Urothelial bladder cancer (UBC) is the most common cancer of the urinary system (1). About one-third of patients are diagnosed with muscle-invasive bladder cancer (MIBC). In recent decades, radiotherapy is still an important adjuvant therapy for MIBC patients. First, radiotherapy is the central part of trimodal therapy, which has long been proposed by multiple teams and recommended as an alternative for carefully selected patients with MIBC (T2-T3 N0M0) (2). In addition, RT can be regarded as the adjuvant therapy after radical cystectomy (RC) in pathologically high-risk patients with local recurrence (3).

Despite the progress of RT, pelvic toxicity is still significant. The risk of developing secondary primary cancer (SPC) is a rare but noteworthy form of advanced toxicity. A body of previous studies has proposed that radiotherapy for pelvis organs will increase the risk of SPC (4, 5). For instance, data from the SEER database suggested that radiotherapy for rectal cancer increased the risk of developing uterine and ovarian cancer (5). A similar study investigated the association between radiotherapy and SPC in the pelvis and found that patients receiving pelvic radiotherapy have an increased risk of developing SPC (6). However, the results are inconsistent regarding the effect of RT from several studies. Warschkow et al. found that the overall risk of the SPC after pelvic radiotherapy was reduced, which was attributed to the decrease in prostate cancer after pelvic radiotherapy (4).

UBC as a pelvic organ is usually treated as a second malignant tumor caused by radiotherapy for other pelvic organs (6, 7). There is still a lack of studies focusing on the association between radiotherapy and SPC for bladder cancer. It is mainly because radiotherapy is more considered as an adjuvant treatment for MIBC or as an alternative treatment for patients who are not suitable for RC (1). In recent years, with the development of management for BC patients, the survival of BC, especially MIBC, has been significantly improved (8). A reported data showed that the 5-year overall survival rate of MIBC patients is approximately 60% to 70% after active treatment (8). Longer survival allows us to consider the potential effect caused by radiotherapy on the survival outcome. Therefore, we used the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database to investigate the effect of radiotherapy on the risk of subsequent SPC in BC patients and to assess their survival outcome.

To the best of our knowledge, this is the first large population-based study to comprehensively evaluate the risk of developing SMN among bladder cancer survivors and to assess the survival outcome of SMN. We found that patients receiving radiotherapy showed a higher risk of developing SMN than those without. In the site-specific analysis, we observed the increasing risk of LAB cancer and hematological malignancies. Notably, we did not obtain a statistical difference in the risk of developing pelvic tumors between patients receiving radiotherapy and without. Then, we observed a poorer OS rate in BC patients developing SMN, LAB cancer, or hematological malignancies compared with those with only primary cancer.

Radiotherapy includes accidental exposure to the surrounding normal tissue, thereby increasing the risk of radiation-induced second cancer for many cancers (10). A relatively convincing explanation for the SMN caused by radiotherapy was that low-dose radiation could cause base damage, single-strand DNA breaks, and double-strand breaks (DSBs) (11). DSB can cause gene mutation then the following transformation from the radiated cell to a malignant cell. In addition, the DNA repair proteins, which usually protect DNA from damage, might be damaged, resulting in the increasing risk of SMN.

Radiotherapy-related SMN can be found in the organs within the radiotherapy range (high dose area) or organs far beyond the radiation range (low dose area). In the long-term follow-up of A-bomb survivors in Hiroshima and Nagasaki, reported data showed the increased rate of leukemia and solid tumors in the population. Moreover, lung cancer is the most common solid tumor in the survivors (11). These results are one of the most conclusive evidence of radiation-induced SMN. Similarly, a study based on the SEER and UK population revealed that lung cancer accounts for the most significant SMN caused by radiotherapy (23.7% of the total) (10). In this study, we also found a significantly higher proportion of patients developing LAB cancer or hematological malignancies in the cohort of radiotherapy. However, the difference in the risk of developing SMN was not found in other low-dose areas. The explanation for the phenomenon might be due to the larger radiation dose considering the relatively larger volume of the lungs. Meanwhile, the possible reason for out-of-field (low dose area) cancers can be the radiation-induced bystander effect, which is defined as intercellular signaling and tissue inflammation leading to the systemic response that can promote carcinogenesis of organs outside the radiation field (11, 12). This may also be a crucial reason why it is still possible to develop SMNs in low-dose areas. Notably, we did not observe the statistical difference in the distribution of developing pelvic tumors (high dose area) between radiotherapy and non- radiotherapy cohorts. The dose of radiotherapy for pelvic organs is usually higher than that for non-pelvic organs. The possible explanation for the phenomenon was hard to make. The sensitivity of different organs to radiotherapy and the area exposed to radiotherapy might be critical influencing factors leading to this result (13, 14). Total mesorectal excision with adjuvant radiation is considered the standard treatment for locally advanced rectal cancer and obtains a significantly improved prognosis compared with surgery only (15). This may indicate that normal rectal tissue has good tolerance to radiotherapy. In addition, the rectum is located deep in the pelvic cavity, which can also reduce the effect of exposure to radiotherapy to some extent (16).

Another interesting finding is that patients with primary BC show significantly better overall survival than those who develop SMN before and after PSM. Moreover, we separately evaluate the prognosis of patients who develop LAB cancer or hematological malignancies following radiotherapy and obtain similar results. In the SEER cancer registry, subsequent malignant tumors of cancer survivors currently account for 18% of all cancer diagnoses, making it the third most common cancer diagnosis (13). Sanath Kumar had previously proposed the concern about SMN, considering that SMN might lead to a decrease in the OS, although there was still a lack of relevant studies (11). In addition, secondary malignant tumors are bound to require more treatment like chemotherapy and radiotherapy. The treatment of this complex disease is challenging (17, 18). Therefore, it is not surprising that SMNs make a decrease in the OS rate, and this effect is more pronounced in cancer survivors who have a longer survival time.

Statistical considerations are crucial to the interpretation of the results. Some previous studies have used Cox regression analysis to evaluate the risk of SMN (19, 20). However, this method may lead to potential statistical bias because the probability of SMN in BC survivors is relatively low. In this study, the Fine-Gray competing risk regression is utilized to evaluate the risk of SMN, and this method can adequately explore the risk of developing SMN against the competing events, including all-cause death or the last follow-up. In addition, Poisson regression is also performed to make our conclusion more reliable and convincing.

Up to now, this is the first study to evaluate the association between radiotherapy and SMN and reported the effect of SMN on overall survival among BC patients. While radiotherapy brings therapeutic effects, we also need to pay attention to some hidden dangers brought by it (11, 21). More technical improvements may be needed to improve radiotherapy to minimize exposure to normal tissue, especially in the low-dose area. Novel treatment techniques like the scanned beam proton radiation could be considered to reduce the exposure of normal tissues to leaked neutrons (11). In the meantime, image guidance can also be used to direct radiotherapy to reduce the additional accumulation dose of normal tissue (3). Moreover, radiotherapy does not increase the risk of secondary pelvic tumors in patients with bladder cancer, which also provides favorable evidence for the use of radiotherapy in the treatment for BC.

Our study has several limitations that deserve attention when interpreting the results. This study is a retrospective study, and the inherent bias is inevitable. Second, some crucial risk factors related to the occurrence of SMN like smoking, genetic background, living environment, and other cancer-related treatments are lacking in the SEER database (4, 22). These unmeasured covariates may be associated with the development of SMN, and we cannot enroll these related factors into the multivariable risk competing model to balance confounding factors. Then, the SEER database lacks more detailed radiotherapy information such as effects of radiation dose, fractionation, and how RT was used (primary or adjuvant). However, relative homogeneity processing methods for many observation groups have been identified in the SEER database. Meanwhile, the probability of SMN was relatively low, but the true probability of SMN should be higher than the data obtained from our study considering the missed follow-up in the SEER program. Lastly, the SEER database only records the initial treatment, and we lack the follow-up treatment strategy. This may underestimate the risk of radiotherapy for SMN.

Radiotherapy for BC is associated with SMN. Radiotherapy increases the risk of secondary low-dose area cancer development, including LAB cancer or hematological malignancies. However, this effect is not observed in the high-dose area involving pelvic tumors. In addition, patients developing SMN showed poorer OS than those without. Therefore, more effects should be made to minimize the impact of factors that may increase the risk of SMN after radiotherapy. In the meantime, attention should be paid to the surveillance of SMN in BC patients receiving radiotherapy.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

Ethics approval and written informed consent was not needed for this study as the data is publicly available in the SEER database and it is de-identified.

RC, XZ and HJ contributed equally to this work and should be considered as co-first authors. XZ was responsible for data collection and analysis. The manuscript was written by the other authors. All authors contributed to the article and approved the submitted version.

This work was supported by Grant 2021QNA070 for Youth Research Fund from Fujian Provincial Health Commission, China, and the National Natural Science Foundation of P.R. China (Grant Nos. 81560419, 81960512, and 81760457).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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