Introduction

Colorectal cancer (CRC) is the fourth most common cancer diagnosed in the United States and the second leading cause of cancer death. Based on projections, it is estimated that the United States will witness approximately 44,850 cases of rectal cancer (RC) by 2022 (26,650 for men, 18,200 for women)1. With ongoing advancements in chemotherapy techniques, adjuvant chemotherapy following surgical intervention has demonstrated the potential to enhance the overall survival (OS) rates of patients diagnosed with staged RC2. Regrettably, individuals who have successfully overcome RC are confronted with a significantly elevated mortality risk from second primary malignancies, surpassing the prevalence rates observed in the general population by 4–8%3,4.

The implementation of multimodal therapies in the management of RC has significantly improved the overall outcomes for patients in the field of oncology. The treatment of RC, including chemotherapy, radiotherapy, and surgery, is constantly advancing achieving the best possible results for tumor control, functional recovery, and patient survival5. In several studies, second primary cancers (SPC) have been associated with RC, with most concluding that radiotherapy is a factor in SPC development6,7,8. However, there have been limited investigations into the impact of chemotherapy after RC among female patients, particularly in relation to the endometrium.

Compared to the general population, individuals diagnosed with CRC face a notably higher likelihood of developing extracolonic SPC. Among these secondary cancers, a considerable portion is attributed to obesity-related cancers, such as endometrial cancer (EC)9,10. Aside from breast, ovarian, cervical, and CRC, EC is the second most prevalent primary cancer11,12,13,14,15, and previous research has indicated that chemotherapy for breast cancer and radiotherapy for cervical cancer elevate the likelihood of second primary endometrial cancer (SEC)16,17.

The age of onset of SEC is similar to that of primary endometrial cancer (PEC), but patients with SEC have worse histologic types and are in a later stage at diagnosis. SEC has a higher 5‐year cancer special survival rate than that of PEC, but SEC survival is lower than that of PEC in absolute terms (i.e., 5‐year survival)18,19. However, there is no significant difference in the molecular characteristics of SEC and PEC, and defective DNA mismatch repair may be one of the pathogenesis of patients with SEC20,21. The most common first primary sites for SEC are breast cancer and CRC, but SEC with a first primary CRC has worse prognosis and a higher risk of EC‐specific death19. Chemotherapy drugs can damage cell DNA, leading to gene recombination and translocation, which indirectly cause cancer patients to develop other tumors22,23. Therefore, it is necessary to explore the relationship between chemotherapy and SEC in patients with RC.

However, chemotherapy and SEC incidence in patients with RC have not been thoroughly investigated. Hence, the primary objective of this retrospective analysis is to evaluate the correlation between chemotherapy and SEC, as well as the occurrence of SEC and the postchemotherapy survival in individuals diagnosed with RC.

Materials and methods

Patient selection

Patient selection and data collection involved identifying female individuals diagnosed with RC as their initial primary cancer. From 1975 to 2018, participants diagnosed with RC as the first primary cancer were enrolled from nine registries of the SEER database in the United States. The inclusion criteria for patients comprised a diagnosis of RC (specifically site codes C19.9 and C20.9), a primary cancer diagnosis, and a comprehensive record of surgical interventions. The exclusion criteria were as follows patients who have not received a confirmed diagnosis of RC, male patients, those with multiple tumors, distant or unknown stage, age below 20 years, no surgery or unknown surgery, patients with a survival time of less than 3 months and patients with unknown clinical information. The detailed screening process for all female RC patients in this analysis is shown in Supplementary Fig. S1.

Informed consent of the patient is not required to obtain or use SEER database. Consequently, informed consent and ethical approval are waived for this study. Instead, the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting cohorts were followed in this study.

Explanation of SEC and subsequent actions

This study explored the development and survival analysis of SEC after chemotherapy. Given that SEC incidence in patients with RC has not yet been thoroughly investigated, the primary objective of this retrospective analysis is to evaluate the correlation between chemotherapy and SEC, as well as the occurrence of SEC and the postchemotherapy survival in individuals diagnosed with RC.

In patients with RC, SEC refers to any form of EC that took place over 3 months after RC treatment and ending either at the point of SEC diagnosis, death from any cause, or within a maximum of 30 years of follow-up, whichever happened earlier. This study partially investigated the survival rates of SEC, including the OS and cancer-specific survival (CSS) rates. The measurements were taken from the moment of RC diagnosis and continued until the diagnosis of any SEC, mortality from any cause, or the completion of a 10-year follow-up, whichever occurred earlier.

Data analyses

We evaluated differences in baseline characteristics of patient and clinical information using the chi-square and Mann–Whitney tests. The study employed Fine–Gray models to evaluate the incidence and probability of SEC following an RC diagnosis. When estimating the hazard ratio (HR) and 95% confidence interval (CI) for the development of SEC, this analysis considered the occurrence of non-SEC events and all-cause mortality. To determine the likelihood of the development of SEC, we used R software (version 4.3.0), a multivariate model, and Poisson regression.

The study utilized the Poisson regression analysis method to determine the risk (RR) and 95% CI for the development of SEC in RC patients who underwent chemotherapy and no-chemotherapy. Furthermore, Poisson regression analysis was employed to estimate the standardized incidence ratio (SIR) and 95% CI, which enable us to evaluate the likelihood of SEC occurrence in female RC patients compared to the general American population. SEER*Stat 8.4.0.1 was utilized to compute the SIR.

To assess the dynamic risks and advancements associated with SEC in relation to chemotherapy, our study employed the RR and SIR models to estimate the duration since the diagnosis of RC, the age of the patient at the time of diagnosis, and the year of diagnosis. Furthermore, we calculated the SIR for race and grade. To minimize bias in the OS and CSS rates, as well as the confounding factors, we employed a 1:1 ratio propensity-score matching (PSM) technique to pair SEC patients with chemotherapy and no-chemotherapy. SEC patients with chemotherapy and no-chemotherapy were also matched with PEC patients at a 1:5 ratio PSM24. We ensured that the baseline characteristics for PSM were similar, including matching for factors, such as age, race, grade, stage, marital status, duration of EC diagnosis, tumor size, histology, and cancer treatment (chemotherapy, radiotherapy, and/or surgery). Patients categorized as PEC were those who had been diagnosed with endometrial cancer as their first and sole malignancy during the follow-up period. The CSS rates of SEC and PEC were determined from the start of randomization until the occurrence of cancer-related death25. The Kaplan–Meier technique was employed to generate survival curves, and the log-rank test was utilized to compare the differences in OS and CSS rates. Statistical significance is conventionally associated with P-values below 0.05. All computational analyses were was conducted using R software (version 4.3.0).

Results

Baseline characteristics of SEC patients

The study included a total of 30,847 individuals diagnosed with RC, all of whom met the necessary inclusion and exclusion criteria. The baseline characteristics of these patients are presented in Table 1. In total, 8176 (26.5%) patients received chemotherapy and 22,671 (73.5%) patients received no-chemotherapy. The age at diagnosis had a median of 67.0 years (57.0–76.0), while the follow-up time had a median of 140.0 months (37.0–176.0). The year of diagnosis had a median of 1993 (1984–2004), and the latency time had a median of 115.5 months (65.0–166.0). Furthermore, patients with RC who received chemotherapy tended to be younger (61 years old), had a higher frequency of diagnosis in later years, were more likely to be married (n = 4540, 55.5%), had a larger tumor size (n = 3565, 43.6%), had a higher incidence of Grade III/IV cancer (n = 1407, 17.2%), had a greater prevalence of mucinous and serous neoplasms (n = 614, 7.5%), had a lower occurrence of localized staging (n = 1728, 21.1%), and had a higher likelihood of receiving radiotherapy (n = 6428, 78.5%) compared to no-chemotherapy patients. Out of the entire patient population, 168 individuals (5.45‰) developed SEC. Among them, chemotherapy was administered to 107 patients (3.47‰), while 61 patients (1.98‰) received no-chemotherapy.

Table 1 Baseline characteristics of patients with surgically treated RC.
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Cumulative incidence of SEC

Over a span of 30 years, the occurrence of SEC in patients with RC who underwent chemotherapy was considerably higher than in those who did not (HR 1.86, 95% CI 1.43–2.42; P-value < 0.001) (Fig. 1a). Moreover, the no-chemotherapy group demonstrated a significant increase in mortality compared to the chemotherapy group (P-value < 0.001; Supplementary Fig. S2). Then, the SEC stage was categorized into two groups: localized disease (HR 1.28, 95% CI 0.74–2.12; P-value = 0.269) and regional disease (HR 2.62, 95% CI 1.81–3.85; P-value < 0.001) (Fig. 1b,c). The results of univariate and multivariate competing risk model from Table 2 are shown (univariate analysis: HR 2.06, 95% CI 1.58–2.67; P-value < 0.001, multivariate analysis: HR 2.26, 95% CI 1.63–3.15; adjusted P-value < 0.001). The results clearly indicate that chemotherapy is a significant and independent risk factor for SEC in female RC patients. The RR estimated the risk of SEC without considering competing events, highlighting a notably higher risk in the chemotherapy group compared to the no-chemotherapy group (RR = 1.53, 95% CI 1.12–2.07; P-value = 0.025; Supplementary Table S1).

Figure 1
figure 1

The cumulative occurrence of SEC in contrast to patients who were not administered CT (a), the overall cohort. (b) Patients with localized disease. (c) Patients with regional disease. NCT no-chemotherapy, CT chemotherapy.

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Table 2 Competing risk regression model for developing SEC in RC.
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Next, an analysis of subgroups was conducted to determine the likelihood of developing SEC using competing risk regression in both the chemotherapy and the no-chemotherapy groups. The findings indicated that nearly all subgroups exhibited an increased risk of developing SEC after chemotherapy (Fig. 2; Supplementary Table S2), including age (50–69 years, HR 1.62, 95% CI 1.16–2.25; P-value = 0.018; > 70 years, HR 2.23, 95% CI 1.3–3.84; P-value = 0.015), race (white, HR 1.97, 95% CI 1.48–2.62; P-value < 0.001), tumor size (2–4 cm, HR 2.01, 95% CI 1.30–3.12; P-value = 0.009), histology (adenocarcinoma, HR 1.81, 95% CI 1.37–2.39; P-value < 0.001; mucinous and serous neoplasms, HR 4.12, 95% CI 1.33–12.80; P-value = 0.040), marital status (married, HR 1.80, 95% CI 1.31–2.48; P-value = 0.002), stage (regional, HR 2.64, 95% CI 1.81–3.15; P-value = 0.001), grade (Grade I/II, HR 1.81, 95% CI 1.35–2.43; P-value = 0.001), year of diagnosis (1985–1994, HR 2.44, 95% CI 1.55–3.86; P-value = 0.001; 1995–2004, HR 1.87, 95% CI 1.16–2.99; P-value = 0.030), and site (rectum, NOS, HR 1.91, 95% CI 1.39–2.62; P-value = 0.001). To rule out the effects of radiotherapy, we conducted a subgroup analysis among patients who did not receive radiotherapy. The results showed that chemotherapy remained a risk factor for SEC in the general population (HR 2.84, 95% CI 1.38–5.85; P-value = 0.017), but it was not statistically significant among subgroups due to the small sample size (Supplementary Fig. S3, Supplementary Table S3).

Figure 2
figure 2

A comparison of the risk of SEC between subgroups is made by analyzing HRs based on competing risk analyses. NCT no-chemotherapy, CT chemotherapy, HRs hazard ratios.

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Dynamic risk and incidence evaluation for SEC

To investigate the dynamic risk and incidence of SEC in the chemotherapy group, we computed the RR-plots, which included the age at RC diagnosis, the year of RC diagnosis, and the duration of time following RC diagnosis (20–49, RR = 0.87, 95% CI 0.43–1.73, P-value = 0.743; 50–69, RR = 1.32, 95% CI 0.94–1.85, P-value = 0.175) and ≥ 70 years with RC reached the highest incidence risk of SEC (≥ 70, RR = 2.11, 95% CI 1.20–3.57, P-value = 0.023; Fig. 3a). The dynamic analysis of RC diagnosis RR plots indicated that the risk of developing SEC was highest during the period of 1985–1994 (1975–1984, RR = 1.17, 95% CI 0.27–3.26, P-value = 0.829; 1985–1994, RR = 2.42, 95% CI 1.52–3.79, P-value = 0.001; 1995–2004, RR = 1.86, 95% CI 1.16–3.00, P-value = 0.031; ≥ 2005, RR = 0.88, 95% CI 0.46–1.67, P-value = 0.751; Fig. 3b). The latency of the RR plots showed the heightened chance of SEC declined as the latency period extended (3–119, RR = 2.14, 95% CI 1.31–3.51, P-value = 0.011; 120–240, RR = 1.90, 95% CI 1.28–2.78, P-value = 0.006; 241–360, RR = 0.81, 95% CI 0.36–1.61, P-value = 0.638; Fig. 3c).

Figure 3
figure 3

RRs and 95% CIs of developing SEC in the chemotherapy group vs the no-chemotherapy group.

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Furthermore, the SIR of SEC was computed to compare the general population in the United States with patients diagnosed with RC. This comparison considered factors such as the age and year of RC diagnosis, the latency period following RC diagnosis, and the grade and race of the patients. The findings revealed that individuals with chemotherapy or no-chemotherapy, and who also had RC, were at an increased risk of developing SEC compared to the general US population. Furthermore, the chemotherapy group exhibited a greater SIR than the no-chemotherapy group (chemotherapy, SIR: 1.65; 95% CI 1.35–1.99; no-chemotherapy, SIR: 1.11; 95% CI 0.98–1.25; Supplementary Table S4; Supplementary Fig. S4).

Survival outcome of SEC

Initially, we assessed the disparity between OS and CSS in individuals with SEC who underwent chemotherapy and no-chemotherapy treatments. No significant disparity was observed in the CSS and OS at 10 years rates between the chemotherapy and no-chemotherapy groups (10-year OS, 10.18‰ vs 5.81‰, P-value = 0.083; 10-year CSS, 8.29‰ vs 7.29‰, P-value = 0.270, Fig. 4a, Supplementary Fig. S5a). Due to the presence bias, a 1:1 ratio of PSM was employed to pair SEC patients with chemotherapy and no-chemotherapy, revealing no notable disparity in the outcomes (10-year OS, 5.81‰ vs 5.81‰, P-value = 0.082; 10-year CSS, 6.58‰ vs 6.58‰, P-value = 0.240, Fig. 4b, Supplementary Fig. S5b, Supplementary Table S5). In addition, we compared the OS and CSS of patients with SEC and PEC between the chemotherapy and the no-chemotherapy groups to further assess the disparity in survival rates. There were clear disparities in the 10-year OS and 10-year CSS between patients who developed SEC and received either chemotherapy or no-chemotherapy treatment and patients who developed PEC and received chemotherapy or no-chemotherapy. These differences were observed both before (10-year OS, 25.58‰ vs 5.59‰, P-value < 0.001; 10-year CSS, 25.28‰ vs 5.14‰, P-value = 0.270; Fig. 4c, Supplementary Fig. S5c) and after 1:5 ratio PSM (10-year OS, 8.20‰ vs 1.66‰, P-value < 0.001; 10-year CSS, 6‰ vs 1.2‰, P-value = 0.009; Fig. 4d, Supplementary Fig. S5d, Supplementary Table S6). In both the chemotherapy and no-chemotherapy groups, the PEC had a higher 10-year OS and 10-year CSS compared to the SEC.

Figure 4
figure 4

Outcomes of patients with SEC in terms of survival. (a) Before matching, OS is performed after diagnosis of SEC. (b) After matching chemotherapy and no-chemotherapy groups, OS of SEC between them. (c) After matching in the chemotherapy group, OS between PEC and SEC. (d) After matching in the no-chemotherapy group, OS between PEC and SEC. SEC second primary endometrial cancer, PEC primary endometrial cancer.

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Discussion

Studies have shown that chemotherapy is safe and effective in treating RC26,27. However, the connection between chemotherapy and SEC has not been explored. Hence, we focused on the potential of chemotherapy to induce SEC by analyzing data from the SEER database. Initially, our findings suggested a strong correlation between chemotherapy and the risk of developing SEC in individuals with RC. Furthermore, individuals diagnosed with RC who underwent chemotherapy had an increased likelihood of experiencing SEC compared to the overall population in the US. Furthermore, among the RC patients undergoing chemotherapy, the likelihood of developing SEC was found to be higher as patients grew older and lower as the time between RC and SEC increased. Additionally, it was observed that the risk of SEC associated with chemotherapy remained consistently high during the period from 1985 to 1994. Additionally, no significant differences were observed in OS between SEC patients treated with chemotherapy and those who were not.

Numerous researches have reported that chemotherapy has the potential to induce cancer in both animals tested in laboratories and humans28,29,30. According to research, individuals who underwent chemotherapy treatment had a 40% higher chance of developing secondary solid tumors compared to cancer patients who solely had surgery31. However, Andreas et al. found that second cancer development was not increased after undergoing chemotherapy for colon cancer32. Therefore, whether patients with RC will develop SEC after receiving chemotherapy remains a controversial topic. Our results reveal that individuals who underwent chemotherapy had an increased likelihood of developing SEC compared to those who underwent surgery. We further conducted a stratified analysis to examine the impact of stage differences on SEC occurrence. The findings revealed that patients with regional disease in the chemotherapy group had a greater likelihood of developing SEC compared to those in the no-chemotherapy group. However, in patients with localized disease, no significant differences were noted between the two groups. The reason for this is that the regional disease group experienced a greater rate of recurrence following chemotherapy treatment and received a higher number of chemotherapy sessions compared to the localized disease group1. The competitive risk model (HR 1.86, 95% CI 1.43–2.42; P-value < 0.001) and multivariate analysis (HR 2.26, 95% CI 1.63–3.15; P-value < 0.001), along with the model of Poisson regression (RR = 1.53, 95% CI 1.12–2.07; P-value = 0.025), which reaffirmed the prior findings.

The subgroup analysis of the total population indicated that the probability of SEC in the chemotherapy group was greatly increased (HR 1.86, 95% CI 1.43–2.42; P-value < 0.001) and chemotherapy continued to be a risk factor in patients with RC after excluding the effect of radiotherapy (HR 2.84, 95% CI 1.38–5.85; P-value = 0.017). However, no correlation was observed between the subgroups of patients who did not receive radiotherapy. The possible reason was that the sample size was too small to ensure a sufficient number of people in the subgroup. Therefore, larger randomized comparison clinical studies were needed to explore the association with SEC in subgroups of patients who did not undergo radiotherapy.

We also generated RR-plot considering age, year of RC, and latency to SEC to further assess the dynamic correlation between chemotherapy and SEC. These plots demonstrated that the likelihood of SEC rises with increasing age, highlighting the need for increased focus on preventing SEC in older women. Furthermore, the likelihood of SEC peaked in 1990 and has shown a steady decline ever since. The reduction of the toxic impact of chemotherapy drugs on the human body could be attributed to the modification of the regimen and dosage of chemotherapy after 199033. Patients with cancer have been shown to retain residual chemotherapy drugs after chemotherapy treatment, which can break the double-strand DNA and lead to secondary malignancies22,33,34. In addition, after exploring the correlation between the duration of initial RC and the likelihood of developing SEC, we observed a gradual decline in the likelihood of SEC over time. Hence, it is crucial to focus on individuals with early RC.

In this study, the relationship between SEC and the decision to undergo chemotherapy in the general population of the United States was investigated. The findings indicated that there was an elevated risk in the general population (chemotherapy: SIR = 1.65, range 1.35–1.99; no-chemotherapy: SIR = 1.11, range 0.98–1.25). According to prior research, it is our belief that the development of SEC is connected to one's way of life, the environment they are exposed to, and the treatment they received for their initial cancer11,12,13. In addition, cancer survivors are at an increased susceptibility of developing and dying to fresh malignancies in contrast to the overall populace10. With the growing number of chemotherapy survivors, our aim is for this study to enhance awareness regarding the occurrence of SEC in RC patients following chemotherapy.

To the best of our knowledge, this study is the first to predict SEC in RC patients undergoing chemotherapy. Chemotherapy drugs may induce different signaling pathways affecting patient prognosis, which in turn, may decrease or improve patient prognosis. No notable disparity in survival was found between the chemotherapy and no-chemotherapy groups among SEC patients. After matching the OS and CSS rates between the chemotherapy and no-chemotherapy groups among SEC patients, we conducted a further comparison of the survival rate between SEC and PEC, which revealed a significant difference according to the results of this study. PEC possesses a significant advantage over SEC in the 10-year OS and 10-year CSS. Furthermore, survival results indicated that RC adversely affected SEC individuals, and SEC with a first primary RC had a worse prognosis. Therefore, women with RC should have long-term follow-up after chemotherapy treatment.

To more precisely examine the incidence and prognosis of SEC, this study had the benefit of using data featuring a substantial patient population and an extended duration of follow-up. This study had certain restrictions. First, potential bias may be related to nonrandomization of initial treatment. Furthermore, the occurrence and development of RC and SEC may be influenced by various factors such as lifestyle, genetic factors, geographical factors, and obesity35, which the SEER database did not contain. This may affect the occurrence and development of RC and SEC. Therefore, we used a multivariable competitive risk model to adjust for confounding variables, aiming to reduce potential bias due to the absence of randomization, although it was not entirely eradicated. Second, specific data on regimens, dosages, and frequencies of chemotherapy, radiation, and molecular subgroups of SEC were not available in the SEER database. A study discovered that various chemotherapy treatments resulted in variations in the likelihood of developing second primary tumors32, although the impact of this factor on the findings of the study was relatively minor. Furthermore, due to the ambiguity surrounding their receipt of delayed chemotherapy, individuals with RC who underwent initial surgical intervention were mistakenly categorized as being part of the no-chemotherapy cohort. This resulted in an underestimation of the likelihood of RC progression to SEC.

Conclusion

Patients diagnosed with RC and undergoing chemotherapy treatment exhibited a higher propensity for SEC development compared to those who were not receiving chemotherapy, suggesting that chemotherapy treatment could adversely affect the prognosis of SEC patients. Hence, it is advisable to closely observe the risk of SEC in middle-aged females who have undergone chemotherapy, specifically within a decade.