Abstract
Purpose
We aimed to explore the risk of secondary prostate cancer (SPC) and secondary bladder cancer (SBC) in male rectal cancer (RC) patients after radiotherapy (RT) and to assess survival outcomes.
Methods
This large population-based study included men with RC from nine registries in the Surveillance, Epidemiology, and End Results (SEER) database between 1973 and 2015. Fine-Gray competing risks and Poisson regression were used to assess the RT-related risk of SPC and SBC in patients who received RT versus those who did not (NRT).
Results
After exclusion, 28,886 RC patients were included in further analysis, including 9763 RT-treated patients (33.8%) and 19,123 patients not treated with RT (66.2%). In competing risk regression analysis, RT was associated with a low risk of developing SPC (adjusted HR = 0.67; 95% CI = 0.64–0.82; P < 0.001) and with a high risk of developing SBC (adjusted HR = 1.44; 95% CI = 1.15–1.80; P = 0.001). In the survival analysis of SPC patients, the NRT group exhibited better 10-year OS and CSS than the RT group (OS: HR = 0.52; 95% CI = 0.43–0.64; P < 0.001; CSS: HR = 0.39; 95% CI = 0.26–0.56; P < 0.001).
Conclusion
Male rectal cancer patients receiving RT had a decreased risk of SPC and an increased risk of SBC, and the prognosis of SPC patients in the RT group was worse compared to that of the NRT group. Follow-up and monitoring of SBC and SPC should not be ignored.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00384-025-04840-x.
Keywords: Rectal cancer, Radiotherapy, Secondary prostate cancer, Secondary bladder cancer, Incidence, Survival outcomes
Introduction
Radiotherapy (RT) plays an important role in the regional control of locally advanced rectal cancer (RC), and several large prospective randomized controlled trials have demonstrated its positive role [1–3]. The National Comprehensive Cancer Network guidelines recommend local RT as an integral part of RC treatment for patients with stage T3 or T4, patients with stage N1 or N2, and patients with incomplete resection [4]. Although RT can significantly improve local control rates, it does not improve the overall survival (OS) of patients [1, 5]. In this situation, it is crucial to correctly evaluate the extent of all possible adverse events. Conventional treatment in the USA consists of posterior pelvic irradiation of approximately 45 Gy, usually supplemented by additional additive irradiation to the tumor or resection bed [6, 7]. The other organs of the pelvis inevitably receive a substantial radiation dose, which has implications for the development of secondary pelvis cancers in RC survivors [8].
Although several current studies have evaluated the effect of RT on the occurrence of secondary pelvis cancers, none of them considered sex differences [9–11]. Due to the differences in the pelvic structure of male and female RC patients, the effect of RT on secondary pelvis cancer is not the same. The uterus and prostate are organs unique to males and females, with different anatomical locations as well as different effects of RT. RT for RC has been found to increase the risk of uterine cancer in women but decrease the risk of secondary prostate cancer (SPC) in men in some current studies [8, 12]. On the other hand, several studies have found that RT for RC increases the risk of secondary bladder cancer (SBC), and this trend is more pronounced in male RC patients [9, 13]. However, some studies have questioned the use of RT for RC to cause secondary pelvic tumors. Huynh et al. showed that RT did not increase the risk of SBC, regardless of gender [14]. Angelis et al. concluded that RT for rectosigmoid colon cancer was not associated with an increased risk of SBC and that exposure to RT did not affect bladder cancer-specific mortality (CSS) [15]. Whether RT adversely affects the survival outcome of secondary pelvis cancer has very important prognostic and therapeutic implications. Therefore, in this study, we used Surveillance, Epidemiology, and End Results (SEER) cancer registry data based on the same population to explore the risk of prostate cancer and bladder cancer in male RC patients after RT and assessed survival outcomes.
Materials and methods
Data source and patient selection
Our study cohort consisted of male patients diagnosed with the first primary RC reported in the nine SEER registries between January 1, 1973, and December 31, 2015. Primary cancer site and histology were coded according to the third edition of the International Classification of Diseases for Oncology (ICDO-3), which includes rectal cancer (C19.9) or rectosigmoid cancer (C20.9). The exclusion criteria were as follows: (1) age < 20 years; (2) race unknown; (3) distant stage and unstaged; (4) no cancer-directed surgery; (5) RC is not the first primary malignant tumor; (6) no positive histology; (7) latency less than 5 years; (8) survival less than 5 years or unknown. Patient selection is outlined in Fig. 1.
Fig. 1.
Flow chart
We categorized the included patients into two groups based on treatment information. The RT group consisted of patients with RC who received surgery and adjuvant external-beam RT. Patients who received other types of RT (i.e., brachytherapy, combination therapy) were excluded. The no-radiotherapy (NRT) group consisted of RC patients who received surgery alone.
The primary outcome of this study was the development of SPC and SBC, which were defined as PC and BC occurring more than 5 years after treatment for rectal cancer because of a latency period of at least 5 years from RT exposure to solid tumor development [16].
This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for cohort studies. A completed STROBE checklist is provided as supplementary material.
Statistical analysis
Statistical analyses were performed using R statistical software. A two-sided P value < 0.05 was considered statistically significant. The RT and NRT groups were compared using the Chi-square test and Fisher’s exact test for categorical variables and the Mann‒Whitney test for continuous variables. We used the Fine-Gray competing risk regression to calculate the hazard ratio (HR) and 95% confidence interval (CI) for the occurrence of SPC and SBC, considering SPC and SBC as competing risks with all-cause mortality, respectively. Poisson regression analysis was used to analyze the relative risk (RR) and its 95% CI of developing SPC and SBC in the RT group compared with the NRT group.
We also used a Poisson regression model to estimate standardized incidence ratios (SIR) and confidence intervals. The SIRs were the ratio of the observed incidence of SPCs and SBCs among RC patients to the expected incidence of PCs and BCs in the general population in the USA. The SIRs were calculated with SEER*Stat 8.4.2. Both the SIR and RR were adjusted for age and calendar year at RC diagnosis. To further evaluate the dynamic risk and incidence of SPCs and SBCs associated with RT, we stratified the SIRs and RRs by age and calendar year at rectal cancer diagnosis and by latency (Fig. S1).
To evaluate the prognosis of patients with SPCs and SBCs, we first collected information on patients with only primary pelvis cancer, which was defined as patients with a lifetime diagnosis of only PC or BC without any other cancer. Then, we used propensity score matching (PSM) to balance the bias in the RT and NRT groups, the RT versus only primary pelvis cancer group, and the NRT versus only primary pelvis cancer group by performing 2:1 matching with a 0.2 caliper width and without variables with an absolute value of the standardized mean difference greater than 0.25. PSM was used to match for age, race, grade, stage, chemotherapy, and radiotherapy. Finally, the 10-year OS and 10-year CSS of PC and BC patients in each group after PSM were compared using the Kaplan‒Meier method.
Results
Patient characteristics
A total of 49,400 patients diagnosed with RC from 1973 to 2015 were screened from the SEER database. After exclusion, 28,886 RC patients were included for further analysis, including 9763 patients (33.8%) treated with RT and 19,123 patients (66. 2%) not treated with RT. The basic data of the two groups are shown in Table 1. After a latency of more than 5 years, in the RT group, 217 patients (2.2%) developed SPCs and 146 patients (1.5%) developed SBCs, and in the NRT group, 956 patients (5.0%) developed SPCs, and 242 patients (1.3%) developed SBCs. Comparisons of the baseline characteristics of RC patients who developed SPCs and SBCs are shown in Tables S1 and S2.
Table 1.
Comparison of the characteristics of all RC patients
| Characteristic | NRT (n = 19,123) | RT (n = 9763) | P |
|---|---|---|---|
| Median age at RC diagnosis (IQR), years | 64 (55–71) | 60 (52–68) | < 0.001 |
| Age at RC diagnosis | < 0.001 | ||
| 20–49 | 2130 (11.1) | 1796 (18.4) | |
| 50–69 | 11,271 (58.9) | 5941 (60.9) | |
| ≥ 70 | 5722 (29.9) | 2026 (20.8) | |
| Year of RC diagnosis | 1994 ± 11.2 | 1999 ± 9.4 | < 0.001 |
| Year of RC diagnosis (IQR) | 1994 (1984–2003) | 2001 (1993–2007) | < 0.001 |
| Year of RC diagnosis | < 0.001 | ||
| 1975–1984 | 4787 (25.0) | 796 (8.2) | |
| 1985–1994 | 4993 (26.1) | 2106 (21.6) | |
| 1995–2004 | 5084 (26.6) | 3311 (33.9) | |
| ≥ 2005 | 4259 (22.3) | 3550 (36.4) | |
| Race | |||
| White | 15,966 (83.5) | 8168 (83.7) | 0.413 |
| Black | 1138 (6.0) | 545 (5.6) | |
| Other | 2019 (10.6) | 1050 (10.8) | |
| Tumor grade | < 0.001 | ||
| Grade I/II | 12,876 (67.3) | 7394 (75.7) | |
| Grade III/IV | 1468 (7.7) | 1422 (14.6) | |
| Unknown | 4779 (25.0) | 947 (9.7) | |
| Tumor stage | < 0.001 | ||
| Localized | 14,813 (77.5) | 3323 (34.0) | |
| Regional | 4310 (22.5) | 6440 (66.0) | |
| Tumor histology | < 0.001 | ||
| Adenocarcinoma | 16,312 (85.3) | 8940 (91.6) | |
| Mucous tumor | 616 (3.2) | 642 (6.6) | |
| Other | 2195 (11.5) | 181 (1.9) | |
| Tumor size (cm) | < 0.001 | ||
| < 2 | 2745 (14.4) | 511 (5.2) | |
| ≥ 2 | 7847 (41.0) | 6963 (71.3) | |
| Unknown | 8531 (44.6) | 2289 (23.4) | |
| Chemotherapy | < 0.001 | ||
| No | 17,781 (93.0) | 2069 (21.2) | |
| Yes | 1342 (7.0) | 7694 (78.8) | |
| Marital status | < 0.001 | ||
| Unmarried | 3854 (20.2) | 2384 (24.4) | |
| Married | 14,361 (75.1) | 7178 (73.5) | |
| Unknown | 908 (4.7) | 201 (2.1) | |
| Median latency between RC and SPC (IQR), month | 142 (94–213) | 132 (89–196) | < 0.001 |
| Median latency between RC and SBC (IQR), month | 147 (96–218) | 133 (90–198) | < 0.001 |
| Median follow-up time of RC (IQR), months | 148 (96–220) | 134 (90–199) | < 0.001 |
| Total person-years at risk (SPC) | 260,771 | 123,449 | |
| Total person-years at risk (SBC) | 266,569 | 124,091 | |
Cumulative incidences and risk of secondary pelvis cancers
The values of cumulative incidence of SPCs and SBCs in the entire study cohort were 5.60% and 2.10%, respectively. For SPC, Fig. 2A shows that the cumulative incidence in the NRT group was significantly higher than that in the RT group (6.47% vs. 3.70%, P < 0.001). As shown in Table 2, we performed univariate and multivariate competing risk analyses, which showed that RT was associated with a low risk of developing SPCs (adjusted HR = 0.67; 95% CI = 0.64–0.82; P < 0.001). In addition, regional tumor staging was also associated with a low risk of developing SPCs (adjusted HR = 0.70; 95% CI = 0.60–0.81). In almost all subgroups analyzed, RT in RC patients was associated with a low risk of developing SPCs (Table S3, Fig. S2A).
Fig. 2.
Comparison of cumulative incidence between RC patients who received RT and those who did not receive RT. A SPC; B SBC
Table 2.
Competing risk regression analysis of SPC in RC patients
| Characteristic | Univariable competing risk regression | Multivariable competing risk regression | ||
|---|---|---|---|---|
| HR (95% Cl) | P | HR (95% Cl) | P | |
| Age at RC diagnosis, per year | 1.00 (0.99–1.01) | 0.100 | – | – |
| Year of RC diagnosis, per year | 0.97 (0.96–0.98) | < 0.001 | 0.98 (0.97–0.98) | < 0.001 |
| Race | ||||
| White | Ref | Ref | ||
| Black | 1.59 (1.29–1.96) | < 0.001 | 1.73 (1.40–2.13) | < 0.001 |
| Other | 1.09 (0.91–1.32) | 0.350 | 1.15 (0.95–1.39) | 0.140 |
| Tumor grade | ||||
| Grade I/II | Ref | Ref | ||
| Grade III/IV | 0.92 (0.75–1.13) | 0.440 | 1.03 (0.83–1.27) | 0.790 |
| Unknown | 1.48 (1.30–1.69) | < 0.001 | 1.19 (1.03–1.38) | 0.019 |
| Tumor stage | ||||
| Localized | Ref | Ref | ||
| Regional | 0.56 (0.49–0.64) | < 0.001 | 0.70 (0.60–0.81) | < 0.001 |
| Tumor histology | ||||
| Adenocarcinoma | Ref | Ref | ||
| Mucous tumor | 0.89 (0.66–1.19) | 0.430 | 1.00 (0.75–1.34) | 0.980 |
| Other | 1.34 (1.09–1.64) | 0.005 | 1.04 (0.83–1.31) | 0.740 |
| Tumor size (cm) | ||||
| < 2 | Ref | Ref | ||
| ≥ 2 | 0.63 (0.53–0.76) | < 0.001 | 0.82 (0.67–1.00) | 0.052 |
| Unknown | 0.91 (0.76–1.09) | 0.300 | 0.77 (0.63–0.94) | 0.009 |
| Chemotherapy | ||||
| No | Ref | Ref | ||
| Yes | 0.48 (0.41–0.56) | < 0.001 | 0.97 (0.77–1.22) | 0.790 |
| Radiation therapy | ||||
| No | Ref | Ref | ||
| Yes | 0.48 (0.41–0.56) | < 0.001 | 0.67 (0.54–0.82) | < 0.001 |
| Marital status | ||||
| Unmarried | Ref | Ref | ||
| Married | 1.47 (1.25–1.72) | < 0.001 | 1.40 (1.19–1.64) | < 0.001 |
| Unknown | 1.43 (1.02–2.01) | 0.041 | 1.27 (0.90–1.79) | 0.180 |
For SBC, Fig. 2B shows that the cumulative incidence of patients in the NRT group was significantly lower than that in the RT group (1.85% vs. 2.79%, P < 0.001). Table 3 shows that RT was associated with a high risk of developing SBCs (adjusted HR = 1.44; 95% CI = 1.15–1.80; P = 0.001), and in almost all subgroups analyzed, RT in rectal cancer patients was associated with a high risk of developing SBCs (Table S4, Fig. S2B).
Table 3.
Competing risk regression analysis of SBC in RC patient
| Characteristic | Univariable competing risk regression | Multivariable competing risk regression | ||
|---|---|---|---|---|
| HR (95% Cl) | P | HR (95% Cl) | P | |
| Age at RC diagnosis, per year | 1.01 (1.00–1.02) | 0.002 | 1.01 (1.00–1.02) | 0.006 |
| Year of RC diagnosis, per year | 0.99 (0.98–1.00) | 0.013 | 0.99 (0.98–1.00) | 0.039 |
| Race | ||||
| White | Ref | Ref | ||
| Black | 0.44 (0.24–0.83) | 0.011 | 0.54 (0.29–1.02) | 0.057 |
| Other | 0.54 (0.35–0.83) | 0.005 | 0.58 (0.38–0.90) | 0.015 |
| Tumor grade | ||||
| Grade I/II | Ref | - | - | |
| Grade III/IV | 1.31 (0.97–1.77) | 0.083 | - | - |
| Unknown | 0.97 (0.75–1.26) | 0.810 | - | - |
| Tumor stage | ||||
| Localized | Ref | - | - | |
| Regional | 0.99 (0.81–1.22) | 0.950 | - | - |
| Tumor histology | ||||
| Adenocarcinoma | Ref | Ref | ||
| Mucous tumor | 1.15 (0.74–1.78) | 0.530 | 1.07 (0.68–1.66) | 0.780 |
| Other | 0.43 (0.24–0.79) | 0.006 | 0.58 (0.31–1.08) | 0.087 |
| Tumor size (cm) | ||||
| < 2 | Ref | - | - | |
| ≥ 2 | 1.04 (0.72–1.51) | 0.830 | - | - |
| Unknown | 1.13 (0.78–1.64) | 0.520 | - | - |
| Chemotherapy | ||||
| No | Ref | - | - | |
| Yes | 1.09 (0.87–1.36) | 0.430 | - | - |
| Radiation therapy | ||||
| No | Ref | Ref | ||
| Yes | 1.33 (1.09–1.64) | 0.006 | 1.44 (1.15–1.80) | 0.001 |
| Marital status | ||||
| Unmarried | Ref | Ref | ||
| Married | 1.53 (1.15–2.03) | 0.003 | 1.46 (1.10–1.94) | 0.010 |
| Unknown | 0.68 (0.29–1.58) | 0.370 | 0.77 (0.33–1.79) | 0.550 |
We also calculated the RR to confirm the risk of SPC and SBC attributable to RT. Table S5 shows a low risk-adjusted RR of 0.55 for combined SPCs (95% CI 0.48–0.64, P < 0.001). Compared to the general US population, the SIR for the development of SPCs was 0.52 (95% CI = 0.45–0.59, P < 0.05) in the RT group and 0.89 (95% CI = 0.84–0.95, P < 0.05) in the NRT group (Table S7). For SBC, there was a high risk-adjusted RR of 1.57 for combined SPCs (95% CI 1.27–1.95, P < 0.001). The SIR was 1.28 (95% CI 1.08–1.50, P < 0.05) in the RT group and 0.85 (95% CI 0.75–0.96, P < 0.05) in the NRT group (Tables S6 and S8).
Dynamic risk and incidence evaluation for secondary pelvis cancers
To further evaluate the dynamic incidence risk of SPC and SBC attributable to RT, we created dynamic RR plots based on latency, diagnosis time, and age at diagnosis of rectal cancer (Tables S5 and S6, Fig. S3).
In a dynamic age-RR plot, the risk of PC after RT was reduced in RC patients aged 20–50 years and reached a minimum of 50–69 years (50–69 years: adjusted RR = 0.47; 95% CI = 0.39–0.57; P < 0.001). The risk of BC after RT was significantly increased in RC patients aged 20–49 years and decreased with increasing age at RC diagnosis (20–49 years: adjusted RR = 2.11; 95% CI = 0.93–4.83; P = 0.071; 50–69 years: adjusted RR = 1.58; 95% CI = 1.21–2.05; P < 0.001).
In the dynamic latency-RR plot, a significantly lower risk of PC was observed at early latency (60–119 months: adjusted RR = 0.50; 95% CI = 0.40–0.62; P < 0.001). In SBC patients, the risk reached a maximum in 240–420 months (240–420 months: adjusted RR = 1.47; 95% CI = 0.78–2.65; P = 0.217).
In the dynamic diagnostic time-RR plot, the risk of PC was slightly reduced after RT in the 1975–1984 group, and this risk gradually decreased, reaching a minimum in the 2005–2015 subgroup (1975–1984: adjusted RR = 0.72; ≥ 2005: adjusted RR = 0.27; 95% CI = 0.16–−0.45; P < 0.001). The risk of BC significantly increased in the 1975–1984 subgroup and fluctuated up and down over the time of subsequent diagnosis (1975–1984: adjusted RR = 1.80; 95% CI = 1.12–2.80; P = 0.011).
We also evaluated the dynamic SIR in patients who received RT and those who did not (Tables S7 and S8, Fig. S4). For the RT group, the SIR of SPC showed a significantly lower risk in almost all subgroups, which is very similar to the results of the RR plot. For patients who did not undergo RT, the SIR of the SPC values was close to 1 and significantly larger than that of the RT group, although some subgroups also showed low risk. Regarding the SIR of SBC, we found that the SIR was higher than the baseline value of 1 in the different subgroups of patients in the RT group, whereas for the NRT group, the SIR was lower than the baseline value of 1 in all the different subgroups, and the SIR in the RT group also showed a similar trend to the RR of SBC.
Survival outcome of secondary pelvis cancers
We propensity-matched SPC and SBC patient characteristics between the RT and NRT groups (Tables S9 and S10).
For PC patients, the NRT group exhibited better OS and CSS after matching (OS: HR = 0.52; 95% CI = 0.43–0.64; P < 0.001; CSS: HR = 0.39; 95% CI = 0.26–0.56; P < 0.001) (Fig. 3). For BC patients, there was no significant difference in OS and CSS between the RT and NRT groups after matching (OS: HR = 0.77; 95% CI = 0.56–1.05; P = 0.30; CSS: HR = 0.68; 95% CI = 0.37–1.25; P = 0.25) (Fig. 4).
Fig. 3.
Survival comparison between RC patients who developed SPC after RT and RC patients who developed SPC after NRT. A, B Before PSM; C, D after PSM
Fig. 4.
Survival comparison between RC patients who developed SBC after RT and RC patients who developed SBC after NRT. A, B Before PSM; C, D after PSM
In addition, we used PSM (propensity score matching) to match only primary PC (OPPC) and only primary PC (OPBC) patients with SPC and SBC patients (Figs. S5 and S6). For PC patients, the results showed that the OS of both groups was not significantly different from that of the OPC group (RT: HR = 1.20; 95% CI = 0.99–1.46; P = 0.14; NRT: HR = 0.93; 95% CI = 0.85–1.02; P = 0.034), but the CSS was higher than that of the OPPC group and was more significantly so in the NRT group (RT: HR = 0.93; 95% CI = 0.68–1.26; P = 0.37; NRT: HR = 0.51; 95% CI = 0.42–0.61; P < 0.001). Both the RT and NRT groups had lower OS for BC patients (RT: HR = 6.95; 95% CI = 4.97–9.73; P < 0.001; NRT: HR = 6.41; 95% CI = 5.17–7.94; P < 0.001) and CSS (RT: HR = 3.30; 95% CI = 1.91–5.73; P < 0.001; NRT: HR = 3.91; 95% CI = 2.67–5.72; P < 0.001) than for OPBC patients.
Discussion
To our knowledge, this is the first general population-based study to explore the risk and prognosis of SPC and SBC in male survivors of RC treated with RT. Regarding the effect of RT for RC on SCs, the results of various studies are currently different and even contradictory. Wiltink et al. analyzed the risk of second tumor development in 1413 patients with RC. The results showed that there was no difference in the probability of developing a second cancer between the RT and NRT groups (15.3% vs. 14.8%; P > 0.05). Due to the limitation of the sample size, SC occurred in only 56 patients [17]. Warschkow et al. included 77,484 patients with RC in the SEER database comparing the occurrence of secondary cancer diagnosed at least 1 year after RC diagnosis between RT and NRT, and found a reduced risk of SPC (HR = 0.42, 95% CI 0.36–0.48, P < 0.001) and an increased risk of SBC (HR = 1.54, 95% CI 1.31–1.80, P < 0.001) [18]. Birgisson et al. looked at the occurrence of SPC and SBC in RC patients treated with RT based on the study population of the Uppsala trial and the Swedish Rectal Cancer Trial and showed that neither preoperative nor postoperative RT resulted in an increased risk of SPC and SBC in RC patients; however, only 21 SPCs and 12 SBCs were observed in this study, and the limited sample size indicated limited statistical validity of the conclusions [19]. The reasons for the conflicting conclusions are multifaceted and may be related to several factors, including the sample size of the cohort population, choice of latency period, length of follow-up, and study methodology. Our study chose a latency period of at least 5 years as an inclusion criterion, as this latency period may be more conducive to reasonable conclusions [12, 20]. In our study, a total of 28,886 male patients with rectal cancer were included, of whom 1173 patients developed SPC and 388 patients developed SBC, providing a sufficient sample size. In addition, we compared the incidence of SPC and SBC in patients with RC to the general US population and calculated the SIR to further understand the effect of RT on SPC and SBC. In summary, the conclusions of this study have validity.
In the literature, previous studies evaluating the risk of SPC after RT treatment in RC patients yielded consistent results [8, 10, 18, 21–23]. This may be related to the following factors:
The presence of confounding factors between the RT and NRT groups.
Hormonal changes induced by radiation scattering to the testes, which reduces the risk of SPC.
RT reduces the usefulness of prostate-specific antigen (PSA) screening in this population.
“Incidental” radiation to prostate tissue during rectal radiation therapy may prevent or delay the development of SPC [8, 22].
We included patients treated with adjuvant external radiation RT and calculated HR, RR, and SIR by comparing RT patients with NRT patients and the general population, all of which indicated that RC patients treated with RT had a reduced risk, minimizing the effect of confounding factors. Some studies have found only slight changes in serum testosterone levels in prostate cancer patients treated with external irradiation [24]. However, none of the published data from prospective studies suggests that circulating androgen levels are associated with prostate cancer risk [25, 25]. Huo et al. proposed and determined that RT treatment initially (within 6 months) elevates serum PSA levels but may permanently impair PSA production and that a downward trend in PSA use for prostate cancer screening did not occur until after 1988 when PSA use for prostate cancer screening became more common in the USA [22]. In the present study, we also found a more pronounced downward trend in prostate cancer risk after 1988. However, in contrast, we included all patients with a latency period greater than 5 years and found that the risk of prostate cancer was lowest 5–10 years after the diagnosis of RC and that this effect gradually decayed over time.
In this study, we performed survival analysis of SPC and OPPC patients. The SPC staging and grading in the RT group was relatively late, and after balancing the bias between the two groups, it was found that the CSS and OS of PC patients in the RT group were still inferior to those of patients in the NRT group. Interestingly, survival analysis after matching PC patients with OPPC patients in the RT and NRT groups revealed that the prognosis of patients in the NRT group was better than that of the OPPC patients, while the prognosis of patients in the RT group was not significantly different from that of patients in the OPPC group. Therefore, although RT treatment reduces the incidence of prostate cancer, prostate cancers occurring in patients who receive RT have a more aggressive and poorer prognosis than those who do not receive RT treatment. By analyzing the survival of 2680 SPC patients after RC, Huo et al. found that the SPC patients in the RT group had a significantly worse prognosis compared with NRT (OS: HR = 1.43; 95% CI = 1.25–1.63; P < 0.001, ref: NRT). Although this study was not further analyzed by PSM, this is generally consistent with the pre-PSM results of our study (OS: HR = 0.76; 95% CI = 0.62–0.91; P < 0.001, ref: RT) [21]. In addition, CSS is superior to OPPC in patients with SPC, but RT may attenuate or even eliminate this advantage. Whether RT for rectal cancer reduces the ability to detect PC or RT slows the development or progression of PC, screening for prostate cancer in this population cannot be ignored.
The effect of RT on the development of SBC in RC survivors has been inconsistent. Guan et al. evaluated the risk of SBC in male and female RC survivors based on the Seer database and found that RT was an independent risk factor for the development of SBC, which is generally consistent with the results of the present study (HR = 1.443, 95% CI = 1.209–1.720; P < 0.001) [9]. In a combined trial cohort study including more than 2500 patients with pelvic tumors conducted, the probability of SBC did not increase in patients who received RT compared with those who received surgical treatment alone [17]. Wang et al. evaluated the effect of RT on the occurrence of SPC in survivors of RC using the National Health Insurance Research Database in Taiwan. They found that preoperative RT did not increase SBC, but postoperative RT increased the risk of SBC (6 vs. 4.1 vs. 11.65%) [13]. The results of all three comparison groups in this study (HR, RR, and SIR) showed that RT is associated with a significantly higher risk of SBC in male RC survivors than in both RC survivors and the general population.
In the dynamic analysis of RR and SIR, younger male patients had the highest risk of SBC compared with older male patients, probably because relatively longer life expectancy increases the risk of SBC, and this trend was similarly found in other studies [9, 11]. In addition, the incidence of SBC was increased in the RT group, especially 10–20 years after the diagnosis of RC, with the RT group exhibiting the highest risk, so long-term monitoring of SBC in RC patients surviving RT treatment is of great clinical importance. In a survival analysis of SBC patients, we found that the SPC staging in the RT group was similar to that in the NRT group. Before and after PSM, there was no significant difference in the prognosis of SPC patients in either group. Similar findings were reported in a study by Guan et al., which concluded that the effects of BC-related treatments, especially chemotherapy, were not different even though RT treatment with radiation induced different genetic signaling pathways [9]. After PSM with OPBC patients, RC survivors, whether treated with RT or not, had a worse prognosis. The results of a pan-cancer analysis performed by Zhou et al. also showed that BC patients with a history of prior cancer had a worse prognosis [26].
Therefore, during follow-up, both patients and physicians should realize that RC patients are more likely to develop SBC and have a worse prognosis compared with the general population, especially RC patients who have undergone RT. In addition, although RT can reduce the incidence of SPC in RC patients, more attention should be paid to the progression of SPC. These findings are important and will help to improve patient counseling.
Limitations of the study
There are some limitations of our study. First, because this is a retrospective study, there is a potential bias in that the occurrence of secondary pelvic cancers in men with RC may not only be related to RT but may also be influenced by other important factors, such as smoking history (BC), genetic background, environmental factors, and details of other cancer-related treatments, including systemic chemotherapy [27], which are missing in the SEER database. We used multivariate competing risk models to adjust for all the confounding risk factors to reduce the potential bias associated with inadequate randomization but could still not fully balance the bias in the groupings. Second, the effect of the dose, division, and timing of RT on the risk of SPC and SBC cannot be determined because this information is also not available in the SEER database. Therefore, we suggest that all the findings of this study should be validated in prospective studies.
Conclusion
In this study, based on the same population, the combined assessment of multiple methods revealed that male rectal cancer patients receiving RT had a decreased risk of SPC and an increased risk of SBC, and the prognosis of SPC patients in the RT group was worse than that of SPC patients in the NRT group, whereas there was no significant difference in the prognosis of SBC patients. In conclusion, we have evaluated the risk of SPC and SBC from multiple dimensions to provide a meaningful reference for the treatment and follow-up of SPC and SBC after RT in male RC patients.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors thank the staff of the SEER program for providing open access to the SEER database.
Author Contribution
Lei Liu: Conceptualization, Methodology, Software, Writing—original draft. Shanglong Liu: Software, Writing—original draft. Xiaomin Xia: Data curation. LongBo Zheng: Visualization. Xianxiang Zhang: Investigation. Jilin Hu: Supervision. Yiheng Ju: Supervision. Yuan Gao: Writing—review & editing. Yun Lu: Writing—review & editing. All authors reviewed the manuscript.
Funding
No funding.
Data Availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
Ethical approval data in the present research was downloaded from the SEER database of the National Cancer Institute. Ethical approval and informed consent were exempted by the ethics committee owing to the public availability of data in the SEER database.
Competing Interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Lei Liu and Shanglong Liu have contributed equally to this work.
Contributor Information
Yuan Gao, Email: gaoyuan@qdu.edu.cn.
Yun Lu, Email: luyun@qdu.edu.cn.
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Supplementary Materials
Data Availability Statement
No datasets were generated or analysed during the current study.