A real-world cohort study reveals the treatment paradox of radiotherapy underuse despite its association with survival advantage

Introduction

Rectal cancer (RC) is one of the most common malignancies of the digestive tract, accounting for approximately 40% of all colorectal cancer cases reported in 2022 (1). It predominantly affects older adults, with 44% of diagnoses occurring in this population, and the age-standardized incidence rate increases steadily with advancing age (2). Against the backdrop of global population aging, the proportion of elderly RC patients continues to rise annually (3). By 2035, individuals aged 65 years and older are projected to represent 15% of the global population, with geriatric tumors expected to account for 58% of all cancer cases. This demographic shift poses unprecedented challenges for healthcare systems, which must increasingly address the complex medical needs of an aging patient population (4).

To date, the exploration of treatment strategies for elderly RC patients remains limited (5,6). Clinical guidelines for managing RC in this demographic are largely extrapolated from studies involving younger cohorts. Surgery remains the cornerstone of curative treatment: early-stage patients are typically directed to surgery alone, while those with advanced disease often receive neoadjuvant or adjuvant therapies in combination with surgical resection (7,8). Evidence confirms that surgery is an independent protective factor for improving overall survival (OS) in elderly RC patients (9). Although age itself is no longer considered a decisive risk factor for surgical outcomes, elderly patients remain vulnerable to undertreatment (10-12). However, comorbidities and age-related physiological decline often lead to increased postoperative complications, higher mortality rates, and reduced life expectancy. As a result, a significant number of elderly patients may be deemed medically ineligible for surgery or may voluntarily decline surgical intervention (13,14). Real-world evidence indicates that approximately 10% of RC patients have definitive contraindications to surgery, about 20% of non-metastatic cases are managed non-operatively, and nearly 15% receive no anticancer treatment at all. In practice, the proportion of elderly non-surgical RC (ENS-RC) patients is likely even higher (15-17). In the absence of randomized trials focused on this growing demographic, treatment decisions for ENS-RC patients remain complex and poorly standardized.

Studies suggest that radiotherapy (RT) is a safe and feasible treatment option for elderly RC patients (18). However, significant variations exist in the application of RT for RC across different countries (19). Current research on RT in older patients predominantly focuses on its role in combination with surgery—such as preoperative neoadjuvant short- or long-course RT, postoperative adjuvant chemoradiotherapy, and non-operative management after a clinical complete response. By contrast, the purely non-surgical ENS-RC population has received comparatively little attention (20,21). Randomized trials have shown that preoperative RT reduces the risk of local recurrence in RC but has no significant impact on long-term survival (8,22). For ENS-RC patients, external beam radiotherapy (EBRT) combined with high-dose-rate brachytherapy has been associated with promising remission rates and local progression-free survival (23). In addition, stereotactic ablative RT has emerged as a valuable technique for re-irradiation in locally recurrent RC (24). Despite these advances, direct comparative studies evaluating the effectiveness of EBRT in ENS-RC patients, particularly elderly ones, remain scarce.

To address this gap, this study utilized a large real-world database to provide complementary evidence on RT use and outcomes in ENS-RC patients, a population underrepresented in clinical trials. Our objectives were to analyze RT utilization patterns, evaluate its association with survival outcomes, identify subgroups with the strongest associations, and generate hypotheses to inform clinical decision-making and future research. We present this study in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2739/rc).

Methods

Data source and study population

This retrospective cohort study utilized data from the Surveillance, Epidemiology, and End Results (SEER) database, specifically version 8.4.2 submitted in November 2020, which encompasses 18 cancer registries from 2010 to 2018. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. As the analysis relied exclusively on de-identified, publicly available data from the SEER program, the requirement for informed consent and ethical approval was waived.

The initial patient cohort was identified using the Collaborative Staging Scheme - American Joint Committee on Cancer (CS Scheme-AJCC) 6th edition criteria based on RC site and morphology codes. The study focused on elderly ENS-RC patients, defined as individuals aged 60 years or older with a confirmed pathological diagnosis who did not undergo any surgical intervention, including endoscopic procedures. The SEER database does not routinely record the specific reasons for foregoing surgical intervention. Therefore, the ‘non-surgical’ cohort in this study is operationally defined based on treatment records and encompasses a heterogeneous population. To derive interpretable findings from this real-world mix, our analytical strategy included both an assessment of the overall cohort and rigorous analyses within predefined, clinically homogeneous subgroups. To further ensure an analyzable cohort, we applied the following exclusion criteria. Cases were excluded if they had a diagnosis of stage 0 disease or carcinoma in situ (Tis), presented with multiple primary malignancies, had records indicating ambiguous RT methods or treatments other than EBRT, or reported zero or unknown survival months. From an initial pool of 212,268 patients with RC identified in the SEER database, 20,951 eligible elderly non-surgical patients were included in the final analysis following the application of inclusion and exclusion criteria (Figure 1).

Figure 1 Patient selection flowchart for the elderly non-surgical rectal cancer cohort. NOS, not otherwise specified; PSM, propensity score matching; RT, radiotherapy; SEER, Surveillance, Epidemiology, and End Results; T, tumor.

Variable definitions

The variables extracted and analyzed in this study are comprehensively detailed in Table 1 and Table S1. These included patient demographics (such as age, sex, race, and marital status), tumor characteristics (including pathological type, grade, overall stage, and tumor/node/metastasis (T/N/M) stage according to the AJCC 6th edition), treatment details, and year of diagnosis. All variables were categorized as presented in the respective tables.

Treatment details included the receipt of EBRT and chemotherapy, both recorded in a binary manner (‘Yes’ or ‘No’). It is important to note that SEER does not specify key treatment parameters: the intent (e.g., definitive vs. palliative), dose, or fractionation of RT, nor the timing of chemotherapy relative to RT. To address these inherent data limitations, a multi-layered analytical strategy was employed in subsequent sections to control for potential confounders and robustly evaluate the effect of RT.

Statistical analysis

Baseline characteristics were summarized using descriptive statistics. Categorical variables were presented as frequencies and percentages, with differences between the RT and non-RT groups assessed using the Chi-squared test or Fisher’s exact test. OS and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method and compared with the log-rank test, with analyses performed in both the overall cohort and propensity score-matched cohorts. All statistical tests were two-sided, and a P value <0.05 was considered statistically significant. Given the observational study design, all analyses aim to estimate associations between treatment and outcomes, not to establish causality.

The association of RT with survival was evaluated using univariate and multivariate Cox proportional hazards models. Variables significant in univariate analysis (P<0.05) or deemed clinically relevant were included in the multivariate model to generate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). To address confounding, propensity score matching (PSM) was performed using a logistic regression model that included demographic, clinical, and treatment-related variables. For the T/N/M stage variables, the ‘Unknown’ category was retained as a valid level to preserve the real-world cohort structure during matching. A 1:1 nearest-neighbor matching algorithm with a caliper width of 0.1 was applied, and covariate balance was assessed using standardized mean differences (SMDs), with an SMD <0.1 considered indicative of good balance.

Subgroup analyses were conducted at several levels to examine the consistency of the treatment effect. First, stratified analyses were performed in the overall cohort before and after matching. Second, to assess associations within more homogeneous clinical populations and to explicitly address potential confounding by metastatic status and treatment fitness, we performed multivariable Cox regression within five predefined subgroups. These subgroups were designed to disentangle these factors: “M0 (no distant metastasis)” and “M1 (distant metastasis present)” (by metastatic status); “chemotherapy” and “non-chemotherapy” (by systemic treatment); and their intersection, “M0 with chemotherapy” (representing a potentially fitter subpopulation). Results are presented as stepwise adjusted models to explicitly demonstrate how the association between RT and survival changes after adjusting for potential confounders, with a focus on isolating the effect from factors such as chemotherapy receipt and metastatic status. Third, interaction analyses were conducted to test for effect modification by chemotherapy status and metastatic status. Finally, to further control for residual confounding within these subgroups, secondary 1:1 PSM was performed within each subgroup, followed by Kaplan-Meier survival comparisons.

Sensitivity analyses were undertaken to test the robustness of the findings. These included (I) analyzing a cohort that excluded patients who died within 60 days of diagnosis; (II) analyzing a complete-case dataset after removing records with missing covariate information; (III) stratifying the analysis by diagnostic period (≤2009, 2010–2014, 2015–2018); and (IV) varying the caliper width and matching algorithm in the PSM procedure to assess methodological stability. All analyses were performed using R software (version 4.3.1).

Results

Patient characteristics before and after matching

The study included 20,951 elderly ENS-RC patients, of whom 9,019 (43.0%) received RT. Prior to matching, significant differences in baseline characteristics were observed between the RT and non-RT groups (all P<0.001) (Table 1). RT recipients were generally younger, with only 38.2% of patients aged ≥85 years receiving RT. They were also more likely to be married, diagnosed in later years, and had higher pathological grades. A strong treatment bundling effect was evident. Among patients receiving chemotherapy, 66.1% also underwent RT, compared to only 18.2% of those not receiving chemotherapy. This pattern likely reflects selection bias, where patients deemed fitter or with more favorable disease characteristics were chosen for more intensive multimodal therapy. RT utilization varied markedly by disease stage. It was higher in M0 patients (55.5%) than in M1 patients (33.0%) and substantially higher in stage II/III patients (approximately 78.7%) than in stage IV patients (33.5%). Analysis of metastatic sites identified the liver (16.4%) as the most common site, followed by lung (9.3%), bone (2.1%), and brain (0.3%). Patients with brain metastases exhibited the highest RT utilization rate (71.0%), while those with liver or lung metastases were significantly less likely to receive RT compared to non-metastatic patients (Table S1).

Following PSM, 9,752 patients (4,876 per group) constituted the balanced cohort (Table 1). Post-matching, the absolute SMDs for all covariates were below 0.1 (Figure S1), confirming that matching effectively mitigated initial selection bias for the measured variables.

Survival analysis before and after matching

In the entire pre-matched cohort (n=20,951), patients receiving RT (n=9,019) had significantly longer median OS than non-RT patients (22 months, 95% CI: 21–22 vs. 13 months, 95% CI: 12–13; log-rank P<0.001) (Table 2) (Figure 2A). OS rates at 1, 3, and 5 years were also consistently higher in the RT group (Table 2). A similar trend was observed for CSS, with a median CSS of 27 months for RT recipients vs. 16 months for non-RT patients (P<0.001) (Figure 2B). More than half of all deaths occurred within 24 months of diagnosis.

Figure 2 Kaplan-Meier survival analysis by radiotherapy status before and after propensity score matching. (A) OS before PSM. (B) CSS before PSM. (C) OS after PSM. (D) CSS after PSM. CSS, cancer-specific survival; OS, overall survival; PSM, propensity score matching; RT, radiotherapy.

In the propensity score-matched cohort (N=9,752), survival metrics for both groups decreased, reflecting the correction of baseline imbalances toward a population with intermediate prognosis. The median OS for the RT group decreased from 22 months pre-match to 16 months post-match, while the non-RT group remained relatively stable (Table 2). Similarly, median CSS for RT patients declined from 27 to 19 months (Table 2). This attenuation suggests that the matching process partially eliminated the overestimation of the RT survival advantage attributable to measured confounders.

A univariable Cox regression analysis within the matched cohort confirmed a significant inverse association between RT and mortality risk, with an HR of 0.87 (95% CI: 0.83–0.91, P<0.001) for OS. Correspondingly, Kaplan-Meier analysis validated these findings, demonstrating that the RT group maintained significantly superior outcomes compared to the non-RT group (log-rank P<0.001 for both, Figure 2C,2D). This analysis provides an estimate of the association [average treatment effect on the treated (ATT)] with reduced measured confounding.

Cox proportional hazards regression analysis in the overall cohort

To explore and describe independent associations between covariates and survival in the broader, unselected population, we performed Cox regression analyses on the pre-matched cohort (Table 3). Univariate analysis revealed that both RT (HR =0.74, 95% CI: 0.72–0.77) and chemotherapy (HR =0.78, 95% CI: 0.75–0.80) were associated with significantly lower mortality risk. Age was a significant independent risk factor, with patients aged ≥85 years having a mortality risk 2.01 times that of those aged 60–74 years (95% CI: 1.92–2.09). Marital status (married vs. single, HR =0.75) and race (other races vs. White, HR =0.83–0.93) were also significantly associated with survival. Furthermore, higher tumor pathological grade and more advanced TNM stage were associated with increased mortality risk, while patients with pathological types other than adenocarcinoma showed better prognosis (HR =0.53, 95% CI: 0.50–0.55). Sex was not significantly associated with OS in univariate analysis.

All variables significant in univariate analysis were included in a subsequent multivariate Cox model (Table 3). After adjusting for these measured confounders, RT remained independently associated with a lower risk of death, although the effect size was attenuated (HR =0.91, 95% CI: 0.87–0.94). This attenuation indicates that a substantial portion of the crude survival advantage was explained by imbalances in the included covariates. Chemotherapy, advanced age, single status, higher tumor grade, and more advanced T and M stage (all P<0.001) remained significant factors associated with increased mortality risk. Notably, in the multivariate model, N stage was no longer significantly associated with OS, potentially due to collinearity with M stage or mediation through other pathways, while female sex emerged as an independent protective factor compared to male sex (HR =0.87, 95% CI: 0.84–0.90).

Subgroup analysis

In the multivariable subgroup analyses of the overall population before and after matching, HRs across stratified factors consistently indicated a protective association between RT and survival (HR <1.0) (Figure 3). Notably, the magnitude of this association varied across different subgroups. Age-stratified analysis revealed a distinct pattern. The strongest inverse association was observed in the oldest-old group (age ≥85 years) with an HR of 0.74 (95% CI: 0.66–0.82), compared to HRs of 0.94 (95% CI: 0.92–1.04) in the 60–74 years group and 0.88 (95% CI: 0.81–0.95) in the 75–84 years group. This suggests that, within this cohort, the magnitude of the inverse association between RT and mortality appeared most pronounced among the oldest patients, despite their lower overall utilization rate (38.2%). After PSM, the survival benefit of RT did not reach statistical significance in some subgroups, including Black patients, grade I, stage I, and stage III patients, likely due to reduced sample size and statistical power in these strata. Notably, RT consistently demonstrated a significant survival benefit in stage IV patients, who constituted the largest subgroup (30.5%) of this elderly cohort. RT groups showed significantly superior survival outcomes compared to non-RT groups regardless of chemotherapy status.

Figure 3 Forest plot: association between radiotherapy and OS across subgroups. HRs and 95% CIs for OS are displayed for each stratified factor, analyzed separately in the overall and PSM populations. All models are mutually adjusted for covariates (i.e., age, sex, year of diagnosis, marital status, race, grade, stage, ICDHis and chemotherapy) except the stratification factor itself. CI, confidence interval; HR, hazard ratio; ICDHis, International Classification of Diseases for Histology; OS, overall survival; PSM, propensity score matching.

To further investigate whether key covariates confounded the assessment of the RT effect, we performed a two-stage analysis focusing on chemotherapy status and metastatic status (Table 4). First, interaction effect analysis showed no significant interactions between RT and either chemotherapy status or metastatic status (all P for interaction >0.05), suggesting a consistent direction of association across these subgroups. Second, to validate this effect within homogeneous populations and control for potential residual confounding, we conducted detailed analyses within five predefined clinical subgroups using the pre-matched population. In the “non-chemotherapy” subgroup, while the unadjusted model initially suggested worse survival with RT (HR: 1.17, 95% CI: 1.11–1.24), stepwise adjustment revealed a clear beneficial association after full adjustment (Model 3 HR: 0.88, 95% CI: 0.83–0.94, P<0.001). Similarly, RT was associated with significant survival improvements in the chemotherapy (Model 3 HR: 0.80), M0 (Model 3 HR: 0.84), and M1 (Model 3 HR: 0.90) subgroups. Most notably, in the “M0 with chemotherapy” subgroup, representing patients in better general condition, the survival benefit associated with RT was particularly pronounced (Model 3 HR: 0.73, 95% CI: 0.64–0.83, P<0.001). Subsequent PSM within each specific subgroup followed by Kaplan-Meier analysis were consistent with these observed survival differences for both overall and CSS (Figure S2).

Sensitivity analysis

Sensitivity analyses supported the robustness of the primary observed association across multiple analytical scenarios (Tables S2,S3). First, after excluding patients who died within 60 days of diagnosis (n=17,768), the observed association between RT and survival remained statistically significant, albeit attenuated, in the fully adjusted model (HR =0.95, 95% CI: 0.92–0.99, P=0.03). Second, in a complete-case analysis addressing missing covariate data (n=5,400), this association remained evident after full adjustment (HR =0.90, 95% CI: 0.85–0.94, P<0.001). Third, stratification by diagnostic period indicated that the association with improved survival was consistent in the contemporary 2010–2018 cohort (adjusted HR =0.86, P<0.001). Finally, the methodological stability was suggested, as the estimated HR for RT remained consistent across variations in the PSM parameters (Table S3).

Discussion

This study leverages a large-scale nationwide cohort to provide a comprehensive real-world analysis of RT utilization patterns and clinical outcomes in elderly ENS-RC patients. Our principal findings reveal a significant underutilization of RT in this population, despite observing a robust and consistent association with longer overall and CSS. Notably, patients aged ≥85 years demonstrated the lowest RT utilization rates, yet exhibited the strongest inverse association with mortality. This finding challenges the potential therapeutic nihilism often applied to the oldest patients and suggests that chronological age alone may be an insufficient criterion for withholding RT. It highlights a critical need for individualized assessment rather than blanket treatment denial in this vulnerable demographic.

While surgery remains the cornerstone of curative RC treatment (25-27), our study addresses the important reality that a substantial proportion of elderly patients, approximately one-fourth in our cohort, are managed non-surgically. In an aging society, there exists a critical need to balance the dual risks of both surgical overtreatment and undertreatment in vulnerable elderly populations (28,29). As previous research has demonstrated, patients over 75 years are significantly less likely to receive guideline-concordant optimal therapy (30). Our study provides the first large-scale, comparative effectiveness evidence specifically for this underserved population—a group largely excluded from clinical trials and for whom evidence-based treatment guidelines are scarce. By examining real-world treatment patterns and outcomes, we aim to inform more nuanced clinical decision-making beyond the traditional surgical paradigm.

Our multi-layered analytical approach provides consistent evidence of an association between RT and improved survival. This association remained evident across multivariate Cox regression models, PSM, and comprehensive subgroup analyses. To partially address the critical issue of unmeasured patient fitness (e.g., performance status), we examined clinically homogeneous subgroups. Among patients with non-metastatic disease who received chemotherapy (a proxy for better general condition), RT was associated with a pronounced reduction in mortality risk (HR: 0.73, 95% CI: 0.64–0.83). The magnitude of this association was greater than that observed in metastatic or non-chemotherapy subgroups. These findings were further supported by sensitivity analyses, including the examination of temporal trends which suggested that the association might be strengthening in more recent diagnostic periods, possibly reflecting advancements in RT delivery or patient selection.

The overall RT utilization rate of 43.6% in our cohort appears suboptimal when compared to the 49.3% rate reported in general population studies and the 64.2% rate specifically for stage II/III disease in the UK (19,31). Significant treatment disparities were evident, with particularly low RT utilization among vulnerable subgroups including the very elderly, women, certain racial groups, and unmarried individuals (32,33), which may reflect broader issues of access and equity in cancer care delivery.

One of the most clinically notable observations relates to patients aged 85 years or older. In our analysis, this subgroup showed the strongest inverse association between RT and mortality. This observation is particularly noteworthy given that non-surgical management is often the default approach for this demographic due to perceived surgical risks (10,34). Previous research indicates that even when elderly patients undergo surgery, they rarely receive neoadjuvant therapy and often experience non-curative resection without clear survival advantage (35,36). In the context of increasing interest in organ-preservation strategies (37,38), our results raise the possibility that RT might be considered as a component of treatment de-escalation in selected elderly patients, potentially offering an alternative for those unsuitable for or declining surgical intervention.

This study has limitations inherent to large-scale, real-world evidence derived from cancer registries, which should be considered when interpreting the findings. First, while the SEER database does not specify the reasons for non-surgical management, precluding stratification by surgical candidacy, our operational definition enabled the study of this broad, real-world population that is often excluded from clinical trials. Second, although details on RT parameters (e.g., intent, dose) and chemotherapy timing are unavailable, limiting regimen-specific analysis, the consistent association observed across eras and subgroups suggests a class effect worthy of further investigation. Third, despite rigorous adjustment via PSM, the absence of direct measures of patient fitness (e.g., performance status) and the non-randomized design mean that residual confounding cannot be ruled out. Finally, the characteristically high rate of missing pathological staging in non-surgical cohorts was addressed by treating “unknown” as a distinct category and through sensitivity analyses; however, it highlights the ongoing challenge of precise risk stratification in this population.

Notwithstanding these limitations, our multi-method analytical approach provides robust, hypothesis-generating evidence. Future prospective studies incorporating comprehensive geriatric assessments and detailed treatment records are needed to confirm these associations and refine patient selection.

Conclusions

This large-scale real-world analysis demonstrates a strong and consistent association between RT delivery and longer survival in elderly ENS-RC patients. Our findings underscore a critical “treatment paradox”, wherein the oldest patients, who derive the greatest relative benefit, are the least likely to receive RT. This highlights an urgent need to address disparities in care and to critically re-evaluate the potential role of RT in therapeutic strategies for this growing population. Future prospective studies are needed to identify which elderly patients are most likely to benefit from RT, ensuring this treatment option is appropriately considered in their care.

Acknowledgments

We want to thank the National Cancer Institute of United States for providing data of the SEER.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2739/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2739/prf

Funding: This study was supported by Research and Development Fund of Shougang Hospital, Peking University (No. SGYYZ202110).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2739/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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