Association between chemotherapy for surgically treated rectal cancer and second primary endometrial cancer

doi:10.21203/rs.3.rs-3633216/v1

Background:

The conventional approach to managing postoperative rectal cancer (RC) entails the administration of chemotherapy (CT) or radiotherapy, both of which carry the potential for adverse effects and the onset of various ailments. However, the potential association between CT treatment for rectal cancer in females and the incidence of second primary endometrial cancer (SEC), as well as its impact on survival rates within this demographic, remains unexplored. Consequently, our study endeavors to examine the potential correlation between CT for RC in females and the likelihood of developing SEC, as well as its implications for overall survival and cancer-specific survival in this particular cohort.

Methods:

This study employed the Surveillance, Epidemiology, and End Results database (SEER) as the primary data source, encompassing a substantial cohort of patients diagnosed with RC between 1975 and 2018. To ascertain the cumulative incidence of SEC and the relative risk (RR) associated with CT compared to no CT (NCT), Fine-Gray competing risk regressions and standardized incidence ratios (SIR) were utilized. Furthermore, the survival outcomes were assessed, encompassing the estimation of overall survival (OS) and cancer-specific survival (CSS) at 10 years.

Results:

This study involved a total of 30,847 individuals who were diagnosed with RC. Among them, 168 individuals (5.45‰) experienced SEC. Furthermore, 107 patients (3.47‰) received CT treatment, while 61 patients (1.98‰) received NCT. The analysis of the overall occurrence of SEC revealed a significant association between SEC and CT treatment (hazard ratio: 1.80; 95% confidence interval (CI): 1.39–2.34; P-value < 0.001). Both univariate and multivariate analyses confirmed a significant association between CT treatment and an increased risk of developing SEC in RC patients (univariate analyses hazard ratio, 2.06; 95% CI, 1.51–2.81; P-value < 0.001; multivariate analyses hazard ratio, 1.99; 95% CI, 1.44–2.75; P-value < 0.001). Through the implementation of a dynamic analysis on the variables of RR and SIR, it was discerned that the likelihood of SEC escalated in tandem with advancing age. The examination of patients who developed SEC received to CT and those who developed SEC did not revealed no substantial disparities in the 10-year overall survival rate and cancer-specific survival rate (10-year OS, 10.81‰ vs 5.18‰; P-value = 0.083; 10-year CSS, 8.29‰% vs 7.29‰; P-value = 0.270), and the result was the same situation after propensity score matching (PSM) (10-year OS, 5.18‰ vs 5.18‰; P = 0.082; 10-year CSS, 6.58‰ vs 6.58‰; P-value = 0.240). Nevertheless, a notable discrepancy emerged when comparing the overall survival rate and cancer-specific survival rate at 10 years between patients afflicted with secondary endometrial cancer (SEC) subsequent to CT and those afflicted with primary endometrial cancer (PEC). (10-year OS, 25.58‰ vs 5.59‰; P-value < 0.001; 10-year CSS, 25.28‰ vs 5.14‰; P-value < 0.001), and the result was the same situation in the NCT group (10-year OS, 8.20‰ vs 1.66‰; P-value < 0.001; 10-year CSS, 6.00‰ vs 1.20‰; P-value = 0.009).

Conclusion:

The utilization of CT in patients diagnosed with RC has been associated with an increased probability of developing specific SEC. Therefore, it is imperative to prioritize efforts aimed at reducing CT-related SEC occurrences and improving the prognosis of affected individuals.

rectal cancer

chemotherapy

second primary endometrial cancer

SEER

survivors

This cohort study aims to examine the relationship between chemotherapy administration and the likelihood of developing secondary endometrial cancers in female patients diagnosed with rectal cancer. Furthermore, this research provides survival outcome estimations for patients affected by secondary endometrial cancers.

Colorectal cancer is the fourth most common cancer diagnosed in the United States and the second leading cause of cancer death. Based on projections, it is anticipated that the United States will witness approximately 44,850 cases of rectal cancer in the year 2022. (26,650 for men, 18,200 for women)^[1]. With the ongoing advancements in chemotherapy techniques, adjuvant chemotherapy following surgical intervention has demonstrated the potential to enhance the overall survival rates of patients diagnosed with staged rectal cancer^[2]. Regrettably, individuals who have successfully overcome rectal cancer 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 rectal cancer has significantly improved the overall outcomes for patients in the field of oncology. The treatment of rectal cancer, including chemotherapy, radiotherapy, and surgery, is constantly advancing in order to achieve the best possible results for tumor control, functional recovery, and patient survival^[5]. In a number of studies, second primary cancers (SPC) have been associated with RC., with most concluding that radiotherapy is a factor in the development of SPC^[6–8]. However, there have been limited investigations into the impact of chemotherapy after RC in females, particularly in relation to the endometrium.

Compared to the general population, individuals diagnosed with colorectal cancer face a notably higher likelihood of developing extracolonic secondary primary cancers. Among these secondary cancers, a considerable portion is attributed to obesity-related cancers like endometrial cancer (EC)^{[9, 10]}. Aside from breast, ovarian, cervical, and colorectal cancers, EC is the second most prevalent primary cancer^[11–15], and Previous research has indicated that chemotherapy for breast cancer and radiotherapy for cervical cancer elevate the likelihood of SEC^{[16, 17]}. CT and SEC incidence in patients with RC, however, have not been thoroughly investigated.

Hence, the primary objective of this retrospective analysis was to evaluate the correlation between CT and SEC, as well as the occurrence of SEC and the post-CT survival in individuals diagnosed with RC.

2.1. Patient selection:

Patient selection and data collection involved identifying female individuals who were diagnosed with rectal cancer as their initial primary cancer. From 1975 to 2018, participants diagnosed with rectal cancer as the first primary cancer were enrolled from nine registries of SEER database in the United States. 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. 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 unknown clinical information are all considered exclusion criteria The detailed screening process for all female RC in this analysis is shown in Supplementary Figure S1.

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

2.2. Explanation of SEC and subsequent actions:

This study mainly explored the development and survival analysis of SEC after CT 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 overall survival (OS) and cancer-specific survival (CSS). 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.

2.3. Data analyses:

We evaluated differences in baseline characteristics of patient and clinical information using the chi-square test and Mann–Whitney test. The study employed Fine-Gray models to evaluate the incidence and probability of SEC following a diagnosis of RC. 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. Using R software (version 4.3.0), a multivariate model and Poisson regression were employed to determine the likelihood of the development of SEC.

The study utilized the Poisson regression analysis method to determine the risk (RR) and 95% confidence interval (CI) for the development of SEC in RC patients who underwent CT and NCT. Additionally, Poisson regression analysis was employed to estimate the standardized incidence ratio (SIR) and 95% CI, in order to evaluate the likelihood of SEC occurrence in female RC patients compared to the general population of the United States. 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 CT, 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 also calculated the SIR for race and grade. In order to minimize bias in the overall survival (OS) and the cancer-specific survival (CSS) and confounding factors, we employed a 1:1 ratio propensity-score matching (PSM) technique to pair SEC patients with CT and NCT. Additionally, SEC patients with CT and NCT were also matched with PEC patients at a 1:5 ratio PSM^[18]. We ensure that the baseline characteristics for PSM are similar, including matching for factors such as age, race, grade, stage, marital status, duration of EC diagnosis, tumor size, histology, and the treatment of cancer (chemotherapy, radiotherapy, 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 of SEC and PEC was determined from the start of randomization until the occurrence of cancer-related death^[19]. The Kaplan-Meier technique was employed to generate survival curves, and the log-rank test was utilized to compare the differences in overall survival (OS) and cancer-specific survival (CSS). Statistical significance is conventionally associated with p-values below 0.05. All computational analysis was conducted using R software (version 4.3.0).

3.1. Baseline characteristics of patients with SEC

The study encompassed 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 were presented in Table 1. In total, 8176 (26.5%) patients received CT and 22671 (73.5%) patients received NCT. The age at diagnosis had a median of 67.0 years (a range of 57.0 to 76.0), while the follow-up time had a median of 140.0 months (a range of 37.0 to 176.0). The year of diagnosis had a median of 1993 (a range of 1984 to 2004), and the latency time had a median of 115.5 months (a range of 65.0 to 166.0). Furthermore, patients with RC received CT 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 (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 NCT patients. Out of the entire patient population, 168 individuals (5.45‰) developed SEC. Among these, CT was administered to 107 patients (3.47‰), while 61 patients (1.98‰) received NCT.

Table 1

Baseline characteristics of patients with surgically treated RC

Variables	Total	CT	NCT	p-value
Number, n (%)	30847（100.0）	8176(26.5)	22671(73.5）
Age,median (IQR), year	67.0（57.0,76.0）	61.0(52.0,70.0）	69.0(59.0,78.0）	＜0.001^a
Age, n (%), year ＜0.001^b
20-49	3457(11.2)	1621(19.8)	1836(8.1)
50-69	13756(44.6)	4356(53.3)	9400(41.5)
≥70	13634(44.2)	2199(26.9)	11435(50.4)
Race, n (%) ＜0.001^b
White	25914(84.0)	6643(81.3)	19271(85.0)
Black	2321(7.5)	624(7.6)	1697(7.5)
Other^c	2612(8.5)	909(11.1)	1703(7.5)
Year,median (IQR)	1993(1984,2004)	2003(1995,2009)	1988(1982,2000)	＜0.001^a
Year, n (%) ＜0.001^b
1975-1984	8616(27.9)	424(5.2)	8190(36.1)
1985-1994	7747(25.1)	1413(17.3)	6334(27.9)
1995-2004	6967(22.6)	2768(33.9)	4199(18.5)
≥2005	7519(24.4)	3571(43.7)	3948(17.4)
Marital status, n (%) ＜0.001^b
Single	2933(9.5)	931(11.4)	2002(8.8)
Married	14897(48.3)	4540(55.5)	10357(45.7)
Other/Unknown^d	13017(42.2)	2705(33.1)	10312(45.5)
Anatomic sites, n (%) ＜0.001^b
Rectosigmoid junction	10842(35.1)	2486(30.4)	8356(36.9)
Rectum，NOS	20005(64.9)	5690(69.6)	14315(63.1)
Tumor size, n (%) ＜0.001^b
＜2	3758(12.2)	551(6.7)	3207(14.1)
2-4	8208(26.6)	3418(41.8)	4790(21.1)
＞4	7380(23.9)	3565(43.6)	3815(16.8)
Unknown	11501(37.3)	642(7.9)	10859(47.9)
Grade, n (%) ＜0.001^b
Grade Ⅰ/Ⅱ	21932(71.1)	6098(74.6)	15834(69.8)
Grade Ⅲ/Ⅳ	3876(12.6)	1407(17.2)	2469(10.9)
Unknown	5039(16.3)	671(8.2)	4368(19.3)
Histology, n (%) ＜0.001^b
Adenomas and adenocarcinomas	28625(92.8)	7422(90.8)	21203(93.5)
Mucinous and serous neoplasms	1737(5.6)	614(7.5)	1123(5.0)
Other	485(1.6)	140(1.7)	345(1.5)
Stage, n (%) ＜0.001^b
Localized	15925(51.6)	1728(21.1)	14197(62.6)
Regional	14922(48.4)	6448(78.9)	8474(37.4)
Radiotherapy, n (%) ＜0.001^b
No	21924(71.1)	1755(21.5)	20169(89.0)
Yes	8930(28.9)	6428(78.5)	2502(11.0)
Follow-up time, median (IQR), months	85.0(37.0,176.0)	82.0(42.0,156.0)	86.0(35.0,184.5)	＜0.001^a
Second Gynecological Malignant Neoplasms, n (%)	168(0.56)	61(0.75)	107(0.49)	＜0.001^b
Latency time, median (IQR), months	115.5(65.0,166.0)	102.0(72.0,130.0)	124.0(56.5,183.0)	0.034^a

Table 1 of abbreviations: IQR, interquartile range; CT, chemotherapy; NCT, no chemotherapy; RC, rectal cancer;

^aP values were analyzed by using the Mann-Whitney test for continuum variables and χ² test.

^bP values were analyzed by using the Mann-Whitney test for Variables that are categorical.

^cOther groups, such as Native Americans/Alaska Natives and individuals of Asian/Pacific Islander descent, are also included.

^dOther/Unknown including a separated, divorced person, widow, unmarried person, or person living with a domestic partner.

3.1. Cumulative incidence of SEC

Over a span of 30 years, the occurrence of SEC in patients with RC who underwent CT was considerably higher than in those who did not (HR = 1.86, 95% CI: 1.43–2.42; P-value <0.001) (Figure 1A). Moreover, the NCT group demonstrated a significant increase in mortality in comparison to the CT group (P-value <0.001; Supplementary Figure 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) (Figure1B, 1C). The results of univariate and multivariate competing risk model from Table2 were shown (univariate analysis: HR = 2.06, 95% CI: 1.51–2.81; P-value <0.001, multivariate analysis: HR = 1.88, 95% CI: 1.36–2.60; adjusted P-value <0.001). The results clearly indicated that CT stands as a significant and independent risk factor for SEC in female patients with RC. The RR estimated the risk of SEC without taking into account competing events, highlighting a notably higher risk in the CT group when compared to the NCT group. (RR=1.53, 95% CI: 1.12–2.07; P-value = 0.025; Supplementary Table S1).

Table 2

Competing risk regression model for developing SEC in RC.

Variables	Univariate analysis		Multivariate analysis
Variables	HR (95% CI)	p	HR (95% CI)	p
Age at diagnosis	2.43(1.58-3.75)	＜0.001	1.96(1.24-3.13)	＜0.001
Year of diagnosis	0.73(0.46-1.15)	＜0.001	0.77(0.47-1.26)	＜0.001
Race
Black	1(Ref)		1(Ref)
White	3.10(1.25-7.70)	0.015	1.69(0.75-3.84)	0.210
Other^a	1.84(0.81-4.16)	0.140	2.48(1.00-6.15)	0.049
Marital status
Married	1(Ref)		1(Ref)
Single	0.57(0.31-1.06)	＜0.001	0.60(0.32-1.11)	0.100
Other/Unknown^b	0.47(0.33-0.66)	0.078	0.50(0.35-0.70)	＜0.001
Anatomic sites
Rectosigmoid junction	1(Ref)		1(Ref)
Rectum，NOS	1.13(0.83-1.56)	0.440
Tumor size
＜2cm	1(Ref)		1(Ref)
2-4cm	1.39(0.78-2.50)	0.270
＞4cm	1.22(0.67-2.23)	0.520
Unknown	0.66(0.37-1.18)	0.160
Grade
Grade Ⅰ/Ⅱ	1(Ref)		1(Ref)
Grade Ⅲ/Ⅳ	0.66(0.39-1.11)	0.120	0.62(0.37-1.05)	0.077
Unknown	0.59(0.36-0.95)	0.030	0.65(0.40-1.06)	0.082
Histology
Adenomas and adenocarcinomas	1(Ref)		1(Ref)
Mucinous and serous neoplasms	0.92(0.47-1.81)	0.810
Other	1.88(0.77-4.56)	0.170
Stage
Localized	1(Ref)		1(Ref)
Regional	1.03(0.76-1.39)	0.850
Chemotherapy
No	1(Ref)		1(Ref)
Yes	2.06(1.51-2.81)	＜0.001	1.88(1.36-2.60)	＜0.001

Table 2 of abbreviations: HR, hazard ratio; Ref., Reference; RC, rectal cancer; CI, confidence interval, SEC, second primary endometrial cancer;

^aOther groups, such as Native Americans/Alaska Natives and individuals of Asian/Pacific Islander descent, are also included.

^bOther/Unknown including a separated, divorced person, widow, unmarried person, or person living with a domestic partner.

After conducting this study, an analysis of subgroups was conducted to determine the likelihood of developing SEC using competing risk regression in both the CT group and the NCT group. The findings indicated that nearly all subgroups exhibit an increased risk of developing SEC after CT (Figure 2; Supplementary Table S2), including age (50-69years, HR=1.62, 95% CI: 1.16–2.25; P-value =0.018; >70years, 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 (2-4cm, 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), site (rectum, NOS, HR=1.91, 95% CI: 1.39–2.62; P-value =0.001).

3.3. Dynamic risk and incidence evaluation for SEC

To investigate the dynamic risk and incidence of SEC in the CT group, this research computed the RR-plots which encompassed the age of 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 ≥70years with RC reached the highest incidence risk of SEC (≥70, RR=2.11, 95% CI: 1.20–3.57, P-value =0.023; Figure 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; Figure 3B). The latency of the RR plots showed that 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; Figure 3C).

Furthermore, the SIR of SEC was computed to compare the general population in the United States with patients diagnosed with RC. This comparison took into account factors such as the age and year of RC diagnosis, the latency period following RC diagnosis, as well as the grade and race of the patients. The findings revealed that individuals with CT or NCT, who also had RC, were at an increased risk of developing SEC compared to the general U.S. population. Additionally, the CT group exhibited a greater SIR than the NCT group (CT, SIR:1.65; 95% CI, 1.35–1.99; NCT, SIR:1.11; 95% CI, 0.98–1.25; Supplementary Table S3; Supplementary Figure S3).

3.4. Survival outcome of SEC

Initially, we assessed the disparity between OS and CSS in individuals with SEC who underwent CT and NCT treatment. No significant disparity was observed in the cancer-specific survival (CSS) and overall survival (OS) at 10 years rates between the CT and NCT groups (10-year OS, 10.18‰vs5.81‰, P-value =0.083; 10-year CSS, 8.29‰vs7.29‰, P-value =0.270, Figure 4A, Supplementary Figure S4 A). Because of the presence bias, a 1:1 ratio of PSM was employed to pair SEC patients with CT and NCT, revealing no notable disparity in the outcomes (10-year OS, 5.81‰vs5.81‰, p=0.082; 10-year CSS, 6.58‰vs6.58‰, P-value =0.240, Figure 4B, Supplementary Figure S4 B, Supplementary Table S4). In addition, we compared the OS and CSS of patients with SEC and PEC between the CT group and the NCT group to further assess the disparity in survival rates. There were clear disparities in the 10-year overall survival (OS) and 10-year cancer-specific survival (CSS) between patients who developed SEC and CT or NCT and patients who developed primary esophageal cancer (PEC) and received CT or NCT. These differences were observed both before (10-year OS, 25.58‰vs5.59‰, P-value <0.001; 10-year CSS, 25.28‰vs5.14‰, P-value =0.270; Figure 4C, Supplementary Figure S4 C) and after 1:5 ratio PSM(10-year OS, 8.20‰vs1.66‰, P-value <0.001; 10-year CSS, 6‰vs1.2‰, P-value =0.009; Figure 4D, Supplementary Figure S4 D, Supplementary Table S5). Regardless of whether in the CT group or NCT group, the PEC had a higher operating system (OS) and cascading style sheets (CSS) compared to the SEC.

Studies have shown that CT is both safe and effective in treating RC ^{[20, 21]}. However, the connection between CT and SEC has not been explored. Hence, we deliberated on the potential of CT to induce SEC by analyzing the SEER database. Initially, our findings suggested a strong correlation between CT and the risk of developing SEC in individuals with RC. Furthermore, individuals diagnosed with RC who underwent CT treatment faced an increased likelihood of experiencing SEC compared to the overall population in the United States. Furthermore, among the RC patients undergoing CT, 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 CT remained consistently high during the period from 1985 to 1994. Additionally, no significant differences were observed in overall survival (OS) between SEC patients treated with CT and those who were not.

Numerous researches have indicated that CT has the potential to induce cancer in both animals tested in laboratories and humans ^[22–24]. According to the research, individuals who underwent CT treatment had a 40% higher chance of developing secondary solid tumors in comparison to cancer patients who solely had surgery ^[25]. However, Andreas et al. found that second cancer development was not increased after CT for colon cancer^[26]. Therefore, whether patients with RC will develop SEC after receiving chemotherapy is still controversial. According to this research, individuals who underwent CT had an increased likelihood of developing SEC in comparison 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 had a greater likelihood of developing SEC in the CT group compared to the NCT group. However, in patients with localized disease, no significant differences were noted between the two groups. The reason for this outcome could be that the regional disease group experienced a greater rate of recurrence following CT treatment and also received a higher number of CT sessions compared to the localized disease group^[1]. The competitive risk model (HR = 1.88, 95% CI: 1.36–2.60; P-value < 0.001) and the model of Poisson regression (RR = 1.53, 95% CI: 1.12–2.07; P-value = 0.025), along with the subgroup analysis (HR = 2.64, 95% CI: 1.81–3.15; P-value = 0.001), which reaffirmed the prior findings.

In order to further assess the dynamic correlation between CT and SEC, we generated RR-plots considering age, year of RC, and latency to 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, it was discovered that the likelihood of SEC peaked in 1990 and has been steadily declining 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 CT after 1990^[27]. Patients still had residual chemotherapy drugs after CT, which can break the double-strand DNA and lead to secondary malignancies^[27–29]. In addition, we explored the correlation between the duration of initial RC and the likelihood of developing SEC, and observed a gradual decline in the likelihood of SEC over time. Hence, it was crucial to give particular focus t individuals with early RC.

In this study, the relationship between SEC and the decision to undergo CT in the general population of the United States was investigated. The findings indicated that there was an elevated risk in the general population (CT: SIR = 1.65, range 1.35–1.99; NCT: 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 cancer^[11–13]. In addition, cancer survivors are at an increased susceptibility of developing and dying to fresh malignancies in contrast to the overall populace^[10]. With the growing number of CT survivors, our aim is for this study to enhance awareness regarding the occurrence of SEC in RC patients following CT.

To the best of our knowledge, this study is pioneering in predicting SEC in RC patients post-CT. Chemotherapy drugs may induce different signaling pathways that affect patient prognosis, which may decrease or improve patient prognosis. No notable disparity in survival were found between the CT and NCT groups among SEC patients. After matching in OS and CSS between the CT group and the NCT group, 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 edge over SEC in both operating systems and cascading style sheets. Therefore, we hypothesize that CT adversely affects SEC individuals, potentially leading to the development of resistance to chemotherapy drugs. Therefore, older women with RC should be carefully considered before CT.

To more precisely examine the incidence and prognosis of SEC, this study had the benefit of a substantial patient population and an extended duration of follow-up. This study had certain restrictions. First, potential bias may be related to non-randomization 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 obesity^[30] that the SEER database did not contain, which may affect the occurrence and development of RC and SEC. Therefore, we utilized 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 information on regimens, dosages and frequencies of CT, radiation, and molecular subgroups of SEC were not available in the SEER database. A study discovered that various chemotherapy treatments result in variations in the likelihood of developing second primary tumors^[26], although the impact of this factor on the findings of the study was relatively minor. Furthermore, individuals with RC who underwent initial surgical intervention were mistakenly categorized as part of the NCT cohort due to the ambiguity surrounding their receipt of delayed CT, resulting in an underestimation of the likelihood of RC progression to SEC.

Patients diagnosed with RC undergoing CT treatment exhibited a higher propensity for SEC development compared to those not receiving CT, suggesting that CT 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 CT, specifically within a decade.

The availability of data and materials

This article uses data from the public SEER database, which can be downloaded and stored.

Funding

This paper is supported by the following projects: The Second Hospital of Lanzhou University Cui Ying Science and Technology Innovation (CY2020-MS04); The Second Hospital of Lanzhou University Cui Ying Xue Zi Program (CYXZ2022-29); Gansu Provincial Science and Technology Project (23JRRA0998).

Contribution of the author to the paper

TG, WL, CW and PD drafted the original paper. TG, WL, DM, WH and DZ analyzed the data, TG, WL, CW, DM and PD edited and reviewed the draft. QW, MC, CY and YF made the figure and table preparation for this article. All authors have read and approved the final manuscript.

Declarations

In this paper, all data used are derived from the SEER database, so ethical approval is not required. All authors have agreed to publish without conflict of interest.

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No competing interests reported.

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Association between chemotherapy for surgically treated rectal cancer and second primary endometrial cancer

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