Clinical characteristics and prognostic analysis of multiple primary malignant neoplasms in patients with rectal cancer : a population-based study

Clinical characteristics and prognostic analysis of multiple primary malignant neoplasms in patients with rectal cancer : a population-based study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Clinical characteristics and prognostic analysis of multiple primary malignant neoplasms in patients with rectal cancer : a population-based study Siyu Zhang, Gangyi Dai, Erli Wang, Yaoxuan Wu, Bing Tang, Lihua Zhou, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5366332/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract This study aims to investigate the clinical characteristics of patients with multiple primary malignant neoplasms (MPMNs) and rectal cancer, as well as to identify the risk factors that impact the prognosis. A retrospective analysis was conducted on eligible rectal cancer patients utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Comprehensive clinical data were incorporated, including patients' age, sex, race, marital status, clinical stage, surgery, chemoradiotherapy, tumor size, tumor differentiation, number of regional lymph nodes examined, survival time, and tumor status. Subsequently, univariate and multivariate Cox regression models were used to identify risk factors affecting the prognosis of MPMNs and rectal cancer patients. Colorectal cancer(22.16%), urological cancer (21.29%), and lung and bronchial cancer(13.13%) were the top three locations of MPMNs linked to rectal cancer. COX multivariate regression analysis showed that tumor Nx stage (HR:9.607, 95%CI: 3.004-30.726, p<0.001), receipt of systemic therapy before surgery (HR:1.578, 95%CI: 1.086-2.295, p=0.017) and number of regional lymph nodes <12 (HR:1.493, 95% CI: 1.184-1.883, P<0.001) were risk factors for poor prognosis of rectal cancer-related MPMNs, whereas a larger city population (HR:0.783, 95%CI:0.625-0.981, P=0.034) was a protective factor for good prognosis. Therefore, rectal cancer patients should be monitored for multiple primary cancers, especially colorectal, lung, and urological cancers. Prognostic markers for rectal cancer with MPMNs were "larger city population," "number of regional lymph nodes <12," "preoperative receipt of systemic therapy," and "tumor Nx stage." Health sciences/Risk factors Biological sciences/Cancer/Gastrointestinal cancer/Colorectal cancer/Rectal cancer Health sciences/Oncology/Cancer Biological sciences/Cancer Biological sciences/Cancer/Cancer prevention Biological sciences/Cancer/Cancer screening Biological sciences/Cancer/Gastrointestinal cancer Biological sciences/Cancer/Tumour biomarkers Rectal cancer multiple primary malignant neoplasms SEER prognostic risk factors Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 INTRODUCTION Colorectal cancer is the third most prevalent and second most deadly malignancy in the United States. It was responsible for more than 1.9 million new cases and 904,000 deaths in the year 2022, accounting for nearly one-tenth of all cancer diagnoses and deaths 1 , 2 . The incidence and mortality rates of colorectal cancer are also on the rise in China, with rectal cancer accounting for about 60 percent of all colorectal cancer cases 3 . With the advancement of diagnostic techniques, comprehensive treatment, and tumor detection technology, the life expectancy of rectal cancer has been dramatically improved 4 , 5 . The five-year survival rate can be as high as 90 percent for patients with early-stage rectal cancer when treated promptly 6 . Owing to various factors, including cancer susceptibility syndromes, specific tumor characteristics, environmental exposures, and delayed effects of treatments, cancer survivors may be susceptible to a wide range of malignancies 7 , leading to a much higher incidence and detection of multiple primary malignant neoplasms (MPMNs) 8 , 9 . The prevalence of MPMNs in the cancer population ranges from 2.4–8% and can be as high as 17% at 20-year follow-up 10 . The proportion of MPMNs varies according to the type of cancer. It is relatively high for cancers with a high incidence and a prolonged survival period, such as breast, prostate, and colorectal cancers 11 . Levi et al. 8 , in a retrospective study that included 24,859 cancer patients, found that 1 in 8 patients had a second primary cancer. Weir et al. found that the incidence of multiple primary cancers in colorectal cancer patients could be as high as 19.7% 12 . Rectal cancer survivors with high survival rates face the possibility of developing MPMNs, which may pose a threat to the patient's long-term survival. Most studies have focused on comparing the risk of subsequent cancers in cancer patients with that in the general population or on describing factors associated with second primary cancers and prognosis in cancer survivors 13 – 15 . Studies based on cancers combined with MPMNs are relatively few and primarily based on single-center, small-sample studies or case reports 16 – 18 . Due to MPMNs' diverse clinical manifestations and low incidence, most clinicians are inexperienced in diagnosing and treating this type of disease. MPMNs are often misdiagnosed as recurrence or metastasis of primary malignant cancers, leading to inappropriate treatment that hurts patients' prognoses. In addition, the standardized treatment of MPMNs has not yet been perfected. Therefore, we attempted to identify the factors affecting the prognosis of MPMNs by analyzing their clinical characteristics. First, we compared the demographic and clinical differences between the MPMNs cohort and the non-MPMNs cohort. Then, we analyzed the clinical characteristics and common sites of MPMNs for patients with rectal cancer, and finally, we identified the factors affecting the survival prognosis of patients with rectal cancer in MPMNs. MATERIALS AND METHODS Data source We extracted data from the latest version of the Surveillance, Epidemiology, and End Results (SEER) research database (released in November 2022). The SEER database is the National Cancer Institute's surveillance, epidemiology, and results database, which provides clinicopathological data, including clinical characteristics, incidence, treatment, and survival data for a wide range of cancers 19 , 20 . Primary cancer site and histology were coded according to the criteria in the International Classification of Diseases of Oncology, 3rd edition (ICD-O-3) and World Health Organization 2008 edition, and patients with rectal cancer were identified using C19.9 and C20.9. All data were downloaded from the SEER database containing information of all cancer patients diagnosed between 2000 and 2020, published in November 2022 [Incidence - SEER Research Plus Data, 17 Registries, Nov 2022 Sub (2000–2020)]. -2020)]. We identified MPMNs primarily based on two critical variables in the SEER database, the ‘total number of in situ/malignant tumors for patient’ and the ‘sequence number.’ The former can be used to identify patients with MPMNs, and the latter to index the sequence of onset of MPMNs. Population and variables Patients diagnosed with rectal cancer from 2000 to 2020 were screened from the SEER database. The main inclusion criteria were patients aged ≥ 18 years with a follow-up period of > 12 months who met the requirements of rectal cancer as the first primary cancer and combined with MPMNs. MPMNs were defined as two or more primary malignancies, excluded as metastatic malignancies, occurring simultaneously or sequentially in the same patient. Cases with missing values on essential covariates such as age, race, tumor size, grade, sex, surgery, and chemoradiotherapy were excluded. In addition, patients diagnosed only by autopsy or death certificate were excluded due to the lack of follow-up information. The flow chart of this study is shown in Fig. 1. This study identified a total of 203,213 patients diagnosed with rectal cancer, from which 46,246 patients were selected as having rectal cancer with MPMNs. Among these, 19,738 patients met the criteria for rectal cancer as the primary cancer. After excluding those who did not meet the conditions, the final cohort comprised 817 patients with rectal cancer as the primary cancer with MPMNs and 45,429 patients without MPMNs. Selected patients were divided into MPMNs and non-MPMNs cohorts, and clinical characteristics included year of diagnosis, age, sex, race, marital status, income, tumor size, number of regional lymph nodes detected, degree of differentiation, tumor stage, radiotherapy (yes or no/unknown), chemotherapy (yes or no/unknown) and surgery (yes or no/unknown), systemic therapy, survival time, and survival status Information. Histological variables were classified as ‘adenocarcinoma (ICD-O-3: 8140, 8210 to 8211, 8220 to 8221, 8261)’, ‘mucinous adenocarcinoma (ICD-O-3: 8480, 8481) ’, ‘stamped cell carcinoma (ICDO-3: 8490)’ and ‘Other.’ Pathological differentiation grade was defined using the following codes: highly differentiated (grade I), moderately differentiated (grade II), poorly differentiated (grade III), undifferentiated (grade IV), and grade unknown. Overall survival (OS, overall survival) was used for the analysis of survival outcomes. Statistical analysis Statistical analyses were performed using IBM SPSS Statistics version 25 (Version 25.0. Chicago, SPSS Inc.) and R software (Version 4.0.3). Descriptive statistical methods were employed to summarize demographic data, and chi-square tests were utilized to compare categorical variables between cases with baseline clinical characteristics in the MPMNs and non-MPMNs cohorts. Survival analyses were conducted through the Kaplan-Meier approach, and differences in survival between groups were evaluated using the Log-rank test. Kaplan-Meier curves were generated to illustrate patient survival rates. Univariate and multivariate Cox proportional hazards models were used to assess the risk or protective factors affecting survival and prognosis. The magnitude of the effect was expressed in terms of hazard ratio (HR) and 95% credibility interval (CI), and the difference was considered statistically significant with a bilateral p < 0.05. RESULTS Characteristics of study patients Table 1 presents the clinical characteristics of the included rectal cancer patients and the results of the comparison of the chi-square test between the MPMNs cohort and the non-MPMNs cohort. There were significant differences between the MPMNs and non-MPMNs cohorts in age, sex, race, tumor size, the extent of disease, number of regional lymph nodes, tumor T-stage, tumor N-stage, tumor M-stage, surgery, radiotherapy, systemic therapy, chemotherapy, and survival status (p < 0.05). The percentage of non-MPMNs and MPMNs groups were in the age <50 years (18.56% VS 6.12%), tumor size <3cm (99.5% VS 66.59%), 3-5cm (0.4% VS 38.27%), T1-2 (35.13%% VS 45.53%), T3-4 (64.87% VS 54.47%) M1 (11.71% VS 3.3%), radiotherapy therapy (44.43% VS 58.18%), and chemotherapy (63.71% VS 51.29%). Both cohorts had more male patients (57.81% VS 65.24%), and most patients underwent surgery (92.30% VS 94.37%). Compared with the non-MPMNs cohort, the proportion of patients in the MPMNs cohort who underwent radiotherapy and chemotherapy treatment was low (44.43% VS 58.18%), (51.29% VS 63.71%), respectively. What’s more, the number of detected regional lymph nodes ≥12 ratio in MPMNs cohort was low compared to non-MPMNs (50.43% VS 57.26%). Though most MPMN patients and non-MPMN patients had received systemic therapy, there was a significant difference in receiving systemic therapy preoperatively (30.19% VS 24.24%). There was no significant difference in marital status, income, size of the city of residence, degree of tumor differentiation, and tumor histology (p > 0.05). Clinical characteristics of MPMNs Morbidity characteristics This study ultimately included 817 rectal cancer patients with MPMNs, with an incidence of 1.77%, of which 88 (10.77%) were bi-primary malignant cancers, 619 (75.76%) were triple primary cancers, 96 (11.75%) were quadruple primary cancers, 11 (1.35%) were quintuple primary cancers, and 3 (0.37%) were sextuple primary cancers. The age distribution of the 817 rectal cancer patients with MPMNs was 19-90 years, with a median age of 65.62. There were 50 patients <50 years old, accounting for 6.12%; 273 patients aged 50-65 years old, accounting for 33.41%; 421 patients aged 65-79 years old, accounting for 51.53%; and 73 patients aged ≥80 years old, accounting for 8.94%. Men with rectal cancer were more likely to develop MPMNs than women (65.24% vs 34.76%). Site of disease Among the 817 patients included, there were 306 cases of concomitant colorectal cancers, accounting for 22.16%; 294 cases of concomitant urological cancers, accounting for 21.29%; 180 cases of concomitant lung and bronchial cancers, accounting for 13.03%; 96 cases of concomitant breast cancers, accounting for 6.95%; 89 cases of concomitant hematological cancers, accounting for 6.44%; 73 cases of concomitant reproductive system cancers, accounting for 5.29%; 63 cases of concomitant skin melanoma, accounting for 4.56%; 57 cases of malignant tumors of the colon, accounting for 4.13%; 42 cases of liver cancers, accounting for 3.04%; and 181 cases of other cancers (including cecum, small intestine, thyroid, oral, gastric cancers, etc.), accounting for 13.11%. See Figure 2 for details. Tumor combinations Out of the 817 patients, 88 cases of double primary cancers were found, of which 20 cases (22.73%) were rectal + colorectal cancer, 21 cases (23.86%) were rectal + lung and bronchial cancer, 18 cases (20.45%) were rectal + urological cancer, 11 cases (12.50%) were rectal + breast cancer, 7 cases (7.95%) were rectal cancer + cutaneous melanoma , 4 cases (4.54%) were rectal + reproductive cancer, 4 cases ( 4.54%) were rectal cancer + hematological cancer and 3 cases (3.41%) were rectal cancer + others. There were 619 cases of triple primary malignant cancers, with incomplete data on multiple cancer sites in 90 patients. Of the 529 data-complete cases of triple primary malignancies, rectal cancer + lung and bronchial cancer+ cancer of the urinary system (62 cases, 11.72%) were the most common, followed by rectal cancer + colorectal cancer + colorectal cancer (56 cases, 10.59%), rectal cancer + colorectal cancer + cancer of the urinary system (48 cases, 9.07%), rectal cancer + colorectal cancer+ cancer of the lung and bronchial ( 40 cases, 7.56%), rectal cancer + cancer of the urinary system + cancer of the hematological system (32 cases, 6.05%), rectal cancer + colorectal cancer + cancer of the reproductive system (30 cases, 5.67%), rectal cancer + cancer of the lung and bronchial + cancer of the reproductive system (26 cases, 4.91%), rectal cancer + colorectal cancer + cancer of the breast (25 cases, 4.73%), rectal cancer + lung and bronchial cancer + hematological system cancer (23 cases, 4.35%), rectal cancer + colorectal cancer + liver cancer (22 cases, 4.16%), rectal cancer + urological cancer + breast cancer (18 cases, 3.40%), rectal cancer + urinary cancer + cutaneous melanoma (14 cases, 2.65%), and the remaining 133 cases of other combinations. Among the 96 cases of quadruple primary malignant cancers, some of the tumor locations were unclear. According to the statistical results of the available data, the most common combinations were, in order, rectal cancer + colorectal cancer + colorectal cancer + urological cancer , rectal cancer + colorectal cancer + urological cancer + cancer of the lung and bronchial, rectal cancer + urological cancer + cancer of the hematological system + melanoma of the skin, and rectal cancer + cancer of the lung and bronchial + cancer of the urological system + cancer of the hematological system, among others. Types of rectal cancer pathology Of the 817 patients, most obtained a pathological diagnosis through surgery, while a few did so via endoscopy or puncture biopsy. The analysis of pathological types of rectal cancer showed that adenocarcinoma (563 cases, 68.91%), adenocarcinoma in tubulovillous adenoma (88 cases, 10.77%), adenocarcinoma in adenomatous polyp (74 cases, 9.06%), mucinous adenocarcinoma (47 cases, 5.75%), and adenocarcinoma in villous adenoma (19 cases, 2.33%). The rest were squamous cell carcinoma (10 cases, 1.22%), signet ring cell carcinoma (6 cases, 0.74%), and others (10 cases, 1.22%). Survival analysis MPMNs vs. non-MPMNs cohort survival comparison. The median survival of the MPMNs and non-MPMNs cohorts was 13.67and 14.08 years, respectively. Patients in the MPMNs cohort had better survival than those in the non-MPMNs cohort during the first 8 years after diagnosis while worse survival than those in the non-MPMNs from 8 years onwards (Figure 3). Analysis of survival and prognostic factors in the MPMNs cohort. Survival analysis revealed that 502 (61.44%) patients died and 315 survived up to the follow-up endpoint. The 12-month, 24-month, 36-month, 60-month and 120-month cumulative survival rates for the entire group of 817 patients were 100%, 96.08%, 91.55%, 79.56% and 40.02% respectively.We also found that the number of primary cancers did not significantly affect the survival of rectal cancer patients (p = 0.20). Our analysis found no statistical differences in survival time by age, sex, race, marital status, income, tumor size, degree of tumor differentiation, number of tumors, surgery, chemoradiotherapy and tumor stage (Fig. 4 A-L, P > 0.05) . Notably, patients with tumor Nx stage had a poorer prognosis than those with tumor stages N0, N1, and N2 (Fig. 5 A, P < 0.001) . Additionally, patients who received preoperative systemic therapy had a better prognosis than those who received systemic therapy postoperatively or did not receive systemic therapy (Fig. 5 B, P = 0.037). Patients with fewer than 12 regional lymph nodes detected had a poorer prognosis than those with 12 or more lymph nodes detected (Fig. 5 C, P < 0.001) . Furthermore, counties with smaller residential populations had a poorer prognosis than those with larger residential populations (Fig. 5 D, P = 0.049) . Univariate COX regression analysis revealed that tumor N-stage, receipt of systemic therapy, the number of regional lymph nodes <12, and city population were significant factors affecting the survival time of patients with MPMNs (p < 0.05). Further, COX multivariate regression analysis showed that tumor Nx stage (HR:9.607, 95%CI: 3.004-30.726, p<0.001), receipt of systemic therapy before surgery (HR:1.578, 95%CI: 1.086-2.295, p=0.017), and number of regional lymph nodes <12 (HR:1.493, 95% CI: 1.184-1.883, P<0.001) were risk factors for poor survival prognosis in patients with rectal cancer and MPMNs, whereas a larger city population (HR:0.783, 95%CI:0.625-0.981, P=0.034) was a protective factor for good prognosis. As shown in Table 2 . DISCUSSION With the advent of treatment modalities such as chemoradiotherapy, immunotherapy, and targeted therapy for rectal cancer, the expected survival time for rectal cancer patient has improved significantly 21 , 22 . However, the long-term survival of rectal cancer survivors is significantly affected by the risk of MPMNs. At the same time, their treatment regimen may be altered or even terminated by the presence of MPMNs 12 , 23 . In terms of clinical presentation, MPMNs need to be differentiated from metastasis or cancer recurrence since MPMNs represent the formation of a new primary malignant tumor that differs greatly from the original primary cancer 17 . There is currently a lack of research on the clinical features and survival analysis of MPMNs related to rectal cancer, and little is understood about these conditions. Small-sample studies and case reports are among the few studies 24 , 25 . Patients with MPMNs secondary to rectal cancer were found in the SEER database for this countrywide population-based study. Our findings are accurate and dependable because SEER is a large database that undergoes stringent quality control and updates its data every year to guarantee data accuracy. In recent years, the survival of cancer patients has been gradually prolonged, and the risk of developing MPMNs has gradually increased. However, studies have shown that the prevalence of MPMNs varies. In a single-center retrospective study in China analyzing 15,321 patients with malignant tumors, the prevalence of MPMNs was 1.09% (167/15,321) 26 . In a Japanese study, 14,167 (8.1%) of 174,477 subjects developed second primary cancers during a median follow-up period of 1.8 years 27 . The prevalence of MPMNs in China ranges from approximately 0.47–2.5% whereas the prevalence in other countries as a whole ranges from approximately 0.73–11.7% 9,28 .In this study, we collected data from 203,213 rectal cancer patients in the SEER database from 2000 to 2020 and excluded cases in which rectal cancer was not the first primary cancer. The probability of MPMNs after rectal cancer was about 1.77%, which was consistent with previous studies. Numerous retrospective studies have shown that a notably high prevalence of MPMNs is observed in individuals around ≥ 70 years of age 29 , 30 . In this study, the median age of onset of rectal cancer combined with MPMNs was 65.62 years, the primary age range of onset was 65–79 years. Additionally, our findings indicated a higher likelihood of MPMNs development in male patients compared to female patients, aligning with existing literature. According to the literature, the prevalence of MPMNs varies from region to region, but in general, the breast, reproductive system, digestive system, urological system, lung, and head and neck are the most common sites of MPMNs 31 , 32 , and Zhai et al. 26 found that the most common sites of MPMNs were the digestive and gastrointestinal systems 28 . Some studies have shown that the main sites of MPMNs in the digestive system are the colon and rectum 33 . Further analysis of the site of occurrence in this study revealed that the top six sites of MPMNs associated with rectal cancer were colorectal cancer (22.16%), urological cancer (21.29%), lung and bronchial cancer (13.03%), breast cancer (6.95%), hematological cancer (6.44%), and cancer s of the reproductive system (5.29%). The present study also showed that patients with rectal cancer exhibited an increased propensity for developing neoplastic colorectal cancers. In terms of cancer combinations, among double primary cancers, the most common combinations were, in descending order, rectal cancer + colorectal cancer, rectal cancer + lung and bronchial cancer, followed by rectal cancer + urinary tract cancer and rectal cancer + breast cancer. Among the three primary cancers, the most common combinations were, in descending order, rectal cancer + lung and bronchial cancer + urological cancer, rectal cancer + colorectal cancer + colorectal cancer, rectal cancer + colorectal cancer + urological cancer, and rectal cancer + colorectal cancer + lung and bronchial cancer. Therefore, in the long-term follow-up screening of rectal cancer patients, it is imperative to emphasize regular screening for colorectal cancer, cancers of the urinary system, and lung cancer. Additionally, female patients should remain vigilant for the potential development of breast cancer. For rectal cancer, the advent of innovative diagnostic and therapeutic approaches have facilitated earlier diagnosis and enhanced treatment. However, the oncogenic effects of radiotherapy is a significant concern, as it may significantly contribute to cancer development 34 , 35 . This raises the possibility that a predisposition to urological cancers following rectal cancer may be associated with radiotherapy administered for the primary cancer. More attention needs to be paid to the diagnosis of rectal cancer combined with lung cancer to differentiate it from lung metastases of rectal cancer. This is crucial given the high incidence of lung metastases associated with rectal cancer, and to prevent misdiagnoses that could have profound implications for treatment strategies 36 . Previous studies have shown that MPMNs are more common with two primary malignancies 9 , 25 . This study delved into the clinical characteristics of patients with rectal cancer as the first primary cancer, with a focus on exploring the incidence of MPMNs. Our findings revealed a higher prevalence of MPMNs in association with rectal cancer among patients with three primary tumors.; the reason for this may be related to the genetic predispositions and the specific genetic profile associated with rectal cancer 37 ; it is also possible that the majority of the subjects in the study belonged to populations distinct from those of Chinese origin, which could account for observed differences. Concurrently, the prognosis for rectal cancer in these populations tends to be more favorable, characterized by longer survival times and a higher likelihood of developing recurrent cancers. Lastly, previous studies usually overlooked the cancer's order of onset of disease as long as it is combined with MPMNs, whereas in our study, rectal cancer had to be the pimary malignancy. The median survival of MPMNs cohort and the non-MPMNs were 13.67 and 14.08 years, respectively, with little overall difference in survival times. Within the first 8 years of diagnosis, the survival of patients in the MPMNs cohort was better than that of non-MPMNs, while from the 8th year onwards, the survival of the MPMNs cohort was worse than that of non-MPMNs patients. The follow-up results indicate that the coexistence of cancers and MPMNs affects the long-term prognosis of patients. It is now believed that MPMNs are multiple relatively independent malignancies rather than advanced malignancies, and their prognosis is also usually better than metastases of malignant tumors 38 – 40 . The overall survival rates of rectal cancer with MPMNs at year 1, year 2, year 3, year 5, and year 10 were 100%, 96.08%, 91.55%, 79.56%, and 40.02%, respectively, in this study. We included patients with a follow-up time greater than 12 months, which may have slightly biased the survival statistics and the survival time may have produced biased results. Our study demonstrated that the overall survival of rectal cancer with MPMNs was superior to that of previously studied patients with rectal cancer with distant metastases 41 , 42 . In analyzing the effect of various factors on survival time, we found that patients with tumor Nx staging had a poorer prognosis than N0, N1, and N2 staging, with Nx indicating the inability to assess regional lymph nodes. Several studies have shown that patients with tumor Nx stage have a poorer prognosis than those with other N stages, and the reason for this may be that the Nx stage is associated with a high rate of distant metastasis 43 , 44 . Patients with Nx stage have a poorer prognosis than other N stages, so more attention should be paid to patients with Nx stage regarding clinical diagnosis and treatment. Meanwhile, the prognosis of patients with < 12 detected regional lymph nodes is worse than that of patients with ≥ 12, similar to previous literature 45 , 46 . The prognosis of patients living in counties with smaller populations is worse than that of patients living in counties with larger populations, possibly because patients in larger cities have better economic and medical conditions. Appropriate treatment for each primary cancer (e.g., aggressive surgery, radiotherapy, immune-targeted drugs, etc.), addressing each cancer individually, and avoiding premature palliation may bring a better prognosis 40 . Our study found that tumor Nx stage, preoperative receipt of systemic therapy, and regional lymph node < 12 were risk factors for poor prognosis in patients with rectal cancer secondary to MPMNs, whereas living in a larger city was a protective factor for a good prognosis. This insight could be instrumental in enhancing clinical diagnostic accuracy and in providing more informed guidance for clinical treatment. This study has several limitations. Firstly, being retrospective in nature, it is subject to selection bias, which may influence the results. Secondly, the SEER database primarily represents the US population, making it potentially less applicable to populations in other countries or regions, thus requiring cautious interpretation.Thirdly, despite the SEER database's stringent inclusion criteria, it still exhibits certain limitations; for example, some records lack detail in areas such as family history, genetic variant information, clinicopathological details, comprehensive treatment records (e.g., specifics of radiotherapy and surgical regimens, sequence of treatments), lifestyle characteristics, and other potentially critical clinical information necessary for thorough analysis. Finally, some of the results in this study differed from those of other studies 9 , 47 , and the reasons for these differences may be due to differences in objective factors such as region, ethnicity, environment, and genetic characteristics, as well as differences in subjective evaluation factors such as coding rules, reporting systems, and follow-up schedules of cancer registries around the world. In the future, we will endeavor to conduct more in-depth and comprehensive studies. Conclusions Our study confirms that patients with rectal cancer as the primary cancer should pay attention to the screening of recurrent cancers. During tumor follow-up screening, it is recommended to focus on colorectal cancer, lung cancer, and urological cancer, and female patients should also be screened for breast cancer. In this study, the overall survival rates of rectal cancer with MPMNs at years 1, 3, 5, and 10 were 100%, 91.55%, 79.56%, and 40.02%, respectively, and the prognosis is usually better than that of metastasis of malignant tumors. In addition, the "Nx stage of the tumor," "preoperative systemic therapy," and “number of regional lymph nodes < 12" may be risk factors for survival and prognosis of rectal cancer with MPMNs. In addition, "larger city population" may be a protective factor for a good prognosis. These factors may provide a reference for the clinical decision-making of individualized treatment. Abbreviations CI Credibility interval HR Hazard ratio MPMNs Multiple primary malignantneoplasms OS Overall survival SEER Surveillance, epidemiology and end results Declarations Authors' contributions SYZ and LHZ conceived and supervised the study. LJG, GYD and ELW recruited data information. SYZ ,LJG, GYD , ELW and YXW analyzed the data and visualized the results. SYZ wrote the original draft. BT AND LHZ reviewed and edited the manuscript. All authors revised and approved the final manuscript. Funding This work was supported by the Chengdu Fifth People's Hospital Key Project Foundation （No. YYZX20180021). Conflict of Interest Statemen The authors report no conflict of interest. Ethics approval and consent to participate Ethical approval was not required for the use of anonymized publicly available data. Consent for publication Not applicable. Data availability Publicly available datasets were analyzed in this study. This data can be found here: https://seer.cancer.gov/. Further dtails and other data that support the findings of this study are available from the corresponding authors upon reasonable request. Acknowledgements We thank all staff of the SEER database for their contribution in data collection, maintenance, distribution and so on. Also we would like to thank all the developers of the R programming package for selflessly sharing their code. Human and animal rights This article does not contain any studies with human participants or animals performed by any of the authors. Additional information Correspondence and requests for materials should be addressed to B.T. or L.H.Z. References Bray, F. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 74 , 229–263. https://doi.org/10.3322/caac.21834 (2024). Siegel, R. L., Giaquinto, A. N. & Jemal, A. Cancer statistics, 2024. CA Cancer J. Clin. 74 , 12–49. https://doi.org/10.3322/caac.21820 (2024). Yang, Y. et al. Current status of surgical treatment of rectal cancer in China. Chin. Med. J. (Engl) . 133 , 2703–2711. https://doi.org/10.1097/cm9.0000000000001076 (2020). Keller, D. S., Berho, M., Perez, R. O., Wexner, S. D. & Chand, M. 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Zhonghua Zhong Liu Za Zhi . 18 , 296–298 (1996). Nagao, Y. & Sata, M. High incidence of multiple primary carcinomas in HCV-infected patients with oral squamous cell carcinoma. Med. Sci. Monit. 15 , Cr453–459 (2009). Parekh, J. D., Kukrety, S., Thandra, A. & Valenta, C. Multiple Primary Malignant Neoplasms in an Elderly Patient. Cureus 10, e2384. (2018). https://doi.org/10.7759/cureus.2384 Etiz, D., Metcalfe, E. & Akcay, M. Multiple primary malignant neoplasms: A 10-year experience at a single institution from Turkey. J. Cancer Res. Ther. 13 , 16–20. https://doi.org/10.4103/0973-1482.183219 (2017). Yang, X. B. et al. High incidence combination of multiple primary malignant tumors of the digestive system. World J. Gastroenterol. 28 , 5982–5992. https://doi.org/10.3748/wjg.v28.i41.5982 (2022). Cheng, H. Y. et al. Clinical analysis of multiple primary malignancies in the digestive system: a hospital-based study. World J. Gastroenterol. 11 , 4215–4219. https://doi.org/10.3748/wjg.v11.i27.4215 (2005). Lin, J. et al. Increased Burden of Second Bladder Cancer and Rectal Cancer in Prostate Cancer Treated With Radiotherapy: Results From Surveillance, Epidemiology, and End Results. Cancer Control . 30 , 10732748231177544. https://doi.org/10.1177/10732748231177544 (2023). Grantzau, T., Thomsen, M. S., Væth, M. & Overgaard, J. Risk of second primary lung cancer in women after radiotherapy for breast cancer. Radiother Oncol. 111 , 366–373. https://doi.org/10.1016/j.radonc.2014.05.004 (2014). Tan, K. K., Gde, L., Sim, R. Jr & L.,. & How uncommon are isolated lung metastases in colorectal cancer? A review from database of 754 patients over 4 years. J. Gastrointest. Surg. 13 , 642–648. https://doi.org/10.1007/s11605-008-0757-7 (2009). Nomizu, T. & Watanabe, I. [Clinical investigation of familial clustering of cancer]. Gan No Rinsho . 32 , 485–492 (1986). Tang, M. et al. Nomogram for predicting occurrence and prognosis of liver metastasis in colorectal cancer: a population-based study. Int. J. Colorectal Dis. 36 , 271–282. https://doi.org/10.1007/s00384-020-03722-8 (2021). Hu, S. et al. Analysis of risk factors and prognosis of 253 lymph node metastasis in colorectal cancer patients. BMC Surg. 21 , 280. https://doi.org/10.1186/s12893-021-01276-2 (2021). Zhao, J. et al. A rare case of eight multiple primary malignant neoplasms in a female patient: A case report and review of the literature. Oncol. Lett. 9 , 587–590. https://doi.org/10.3892/ol.2014.2789 (2015). Zhao, F. Q. et al. Analysis of prognosis and influencing factors of 253 lymph node metastasis in descending colon, sigmoid colon, and rectal cancer: a multicenter study]. Zhonghua Wai Ke Za Zhi . 61 , 760–767. https://doi.org/10.3760/cma.j.cn112139-20230331-00132 (2023). Ge, Y. et al. Incidence and prognosis of pulmonary metastasis in colorectal cancer: a population-based study. Int. J. Colorectal Dis. 35 , 223–232. https://doi.org/10.1007/s00384-019-03434-8 (2020). Liu, Z. et al. The prognosis of NX stage differentiated thyroid cancer based on propensity score matching and SEER data. Am. J. Transl Res. 10 , 3782–3789 (2018). Zhang, J. et al. The Association Between Lymph Node Stage and Clinical Prognosis in Thyroid Cancer. Front. Endocrinol. (Lausanne) . 11 , 90. https://doi.org/10.3389/fendo.2020.00090 (2020). Zhu, L. et al. Examined lymph node numbers influence prognosis in rectal cancer treated with neoadjuvant therapy. Cancer Pathog Ther. 1 , 168–176. https://doi.org/10.1016/j.cpt.2023.01.001 (2023). Pitto, F. et al. Lymph node number, surface area and lymph node ratio are important prognostic indicators in neoadjuvant chemoradiotherapy treated rectal cancer. J. Clin. Pathol. 73 , 162–166. https://doi.org/10.1136/jclinpath-2019-206139 (2020). Qiu, M. et al. Treatment and prognosis of multiple primary malignant neoplasms complicated with renal cell carcinoma]. Beijing Da Xue Xue Bao Yi Xue Ban . 54 , 680–685. https://doi.org/10.19723/j.issn.1671-167X.2022.04.016 (2022). Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table2.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 14 Mar, 2026 Reviews received at journal 13 Mar, 2025 Reviewers agreed at journal 28 Feb, 2025 Reviewers invited by journal 25 Feb, 2025 Editor assigned by journal 15 Nov, 2024 Editor invited by journal 15 Nov, 2024 Submission checks completed at journal 14 Nov, 2024 First submitted to journal 31 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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07:01:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3834385,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5366332/v1/6ce40cad-6577-4a9a-9b93-afaa353521aa.pdf"},{"id":71730341,"identity":"e2c1fcf6-a9c3-487f-aeab-a5c0bf1eadf9","added_by":"auto","created_at":"2024-12-18 06:45:08","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18633,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5366332/v1/a5e747a02ef81a61b6d51276.docx"},{"id":71730338,"identity":"c8245b55-68f4-4eab-a9d3-78de43593d47","added_by":"auto","created_at":"2024-12-18 06:45:07","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":13017,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-5366332/v1/3dfbf4822a21586ebe1b9fe4.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical characteristics and prognostic analysis of multiple primary malignant neoplasms in patients with rectal cancer : a population-based study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eColorectal cancer is the third most prevalent and second most deadly malignancy in the United States. It was responsible for more than 1.9\u0026nbsp;million new cases and 904,000 deaths in the year 2022, accounting for nearly one-tenth of all cancer diagnoses and deaths\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. The incidence and mortality rates of colorectal cancer are also on the rise in China, with rectal cancer accounting for about 60 percent of all colorectal cancer cases\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. With the advancement of diagnostic techniques, comprehensive treatment, and tumor detection technology, the life expectancy of rectal cancer has been dramatically improved\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. The five-year survival rate can be as high as 90 percent for patients with early-stage rectal cancer when treated promptly\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Owing to various factors, including cancer susceptibility syndromes, specific tumor characteristics, environmental exposures, and delayed effects of treatments, cancer survivors may be susceptible to a wide range of malignancies\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, leading to a much higher incidence and detection of multiple primary malignant neoplasms (MPMNs)\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. The prevalence of MPMNs in the cancer population ranges from 2.4\u0026ndash;8% and can be as high as 17% at 20-year follow-up\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. The proportion of MPMNs varies according to the type of cancer. It is relatively high for cancers with a high incidence and a prolonged survival period, such as breast, prostate, and colorectal cancers\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Levi et al.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, in a retrospective study that included 24,859 cancer patients, found that 1 in 8 patients had a second primary cancer. Weir et al. found that the incidence of multiple primary cancers in colorectal cancer patients could be as high as 19.7% \u003csup\u003e12\u003c/sup\u003e. Rectal cancer survivors with high survival rates face the possibility of developing MPMNs, which may pose a threat to the patient's long-term survival.\u003c/p\u003e \u003cp\u003eMost studies have focused on comparing the risk of subsequent cancers in cancer patients with that in the general population or on describing factors associated with second primary cancers and prognosis in cancer survivors\u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Studies based on cancers combined with MPMNs are relatively few and primarily based on single-center, small-sample studies or case reports\u003csup\u003e\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Due to MPMNs' diverse clinical manifestations and low incidence, most clinicians are inexperienced in diagnosing and treating this type of disease. MPMNs are often misdiagnosed as recurrence or metastasis of primary malignant cancers, leading to inappropriate treatment that hurts patients' prognoses. In addition, the standardized treatment of MPMNs has not yet been perfected. Therefore, we attempted to identify the factors affecting the prognosis of MPMNs by analyzing their clinical characteristics. First, we compared the demographic and clinical differences between the MPMNs cohort and the non-MPMNs cohort. Then, we analyzed the clinical characteristics and common sites of MPMNs for patients with rectal cancer, and finally, we identified the factors affecting the survival prognosis of patients with rectal cancer in MPMNs.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData source\u003c/h2\u003e \u003cp\u003eWe extracted data from the latest version of the Surveillance, Epidemiology, and End Results (SEER) research database (released in November 2022). The SEER database is the National Cancer Institute's surveillance, epidemiology, and results database, which provides clinicopathological data, including clinical characteristics, incidence, treatment, and survival data for a wide range of cancers\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Primary cancer site and histology were coded according to the criteria in the International Classification of Diseases of Oncology, 3rd edition (ICD-O-3) and World Health Organization 2008 edition, and patients with rectal cancer were identified using C19.9 and C20.9. All data were downloaded from the SEER database containing information of all cancer patients diagnosed between 2000 and 2020, published in November 2022 [Incidence - SEER Research Plus Data, 17 Registries, Nov 2022 Sub (2000\u0026ndash;2020)]. -2020)]. We identified MPMNs primarily based on two critical variables in the SEER database, the \u0026lsquo;total number of in situ/malignant tumors for patient\u0026rsquo; and the \u0026lsquo;sequence number.\u0026rsquo; The former can be used to identify patients with MPMNs, and the latter to index the sequence of onset of MPMNs.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePopulation and variables\u003c/h3\u003e\n\u003cp\u003ePatients diagnosed with rectal cancer from 2000 to 2020 were screened from the SEER database. The main inclusion criteria were patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years with a follow-up period of \u0026gt;\u0026thinsp;12 months who met the requirements of rectal cancer as the first primary cancer and combined with MPMNs. MPMNs were defined as two or more primary malignancies, excluded as metastatic malignancies, occurring simultaneously or sequentially in the same patient. Cases with missing values on essential covariates such as age, race, tumor size, grade, sex, surgery, and chemoradiotherapy were excluded. In addition, patients diagnosed only by autopsy or death certificate were excluded due to the lack of follow-up information. The flow chart of this study is shown in \u003cb\u003eFig.\u0026nbsp;1.\u003c/b\u003e This study identified a total of 203,213 patients diagnosed with rectal cancer, from which 46,246 patients were selected as having rectal cancer with MPMNs. Among these, 19,738 patients met the criteria for rectal cancer as the primary cancer. After excluding those who did not meet the conditions, the final cohort comprised 817 patients with rectal cancer as the primary cancer with MPMNs and 45,429 patients without MPMNs. Selected patients were divided into MPMNs and non-MPMNs cohorts, and clinical characteristics included year of diagnosis, age, sex, race, marital status, income, tumor size, number of regional lymph nodes detected, degree of differentiation, tumor stage, radiotherapy (yes or no/unknown), chemotherapy (yes or no/unknown) and surgery (yes or no/unknown), systemic therapy, survival time, and survival status Information. Histological variables were classified as \u0026lsquo;adenocarcinoma (ICD-O-3: 8140, 8210 to 8211, 8220 to 8221, 8261)\u0026rsquo;, \u0026lsquo;mucinous adenocarcinoma (ICD-O-3: 8480, 8481) \u0026rsquo;, \u0026lsquo;stamped cell carcinoma (ICDO-3: 8490)\u0026rsquo; and \u0026lsquo;Other.\u0026rsquo; Pathological differentiation grade was defined using the following codes: highly differentiated (grade I), moderately differentiated (grade II), poorly differentiated (grade III), undifferentiated (grade IV), and grade unknown. Overall survival (OS, overall survival) was used for the analysis of survival outcomes.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using IBM SPSS Statistics version 25 (Version 25.0. Chicago, SPSS Inc.) and R software (Version 4.0.3). Descriptive statistical methods were employed to summarize demographic data, and chi-square tests were utilized to compare categorical variables between cases with baseline clinical characteristics in the MPMNs and non-MPMNs cohorts. Survival analyses were conducted through the Kaplan-Meier approach, and differences in survival between groups were evaluated using the Log-rank test. Kaplan-Meier curves were generated to illustrate patient survival rates. Univariate and multivariate Cox proportional hazards models were used to assess the risk or protective factors affecting survival and prognosis. The magnitude of the effect was expressed in terms of hazard ratio (HR) and 95% credibility interval (CI), and the difference was considered statistically significant with a bilateral p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eCharacteristics of study patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u0026nbsp;\u003c/strong\u003epresents the clinical characteristics of the included rectal cancer patients and the results of the comparison of the chi-square test between the MPMNs cohort and the non-MPMNs cohort. There were significant differences between the MPMNs and non-MPMNs cohorts in age, sex, race, tumor size, the extent of disease, number of regional lymph nodes, tumor T-stage, tumor N-stage, tumor M-stage, surgery, radiotherapy, systemic therapy, chemotherapy, and survival status (p \u0026lt; 0.05). The percentage of non-MPMNs and MPMNs groups were in the age \u0026lt;50 years (18.56% VS 6.12%), tumor size \u0026lt;3cm (99.5% VS 66.59%), 3-5cm (0.4% VS 38.27%), T1-2 (35.13%% VS 45.53%), T3-4 (64.87% VS 54.47%) M1 (11.71% VS 3.3%), radiotherapy therapy (44.43% VS 58.18%), and chemotherapy (63.71% VS 51.29%). Both cohorts had more male patients (57.81% VS 65.24%), and most patients underwent surgery (92.30% VS 94.37%). Compared with the non-MPMNs cohort, the proportion of patients in the MPMNs cohort who underwent radiotherapy and chemotherapy treatment was low (44.43% VS 58.18%), (51.29% VS 63.71%), respectively. What\u0026rsquo;s more, the number of detected regional lymph nodes \u0026ge;12 ratio in MPMNs cohort was low compared to non-MPMNs (50.43% VS 57.26%). Though most MPMN patients and non-MPMN patients had received systemic therapy, there was a significant difference in receiving systemic therapy preoperatively (30.19% VS 24.24%). There was no significant difference in marital status, income, size of the city of residence, degree of tumor differentiation, and tumor histology (p \u0026gt; 0.05).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical characteristics of MPMNs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMorbidity characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study ultimately included 817 rectal cancer patients with MPMNs, with an incidence of 1.77%, of which 88 (10.77%) were bi-primary malignant cancers, 619 (75.76%) were triple primary cancers, 96 (11.75%) were quadruple primary cancers, 11 (1.35%) were quintuple primary cancers, and 3 (0.37%) were sextuple primary cancers. The age distribution of the 817 rectal cancer patients with MPMNs was 19-90 years, with a median age of 65.62. There were 50 patients \u0026lt;50 years old, accounting for 6.12%; 273 patients aged 50-65 years old, accounting for 33.41%; 421 patients aged 65-79 years old, accounting for 51.53%; and 73 patients aged \u0026ge;80 years old, accounting for 8.94%. Men with rectal cancer were more likely to develop MPMNs than women (65.24% vs 34.76%). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSite of disease\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 817 patients included, there were 306 cases of concomitant colorectal cancers, accounting for 22.16%; 294 cases of concomitant urological cancers, accounting for 21.29%; 180 cases of concomitant lung and bronchial cancers, accounting for 13.03%; 96 cases of concomitant breast cancers, accounting for 6.95%; 89 cases of concomitant hematological cancers, accounting for 6.44%; 73 cases of concomitant reproductive system cancers, accounting for 5.29%; 63 cases of concomitant skin melanoma, accounting for 4.56%; 57 cases of malignant tumors of the colon, accounting for 4.13%; 42 cases of liver cancers, accounting for 3.04%; and 181 cases of other cancers (including cecum, small intestine, thyroid, oral, gastric cancers, etc.), accounting for 13.11%. See \u003cstrong\u003eFigure 2\u0026nbsp;\u003c/strong\u003efor details.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTumor combinations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOut of the 817 patients, 88 cases of double primary cancers were found, of which 20 cases (22.73%) were rectal + colorectal cancer, 21 cases (23.86%) were rectal + lung and bronchial cancer, 18 cases (20.45%) were rectal + urological cancer, 11 cases (12.50%) were rectal + breast cancer, 7 cases (7.95%) were rectal cancer + cutaneous melanoma , 4 cases (4.54%) were rectal + reproductive cancer, 4 cases ( 4.54%) were rectal cancer + hematological cancer and 3 cases (3.41%) were rectal cancer + others.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere were 619 cases of triple primary malignant cancers, with incomplete data on multiple cancer sites in 90 patients. Of the 529 data-complete cases of triple primary malignancies, rectal cancer + lung and bronchial cancer+ cancer of the urinary system (62 cases, 11.72%) were the most common, followed by rectal cancer + colorectal cancer + colorectal cancer (56 cases, 10.59%), rectal cancer + colorectal cancer + cancer of the urinary system (48 cases, 9.07%), rectal cancer + colorectal cancer+ cancer of the lung and bronchial ( 40 cases, 7.56%), rectal cancer + cancer of the urinary system + cancer of the hematological system (32 cases, 6.05%), rectal cancer + colorectal cancer + cancer of the reproductive system (30 cases, 5.67%), rectal cancer + cancer of the lung and bronchial + cancer of the reproductive system (26 cases, 4.91%), rectal cancer + colorectal cancer + cancer of the breast (25 cases, 4.73%), rectal cancer + lung and bronchial cancer + hematological system cancer (23 cases, 4.35%), rectal cancer + colorectal cancer + liver cancer (22 cases, 4.16%), rectal cancer + urological cancer + breast cancer (18 cases, 3.40%), rectal cancer + urinary cancer + cutaneous melanoma (14 cases, 2.65%), and the remaining 133 cases of other combinations.\u003c/p\u003e\n\u003cp\u003eAmong the 96 cases of quadruple primary malignant cancers, some of the tumor locations were unclear. According to the statistical results of the available data, the most common combinations were, in order, rectal cancer + colorectal cancer + colorectal cancer \u0026nbsp;+ urological cancer , rectal cancer + colorectal cancer + urological cancer + cancer of the lung and bronchial, rectal cancer + urological cancer + cancer of the hematological system + melanoma of the skin, and rectal cancer + cancer of the lung and bronchial + cancer of the urological system + cancer of the hematological system, among others.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTypes of rectal cancer pathology\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 817 patients, most obtained a pathological diagnosis through surgery, while a few did so via endoscopy or puncture biopsy. The analysis of pathological types of rectal cancer showed that adenocarcinoma (563 cases, 68.91%), adenocarcinoma in tubulovillous adenoma (88 cases, 10.77%), adenocarcinoma in adenomatous polyp (74 cases, 9.06%), mucinous adenocarcinoma (47 cases, 5.75%), and adenocarcinoma in villous adenoma (19 cases, 2.33%). The rest were squamous cell carcinoma (10 cases, 1.22%), signet ring cell carcinoma (6 cases, 0.74%), and others (10 cases, 1.22%).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurvival analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMPMNs vs. non-MPMNs cohort survival comparison.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median survival of the MPMNs and non-MPMNs cohorts was 13.67and 14.08 years, respectively. Patients in the MPMNs cohort had better survival than those in the non-MPMNs cohort during the first 8 years after diagnosis while worse survival than those in the non-MPMNs from 8 years onwards\u003cstrong\u003e\u0026nbsp;(Figure 3).\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnalysis of survival and prognostic factors in the MPMNs cohort.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSurvival analysis revealed that 502 (61.44%) patients died and 315 survived up to the follow-up endpoint. The 12-month, 24-month, 36-month, 60-month and 120-month cumulative survival rates for the entire group of 817 patients were 100%, 96.08%, 91.55%, 79.56% and 40.02% respectively.We also found that the number of primary cancers did not significantly affect the survival of rectal cancer patients (p = 0.20). Our analysis found no statistical differences in survival time by age, sex, race, marital status, income, tumor size, degree of tumor differentiation, number of tumors, surgery, chemoradiotherapy and tumor stage \u003cstrong\u003e(Fig.\u003c/strong\u003e\u003cstrong\u003e4\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eA-L, P \u0026gt; 0.05)\u003c/strong\u003e. Notably, patients with tumor Nx stage had a poorer prognosis than those with tumor stages N0, N1, and N2\u003cstrong\u003e\u0026nbsp;(Fig.\u003c/strong\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003cstrong\u003eA, P \u0026lt; 0.001)\u003c/strong\u003e. Additionally, patients who received preoperative systemic\u0026nbsp;therapy\u0026nbsp;had a better prognosis than those who received systemic\u0026nbsp;therapy\u0026nbsp;postoperatively or did not receive systemic\u0026nbsp;therapy\u003cstrong\u003e\u0026nbsp;(Fig.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003cstrong\u003eB, P = 0.037).\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ePatients with fewer than 12 regional lymph nodes detected had a poorer prognosis than those with 12 or more lymph nodes detected\u003cstrong\u003e\u0026nbsp;(Fig.\u003c/strong\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003cstrong\u003eC, P \u0026lt; 0.001)\u003c/strong\u003e. Furthermore,\u0026nbsp;counties with smaller residential populations had a poorer prognosis than those with larger residential populations\u003cstrong\u003e\u0026nbsp;(Fig.\u003c/strong\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003cstrong\u003eD, P = 0.049)\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnivariate COX regression analysis revealed that tumor N-stage, receipt of systemic therapy, the number of regional lymph nodes \u0026lt;12, and city population were significant factors affecting the survival time of patients with MPMNs (p \u0026lt; 0.05). Further, COX multivariate regression analysis showed that tumor Nx stage (HR:9.607, 95%CI: 3.004-30.726, p\u0026lt;0.001), receipt of systemic therapy before surgery (HR:1.578, 95%CI: 1.086-2.295, p=0.017), and number of regional lymph nodes \u0026lt;12 (HR:1.493, 95% CI: 1.184-1.883, P\u0026lt;0.001) were risk factors for poor survival prognosis in patients with rectal cancer and MPMNs, whereas a larger city population (HR:0.783, 95%CI:0.625-0.981, P=0.034) was a protective factor for good prognosis. As shown in \u003cstrong\u003eTable 2\u003c/strong\u003e.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eWith the advent of treatment modalities such as chemoradiotherapy, immunotherapy, and targeted therapy for rectal cancer, the expected survival time for rectal cancer patient has improved significantly\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. However, the long-term survival of rectal cancer survivors is significantly affected by the risk of MPMNs. At the same time, their treatment regimen may be altered or even terminated by the presence of MPMNs\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. In terms of clinical presentation, MPMNs need to be differentiated from metastasis or cancer recurrence since MPMNs represent the formation of a new primary malignant tumor that differs greatly from the original primary cancer\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. There is currently a lack of research on the clinical features and survival analysis of MPMNs related to rectal cancer, and little is understood about these conditions. Small-sample studies and case reports are among the few studies\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Patients with MPMNs secondary to rectal cancer were found in the SEER database for this countrywide population-based study. Our findings are accurate and dependable because SEER is a large database that undergoes stringent quality control and updates its data every year to guarantee data accuracy.\u003c/p\u003e \u003cp\u003eIn recent years, the survival of cancer patients has been gradually prolonged, and the risk of developing MPMNs has gradually increased. However, studies have shown that the prevalence of MPMNs varies. In a single-center retrospective study in China analyzing 15,321 patients with malignant tumors, the prevalence of MPMNs was 1.09% (167/15,321) \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. In a Japanese study, 14,167 (8.1%) of 174,477 subjects developed second primary cancers during a median follow-up period of 1.8 years\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. The prevalence of MPMNs in China ranges from approximately 0.47\u0026ndash;2.5% whereas the prevalence in other countries as a whole ranges from approximately 0.73\u0026ndash;11.7%\u003csup\u003e9,28\u003c/sup\u003e.In this study, we collected data from 203,213 rectal cancer patients in the SEER database from 2000 to 2020 and excluded cases in which rectal cancer was not the first primary cancer. The probability of MPMNs after rectal cancer was about 1.77%, which was consistent with previous studies. Numerous retrospective studies have shown that a notably high prevalence of MPMNs is observed in individuals around \u0026ge;\u0026thinsp;70 years of age\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. In this study, the median age of onset of rectal cancer combined with MPMNs was 65.62 years, the primary age range of onset was 65\u0026ndash;79 years. Additionally, our findings indicated a higher likelihood of MPMNs development in male patients compared to female patients, aligning with existing literature. According to the literature, the prevalence of MPMNs varies from region to region, but in general, the breast, reproductive system, digestive system, urological system, lung, and head and neck are the most common sites of MPMNs\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e, and Zhai et al.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e found that the most common sites of MPMNs were the digestive and gastrointestinal systems\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Some studies have shown that the main sites of MPMNs in the digestive system are the colon and rectum\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Further analysis of the site of occurrence in this study revealed that the top six sites of MPMNs associated with rectal cancer were colorectal cancer (22.16%), urological cancer (21.29%), lung and bronchial cancer (13.03%), breast cancer (6.95%), hematological cancer (6.44%), and cancer s of the reproductive system (5.29%). The present study also showed that patients with rectal cancer exhibited an increased propensity for developing neoplastic colorectal cancers. In terms of cancer combinations, among double primary cancers, the most common combinations were, in descending order, rectal cancer\u0026thinsp;+\u0026thinsp;colorectal cancer, rectal cancer\u0026thinsp;+\u0026thinsp;lung and bronchial cancer, followed by rectal cancer\u0026thinsp;+\u0026thinsp;urinary tract cancer and rectal cancer\u0026thinsp;+\u0026thinsp;breast cancer. Among the three primary cancers, the most common combinations were, in descending order, rectal cancer\u0026thinsp;+\u0026thinsp;lung and bronchial cancer\u0026thinsp;+\u0026thinsp;urological cancer, rectal cancer\u0026thinsp;+\u0026thinsp;colorectal cancer\u0026thinsp;+\u0026thinsp;colorectal cancer, rectal cancer\u0026thinsp;+\u0026thinsp;colorectal cancer\u0026thinsp;+\u0026thinsp;urological cancer, and rectal cancer\u0026thinsp;+\u0026thinsp;colorectal cancer\u0026thinsp;+\u0026thinsp;lung and bronchial cancer. Therefore, in the long-term follow-up screening of rectal cancer patients, it is imperative to emphasize regular screening for colorectal cancer, cancers of the urinary system, and lung cancer. Additionally, female patients should remain vigilant for the potential development of breast cancer.\u003c/p\u003e \u003cp\u003eFor rectal cancer, the advent of innovative diagnostic and therapeutic approaches have facilitated earlier diagnosis and enhanced treatment. However, the oncogenic effects of radiotherapy is a significant concern, as it may significantly contribute to cancer development\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. This raises the possibility that a predisposition to urological cancers following rectal cancer may be associated with radiotherapy administered for the primary cancer. More attention needs to be paid to the diagnosis of rectal cancer combined with lung cancer to differentiate it from lung metastases of rectal cancer. This is crucial given the high incidence of lung metastases associated with rectal cancer, and to prevent misdiagnoses that could have profound implications for treatment strategies\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePrevious studies have shown that MPMNs are more common with two primary malignancies\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. This study delved into the clinical characteristics of patients with rectal cancer as the first primary cancer, with a focus on exploring the incidence of MPMNs. Our findings revealed a higher prevalence of MPMNs in association with rectal cancer among patients with three primary tumors.; the reason for this may be related to the genetic predispositions and the specific genetic profile associated with rectal cancer\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e; it is also possible that the majority of the subjects in the study belonged to populations distinct from those of Chinese origin, which could account for observed differences. Concurrently, the prognosis for rectal cancer in these populations tends to be more favorable, characterized by longer survival times and a higher likelihood of developing recurrent cancers. Lastly, previous studies usually overlooked the cancer's order of onset of disease as long as it is combined with MPMNs, whereas in our study, rectal cancer had to be the pimary malignancy.\u003c/p\u003e \u003cp\u003eThe median survival of MPMNs cohort and the non-MPMNs were 13.67 and 14.08 years, respectively, with little overall difference in survival times. Within the first 8 years of diagnosis, the survival of patients in the MPMNs cohort was better than that of non-MPMNs, while from the 8th year onwards, the survival of the MPMNs cohort was worse than that of non-MPMNs patients. The follow-up results indicate that the coexistence of cancers and MPMNs affects the long-term prognosis of patients. It is now believed that MPMNs are multiple relatively independent malignancies rather than advanced malignancies, and their prognosis is also usually better than metastases of malignant tumors\u003csup\u003e\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. The overall survival rates of rectal cancer with MPMNs at year 1, year 2, year 3, year 5, and year 10 were 100%, 96.08%, 91.55%, 79.56%, and 40.02%, respectively, in this study. We included patients with a follow-up time greater than 12 months, which may have slightly biased the survival statistics and the survival time may have produced biased results. Our study demonstrated that the overall survival of rectal cancer with MPMNs was superior to that of previously studied patients with rectal cancer with distant metastases\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn analyzing the effect of various factors on survival time, we found that patients with tumor Nx staging had a poorer prognosis than N0, N1, and N2 staging, with Nx indicating the inability to assess regional lymph nodes. Several studies have shown that patients with tumor Nx stage have a poorer prognosis than those with other N stages, and the reason for this may be that the Nx stage is associated with a high rate of distant metastasis\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Patients with Nx stage have a poorer prognosis than other N stages, so more attention should be paid to patients with Nx stage regarding clinical diagnosis and treatment. Meanwhile, the prognosis of patients with \u0026lt;\u0026thinsp;12 detected regional lymph nodes is worse than that of patients with \u0026ge;\u0026thinsp;12, similar to previous literature\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. The prognosis of patients living in counties with smaller populations is worse than that of patients living in counties with larger populations, possibly because patients in larger cities have better economic and medical conditions. Appropriate treatment for each primary cancer (e.g., aggressive surgery, radiotherapy, immune-targeted drugs, etc.), addressing each cancer individually, and avoiding premature palliation may bring a better prognosis\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Our study found that tumor Nx stage, preoperative receipt of systemic therapy, and regional lymph node\u0026thinsp;\u0026lt;\u0026thinsp;12 were risk factors for poor prognosis in patients with rectal cancer secondary to MPMNs, whereas living in a larger city was a protective factor for a good prognosis. This insight could be instrumental in enhancing clinical diagnostic accuracy and in providing more informed guidance for clinical treatment.\u003c/p\u003e \u003cp\u003eThis study has several limitations. Firstly, being retrospective in nature, it is subject to selection bias, which may influence the results. Secondly, the SEER database primarily represents the US population, making it potentially less applicable to populations in other countries or regions, thus requiring cautious interpretation.Thirdly, despite the SEER database's stringent inclusion criteria, it still exhibits certain limitations; for example, some records lack detail in areas such as family history, genetic variant information, clinicopathological details, comprehensive treatment records (e.g., specifics of radiotherapy and surgical regimens, sequence of treatments), lifestyle characteristics, and other potentially critical clinical information necessary for thorough analysis. Finally, some of the results in this study differed from those of other studies\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e, and the reasons for these differences may be due to differences in objective factors such as region, ethnicity, environment, and genetic characteristics, as well as differences in subjective evaluation factors such as coding rules, reporting systems, and follow-up schedules of cancer registries around the world. In the future, we will endeavor to conduct more in-depth and comprehensive studies.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur study confirms that patients with rectal cancer as the primary cancer should pay attention to the screening of recurrent cancers. During tumor follow-up screening, it is recommended to focus on colorectal cancer, lung cancer, and urological cancer, and female patients should also be screened for breast cancer. In this study, the overall survival rates of rectal cancer with MPMNs at years 1, 3, 5, and 10 were 100%, 91.55%, 79.56%, and 40.02%, respectively, and the prognosis is usually better than that of metastasis of malignant tumors. In addition, the \"Nx stage of the tumor,\" \"preoperative systemic therapy,\" and \u0026ldquo;number of regional lymph nodes\u0026thinsp;\u0026lt;\u0026thinsp;12\" may be risk factors for survival and prognosis of rectal cancer with MPMNs. In addition, \"larger city population\" may be a protective factor for a good prognosis. These factors may provide a reference for the clinical decision-making of individualized treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCI Credibility interval\u003c/p\u003e\n\u003cp\u003eHR Hazard ratio \u003c/p\u003e\n\u003cp\u003eMPMNs Multiple primary malignantneoplasms \u003c/p\u003e\n\u003cp\u003eOS Overall survival \u003c/p\u003e\n\u003cp\u003eSEER Surveillance, epidemiology and end results\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSYZ and LHZ conceived and supervised the study. LJG, GYD and ELW recruited data information. SYZ ,LJG, GYD , ELW and YXW analyzed the data and visualized the results. SYZ wrote the original draft. BT AND LHZ reviewed and edited the manuscript. All authors revised and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Chengdu Fifth People\u0026apos;s Hospital Key Project Foundation\u0026nbsp;（No. YYZX20180021).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statemen\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors report no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was not required for the use of anonymized publicly available data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePublicly available datasets were analyzed in this study. This data can be found here: https://seer.cancer.gov/. Further dtails and other data that support the findings of this study are available from the corresponding authors upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all staff of the SEER database for their contribution in data collection, maintenance, distribution and so on. Also we would like to thank all the developers of the R programming package for selflessly sharing their code.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman and animal rights\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis article does not contain any studies with human participants or animals performed by any of the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence and requests for materials should be addressed to B.T. or L.H.Z.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray, F. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. \u003cem\u003eCA Cancer J. 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A retrospective analysis was conducted on eligible rectal cancer patients utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Comprehensive clinical data were incorporated, including patients' age, sex, race, marital status, clinical stage, surgery, chemoradiotherapy, tumor size, tumor differentiation, number of regional lymph nodes examined, survival time, and tumor status. Subsequently, univariate and multivariate Cox regression models were used to identify risk factors affecting the prognosis of MPMNs and rectal cancer patients. Colorectal cancer(22.16%), urological cancer (21.29%), and lung and bronchial cancer(13.13%) were the top three locations of MPMNs linked to rectal cancer. COX multivariate regression analysis showed that tumor Nx stage (HR:9.607, 95%CI: 3.004-30.726, p\u0026lt;0.001), receipt of systemic therapy before surgery (HR:1.578, 95%CI: 1.086-2.295, p=0.017) and number of regional lymph nodes \u0026lt;12 (HR:1.493, 95% CI: 1.184-1.883, P\u0026lt;0.001) were risk factors for poor prognosis of rectal cancer-related MPMNs, whereas a larger city population (HR:0.783, 95%CI:0.625-0.981, P=0.034) was a protective factor for good prognosis. Therefore, rectal cancer patients should be monitored for multiple primary cancers, especially colorectal, lung, and urological cancers. Prognostic markers for rectal cancer with MPMNs were \"larger city population,\" \"number of regional lymph nodes \u0026lt;12,\" \"preoperative receipt of systemic therapy,\" and \"tumor Nx stage.\"\u003c/p\u003e","manuscriptTitle":"Clinical characteristics and prognostic analysis of multiple primary malignant neoplasms in patients with rectal cancer : a population-based study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-18 06:45:03","doi":"10.21203/rs.3.rs-5366332/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"312286161896663594865433020801669965285","date":"2026-03-15T03:33:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-13T23:37:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"73905346536319465253411805901855269046","date":"2025-02-28T07:53:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-02-25T12:06:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-15T17:07:48+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-11-15T11:42:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-14T07:35:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-10-31T09:07:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8347c76b-e032-4816-837d-963681dc5443","owner":[],"postedDate":"December 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":40761222,"name":"Health sciences/Risk factors"},{"id":40761223,"name":"Biological sciences/Cancer/Gastrointestinal cancer/Colorectal cancer/Rectal cancer"},{"id":40761224,"name":"Health sciences/Oncology/Cancer"},{"id":40761225,"name":"Biological sciences/Cancer"},{"id":40761226,"name":"Biological sciences/Cancer/Cancer prevention"},{"id":40761227,"name":"Biological sciences/Cancer/Cancer screening"},{"id":40761228,"name":"Biological sciences/Cancer/Gastrointestinal cancer"},{"id":40761229,"name":"Biological sciences/Cancer/Tumour biomarkers"}],"tags":[],"updatedAt":"2024-12-18T06:45:03+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-18 06:45:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5366332","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5366332","identity":"rs-5366332","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}