevalence of prior cancer. We had decided to exclude prior cancers at the same site as the index cancer to avoid potential double counting because we would be unable to determine if the index cancer was metastatic or primary.
The prevalence of prior cancer was found to be higher in index cancer patients with localized tumors, and prior cancers were generally diagnosed in the early localized stage across all index cancers. A possible explanation for the former observation is that patients with prior cancer would undergo regular follow-up examinations, which would support the prompt incidental detection of new tumors in the early stages. This may also contribute to the high prevalence of prior cancer for patients whose index cancers were incidentally detected during examinations for another disease. For the latter observation, we posit that patients with cancers diagnosed in the earlier stages would receive prompt treatment and have longer survival, thereby increasing the opportunities for other cancers to develop. Our results also showed that surgical treatment was often selected for prior cancer, which may be due to the high proportion of earlystage cancers.
In the present study, the prevalence of prior cancers in male patients was higher than in female patients. In particular, the proportion of male patients with two or more prior cancers was higher than female patients for new cases of lung cancer, stomach cancer, and colorectal cancer. The cumulative proportions of the most recent prior cancers diagnosed within 5 years before the index cancer diagnosis were higher in male patients ( Table 2 and Table 3). These observations may be in uenced by the higher incidence of cancers in men, lifestyle differences, and other sex-based differences [29].
While our data did not include information on tobacco consumption, smoking-related prior cancers were found to be less common in female patients newly diagnosed with lung, stomach, and colorectal cancer than their male counterparts. The proportions of smoking-related prior cancers were 73.1% in male patients and 53.0% in female patients among the general population of cancer patients (P < 0.001). This may indicate a biological difference in susceptibility to smoking-related cancer between the sexes [30,31]. In addition, the proportion of smokers may be higher among male patients, which could have contributed to their higher prevalence of smoking-related prior cancers. Furthermore, female patients with index breast cancer had a higher proportion of smoking-related prior cancers than those with other index cancers. Although several studies have reported that smoking is associated with an increased risk of breast cancer [32][33][34], the evidence remains inconclusive and further research is needed to understand these ndings. Patients with cervical cancer had a signi cantly higher rate of smoking-related cancers than those with corpus uterine cancer, likely because cervical cancer is a smoking-related cancer and has a common cause, such as smoking.
Our results also showed that patients with index breast cancer had a higher prevalence of prior corpus uterine cancer (8.3%) relative to the general cancer population (3.7%) in the OCR [15]. Similarly, patients with index corpus uterine cancer had a higher prevalence of prior breast cancer (46.6%) relative to the general cancer population (20.7%) in the OCR [15]. In addition, there was a slightly higher prevalence of prior ovary cancer in patients with index breast cancer (3.8%) than the general cancer population (2.4%) [15]. This may be indicative of hereditary cancers (such as hereditary breast and ovarian cancer syndrome, Lynch syndrome, and Li-Fraumeni syndrome) or the effects of previous treatments for prior cancers [35,36].
Cases with prior cancer are frequently excluded from clinical research. However, the relatively high prevalence of prior cancer in newly diagnosed cancer patients suggests that their exclusion would have a substantial effect on research outcomes. Approximately 80% of previous clinical trials for lung cancer patients excluded those with prior cancer, and most trials employ a 5-year exclusion window [13,37]. Patients with prior cancer are also sometimes excluded from observational studies due to concerns that they may affect outcome measurements [38,39]. Our present study found that approximately 70% of lung, stomach, and colorectal cancer patients with prior cancer had a diagnostic interval of 5 years or less between the prior and index cancers. In addition, the most frequent diagnostic interval was 1-5 years for all index cancer sites. Even after excluding cancer patients with a diagnostic interval of 3 months or less, individuals who had a diagnostic interval of 5 years or less still accounted for more than 60% of patients with prior cancer. Accordingly, a considerable proportion of patients with prior cancer would not be eligible to participate in trials with a 5-year exclusion window. The impact of prior cancer on survival should be examined with scienti c evidence, and cancer survivors should not be excluded from studies as a matter of course [40]. Quantifying the prevalence of prior cancer in newly diagnosed cancer patients can aid our understanding of these patients and support the formulation of comprehensive treatment strategies. For example, medical institutions, government agencies, and insurers may be able to design more e cient strategies to allocate health resources and develop treatment plans that account for cancer survivors [41][42][43][44].
This study has the following limitations. First, we created sequence numbers for multiple cancers in the OCR with the assumption that patients did not move outside of the cancer registry catchment area (i.e., Osaka prefecture). However, the number of prior cancers may be underestimated if there was substantial movement out of this area. Nevertheless, if the actual prevalence of prior cancer is actually higher, this would further reinforce our conclusions. Second, there were limitations to the types of information available in the registry, which prevented a more detailed analysis of patient background factors such as tobacco use, alcohol use, and obesity.
Our study has several strengths. Using a historic, large-scale cancer registry database, we were able to identify and characterize prior cancers in newly diagnosed cancer patients residing in a major metropolitan area in Japan. To the best of our knowledge, this is the rst study to reveal recent trends in the age-adjusted prevalence of prior cancers strati ed by sex.

Conclusions
This study provided globally comparable estimates of the prevalence and characteristics of prior cancer in newly diagnosed cancer patients using a longterm population-based cancer registry. The prevalence of prior cancer increased in recent years, and approximately 70% of prior cancers in male patients were potentially smoking-related. In light of the increasing number of cancer survivors worldwide, our ndings suggest that a deeper understanding of the prevalence and characteristics of prior cancer in cancer patients is needed to promote more inclusive clinical research and support the expansion of treatment options.