Introduction

Despite recent advancements in diagnostic and therapeutic techniques, renal cell carcinoma (RCC) remains one of the most common and lethal malignancies of the urinary system1. Globally, the incidence of RCC ranks 14th among all malignancies, with the highest rates observed in Europe and North America2. Approximately 25–35% of patients are initially diagnosed with metastatic RCC, and their five-year survival rate is only around 12%, significantly lower than the 60% five-year survival rate for non-metastatic patients3. Data from 2020 indicates that there are over 140,000 RCC-related deaths annually, with systemic metastasis being the primary cause of death for RCC patients4.

The treatment of patients with metastatic clear cell renal cell carcinoma (mccRCC) is particularly critical. Traditional treatment methods mainly focus on cytoreductive surgery combined with systemic drug therapy5. Po-Yen Hsieh and others found that cytoreductive surgery can maximize tumor resection, improve patients’ quality of life, prolong lifespan, and increase survival time6,7,8. However, there is still no unified conclusion on the specific post-surgical treatment plan after cytoreductive surgery. Muhammad Ali and others discovered that radiotherapy can be safely and effectively used to treat mccRCC patients, especially those who cannot tolerate surgery, and the treatment effect is related to the dose of radiotherapy9,10. Nevertheless, Bingran Wang et al.‘s research seems to contradict this conclusion, suggesting that radiotherapy is not recommended for mccRCC patients, with a five-year survival rate of less than 10%11. Therefore, to investigate the impact of radiotherapy after cytoreductive surgery on the prognosis of mccRCC patients, this study conducted a comprehensive analysis using the SEER database to compare their survival rates.

Methods

Patients selection

All patient cases in this study were sourced from the SEER database (https://seer.cancer.gov/), which records basic information about cancer patients in the United States, including age, gender, race, marital status, tumor size, tumor grade, TNM staging, metastasis, treatment methods, survival status, and survival time12. Using SEER*Stat software (version 8.4.4), we extracted data on 276,265 kidney cancer patients from the SEER database spanning from 2000 to 2020.

Initially, we retained 133,167 cases of clear cell renal cell carcinoma (ccRCC). Among these, 121,794 patients underwent surgical treatment. Specifically, 2,312 patients were in the M1 stage, indicating distant metastasis. We further screened these 2,312 surgically treated mccRCC patients using the following exclusion criteria (Fig. 1): (1) unknown or unmeasurable tumor size (n = 80); (2) T-stage could not be assessed (n = 26); (3) N-stage could not be assessed (n = 113); (4) unknown race (n = 5); (5) unknown bone metastasis (n = 33); (6) unknown brain metastasis (n = 43); (7) unknown liver metastasis (n = 36); (8) unknown lung metastasis (n = 41). Finally, we identified data for 2,076 eligible surgically treated mccRCC patients.

Fig. 1
figure 1

Flowchart of surgically treated mccRCC patients selection.

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Study variables

The variables included in this study are age, gender, race, marital status, tumor size, tumor grade, radiotherapy, chemotherapy, metastasis to lungs, liver, bones, and brain, survival status, and survival months. Next, we grouped these variables. Firstly, age was categorized into two groups: <60 years and ≥ 60 years, with 60 years as the cutoff. Race was divided into three groups: White, Black, and Other. The “Other” group included “Asian or Pacific Islander” and “Asian or Pacific Islander”. Marital status was defined as married or single/unknown, where “separated/divorced”, “single”, and “widowed” were all grouped under “single/unknown”. Due to the small number of patients in the well-differentiated grade I tumor group, tumor grades were classified into four categories: well or moderately differentiated I/II, poorly differentiated III, undifferentiated IV, and other. Additionally, tumor size was categorized into two groups based on a cutoff of 7 centimeters: <7 cm and ≥ 7 cm. Both radiotherapy and chemotherapy were classified as “yes” or “no/unknown”. The radiotherapy group included “beam radiation”, “radiation, NOS (method or source not specified)”, and “radioactive implants”, with almost all patients receiving “beam radiation”.

Statistical analysis

Firstly, this study divided the mccRCC patients undergoing surgery into two groups: those who received radiotherapy and those who did not, with all patients receiving routine systemic therapy postoperatively. A 1:1 propensity score matching (PSM) was employed to minimize selection bias and potential confounding factors between the two groups, with a P-value > 0.05 indicating that we had roughly balanced the influence of these factors. Subsequently, we used Kaplan-Meier curves to examine the overall survival (OS) of patients with mccRCC treated surgically and analyzed differences between the curves using the log-rank test. Furthermore, we conducted subgroup analyses for patients with metastases in different locations to examine the prognostic impact of radiotherapy on surgically treated ccRCC with metastases in various sites. Next, we utilized a univariate model to analyze prognostic factors associated with surgically treated mccRCC, incorporating variables with a p-value < 0.05 into a multivariable Cox model to further identify independent prognostic factors and measure hazard ratios (HR) and 95% confidence intervals (CI). Finally, based on the results of the multivariable Cox proportional hazards regression model, variables with independent prognostic influence were selected to construct a prognostic nomogram for mccRCC patients treated surgically, predicting the survival rate of each patient.

Results

Study cohort selection and propensity score matching

We screened a total of 276,265 patients with RCC from the SEER database and selected them based on inclusion and exclusion criteria, ultimately obtaining information on 2,076 patients with surgically treated mccRCC (Fig. 1). This study employed propensity score matching (PSM) to reduce the impact of selection bias and other potential confounding factors (Table 1). Before PSM, 1,538 patients (74.08%) with mccRCC who underwent surgery did not receive radiotherapy, while 538 patients (25.92%) did. Among the indicators included in this study, age (p = 0.002), tumor size (p < 0.001), T stage (p = 0.001), chemotherapy (p < 0.001), and metastasis to lungs, liver, bones, and brain (p < 0.001) were all statistically significant, which may have a critical impact on our discussion. Therefore, we performed 1:1 matching to reduce selection bias and potential confounding factors between the two groups. After PSM, among the surgically treated mccRCC patients, there were 300 patients in the radiotherapy group and 300 patients in the non-radiotherapy group, accounting for 50% each. Age (p = 0.741), tumor size (p = 0.396), T stage (p = 0.684), chemotherapy (p = 0.869), lung metastasis (p = 0.870), liver metastasis (p = 0.615), bone metastasis (p = 0.594), and brain metastasis (p = 0.483) - all the indicators we included had p-values > 0.05. Thus, PSM minimized potential confounding factors.

Table 1 Baseline characteristics of patients before and after PSM.
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Survival analysis on OS

By comparing the overall survival (OS) between the matched radiotherapy group (300 cases) and the non-radiotherapy group (300 cases), we found that the median survival time for patients receiving radiotherapy was 25 months, whereas it was 31 months for the non-radiotherapy group, showing a statistically significant difference (p = 0.05) (Fig. 2). This suggests that radiotherapy may lead to poorer prognosis for mccRCC patients who have undergone surgery.

Fig. 2
figure 2

Survival curve of surgically treated mccRCC patients by radiotherapy.

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Furthermore, we conducted a subgroup analysis of post-surgical mccRCC patients. Based on whether bone metastasis occurred, we discovered that for patients without bone metastasis, the median survival time was 33 months in the non-radiotherapy group and 19 months in the radiotherapy group (p < 0.05), indicating statistical significance (Fig. 3). Similarly, when considering brain metastasis, the study found that in the absence of brain metastasis, the prognosis was poorer in the radiotherapy group compared to the non-radiotherapy group, with median survival times of 26 and 31 months, respectively (p < 0.05), demonstrating statistical significance (Fig. 4). For patients without liver metastasis, the prognosis was better in the non-radiotherapy group, with median survival times of 30 and 25 months, respectively (p < 0.05), again showing statistical significance (Fig. 5). Finally, we discussed lung metastasis and found that in the group with lung metastasis, the prognosis was better in the non-radiotherapy group, with median survival times of 20 and 16 months, respectively (p < 0.05), indicating statistical significance (Fig. 6). Other groups in this study did not show statistical significance, possibly due to the small sample size, as we hypothesize.

Fig. 3
figure 3

Survival curve of surgically treated mccRCC patients by radiotherapy and bone metastasis.

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Fig. 4
figure 4

Survival curve of surgically treated mccRCC patients by radiotherapy and brain metastasis.

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Fig. 5
figure 5

Survival curve of surgically treated mccRCC patients by radiotherapy and liver metastasis.

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Fig. 6
figure 6

Survival curve of surgically treated mccRCC patients by radiotherapy and lung metastasis.

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Univariate and multivariate analysis

In this study, univariate and multivariate Cox regression analyses were performed on the post-PSM cohort. Based on the results of the univariate Cox regression analysis, tumor size (p = 0.050), tumor grade (p < 0.001), T stage (p < 0.001), N stage (p < 0.001), radiotherapy (p = 0.003), chemotherapy (p = 0.002), lung metastasis (p < 0.001), and liver metastasis (p = 0.002) all affected the OS of patients. Consequently, we incorporated these variables into a multivariate Cox model, which revealed that tumor grade (p < 0.001), N stage (p < 0.001), radiotherapy (p < 0.001), lung metastasis (p = 0.013), and liver metastasis (p = 0.035) independently influenced the survival of surgically treated mccRCC patients (Table 2).

Table 2 Univariate and multivariate analyses for MccRCC.
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Nomogram construction

Based on the independent factors identified through Cox multivariate regression analysis and their clinical applicability, this study constructed a nomogram (Fig. 7) that incorporates tumor grade, N stage, radiotherapy, lung metastasis, and liver metastasis as variables. Each variable is assigned a corresponding score aligned with the scale at the top of the nomogram. For instance, the administration of radiotherapy is assigned a score of 35. Consequently, by summing up the respective points, we can determine the 1-year, 3-year, and 5-year survival rates.

Fig. 7
figure 7

Nomogram construction of surgically treated mccRCC patients by multivariate cox regression analysis.

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Discussion

The treatment of patients with mccRCC remains controversial. Muhammad Ali et al. believe that radiotherapy is meaningful and can improve patients’ survival time, while Bingran Wang et al. hold the opposite view9,11,13,14. Therefore, whether patients can benefit from radiotherapy after cytoreductive surgery has not yet reached a clear conclusion, and research in this area is scarce. Further investigation into the role of radiotherapy in this context remains challenging.

In this study, we used data from the SEER database, which provides information on various tumor patients in the United States to explore the impact of different variables on the survival of tumor patients. We divided patients with mccRCC who underwent cytoreductive surgery into two groups based on whether they received radiotherapy. We found that compared with patients who did not receive radiotherapy, the OS of patients in the radiotherapy group was significantly reduced by approximately 6 months. Subgroup analysis also indicated that radiotherapy might have a negative impact on patients’ prognosis. Multivariate Cox regression analysis showed that radiotherapy was an independent harmful factor affecting the prognosis of mccRCC.

The question of whether radiotherapy is necessary for patients with mccRCC undergoing cytoreductive surgery remains ambiguous. However, numerous studies have demonstrated that aggressive multimodal therapy can enhance treatment efficacy and survival outcomes for these patients. In this study, we aimed to investigate the impact of radiotherapy on the prognosis of surgically treated mccRCC and identify independent factors that may affect patient survival. We employed propensity score matching (PSM) to minimize selection bias and potential confounding factors.

Our findings indicate that radiotherapy significantly reduces overall survival in patients with mccRCC who have undergone cytoreductive surgery. Subgroup analysis revealed that the efficacy of radiotherapy is particularly detrimental to survival in patients without brain, bone, or liver metastases, as well as in those with lung metastases. Additionally, Cox regression analysis identified tumor grade, lymph node metastasis, lung metastasis, and liver metastasis as independent factors influencing patient prognosis, beyond the effects of radiotherapy. We incorporated these indicators into a nomogram to explore their impact on one-year, three-year, and five-year survival rates for patients with mccRCC undergoing cytoreductive surgery (Fig. 7).

The reasons for the disadvantage of postoperative radiotherapy in patients with mccRCC may come from the following aspects. Firstly, radiotherapy not only targets tumor cells but may also affect the surrounding tissues and organs15,16, thus triggering some radiotherapy-related complications, such as radiation enteritis17. Once these complications occur, they will deteriorate the patient’s physical condition after surgery and ultimately affect the patient’s survival. In addition, postoperative radiotherapy may suppress the immune system. The immune system plays a crucial role in fighting cancer. Radiation can damage immune cells and affect the body’s immune response18. A weakened immune system may reduce its ability to recognize and eliminate residual cancer cells, thereby increasing the risk of cancer recurrence and metastasis19,20. Moreover, radiotherapy may trigger genetic and molecular changes in cancer cells. Although the aim of radiotherapy is to kill cancer cells, it may also cause some cancer cells to undergo genetic mutations or epigenetic changes. These changes will make cancer cells more resistant to treatment or more invasive, thus worsening the patient’s prognosis21. Furthermore, early research by Lei Yao and others has found that ccRCC, a specific type of tumor, is not sensitive to radiotherapy and chemotherapy22,23,24. Therefore, in the treatment of mccRCC, radiotherapy has been placed in a position after targeted therapy and immunotherapy. Notably, Siva S and colleagues discovered that the combination of radiotherapy and immunotherapy can be beneficial for patient prognosis, and this effect is influenced by the radiation dose, possibly due to high-dose radiation stimulating anti-tumor immune capabilities25,26. Nevertheless, in clinical practice, it is essential to conduct individualized analysis based on the patient’s specific condition to facilitate the formulation of treatment strategies. Although this study has demonstrated that the significant efficacy of radiotherapy is detrimental to the survival of mccRCC patients undergoing cytoreductive surgery, it still has certain limitations. Firstly, as a retrospective study, despite the use of the PSM method, it is still not possible to completely eliminate all biases. Secondly, detailed records of radiotherapy information, such as specific radiotherapy targets and radiotherapy doses, are not available in the SEER database. These factors may affect the prognosis of patients. Furthermore, targeted therapy and immunotherapy have been proven to play important roles in clear cell renal carcinoma and have been clinically applied. However, the SEER database lacks information on targeted therapy and immunotherapy. Therefore, further validation of this study is needed through multi-center, randomized controlled clinical trials.

Conclusions

mccRCC is a challenging disease that requires multidisciplinary management and multimodal therapy. Although cytoreductive surgery can improve patients’ quality of life, postoperative radiotherapy may adversely affect the prognosis of mccRCC patients, reducing their median survival by approximately 6 months.