The prognostic impact of preoperative radiotherapy in stage I rectal cancer: a retrospective cohort study revealing no survival benefit from SEER database analysis

Introduction

Early-stage rectal cancer (RC) is primarily addressed through surgical intervention, in accordance with the National Comprehensive Cancer Network (NCCN) guidelines, followed by vigilant observation (1). Nevertheless, recent reviews underscore the insufficiency of literature concerning treatment modalities for early-stage RC (2-4). For early-stage patients, particularly those with T2N0M0 disease who are candidates for local excision, the decision to omit preoperative radiotherapy (RT) remains a subject of debate (3,5). Proponents hypothesize that RT may improve oncological outcomes for local excision candidates through enhanced tumor control (6-10), while critics counter that its established benefits in reducing recurrence for advanced RC (as demonstrated in stage II to III RT by the CAO/ARO/AIO 94 trial) remain unproven in T1/T2N0M0 disease (11). Skeptics further caution against overtreatment, emphasizing that early-stage patients achieving complete local excision derive a minimal survival benefit from RT while remaining exposed to its associated toxicities.

Preoperative RT has been regarded as the standard neoadjuvant treatment to decrease the rate of local recurrence of RC compared with surgery alone even after total mesorectal excision (TME), and might be associated with the rapidly reducing perioperative mortality in recent years (12-15). Thus, preoperative RT has been recommended in the NCCN guidelines for locally advanced RC patients (1). However, the potential benefits of preoperative RT for patients with early-stage RC are yet to be thoroughly investigated. In recent years, several studies on preoperative RT combined with local surgical treatment for early-stage RC have demonstrated the beneficial effects of preoperative RT on early-stage patients (16-18). However, these studies are either single-arm trials or involve comparisons between local excision and radical resection, lacking direct validation of the impact of preoperative RT on the survival of early-stage RC patients.

The Surveillance, Epidemiology, and End Results (SEER) database offers unique advantages to resolve these uncertainties. Its large-scale, population-based design enables statistically powered subgroup analyses that are infeasible in single-center studies (https://seer.cancer.gov). Propensity score matching (PSM) further minimizes selection bias inherent to retrospective data, while long-term follow-up captures delayed survival effects often missed in clinical trials. Additionally, SEER reflects real-world practice heterogeneity, allowing validation of trial findings in diverse clinical settings.

Therefore, this study retrospectively examined a substantial volume of data from the SEER database pertaining to stage I RC patients. It aimed to explore whether preoperative RT conferred benefits to stage I RC patients who underwent surgery. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2570/rc).

Methods

Patients

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Anonymized patient-level data were obtained from the SEER database, which is the largest publicly available database of patients with cancer in the United States and contains high-quality information on cancer incidence and survival (https://seer.cancer.gov). The SEER database covers approximately 28% of the United States population across diverse geographic regions and demographics, ensuring the representation of real-world clinical practice. SEER is nationally representative and prioritizes demographic diversity, encompassing varied racial and ethnic groups, geographic regions, and socioeconomic backgrounds. The database (Incidence-SEER Research Plus Data, 17 registries, Nov 2021 Sub, 2000–2023) was searched to identify primary RC (C20.9) cases diagnosed between 2004 and 2021 corresponding locations [site recode: International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3)/World Health Organization (WHO) 2008: rectum]. A total of 16,961 stage I RC patients (T1–2N0M0) diagnosed between 2004 and 2021 were identified from the SEER database. Patients receiving chemotherapy were excluded from the analysis. All enrolled patients underwent definitive surgical intervention, including either local excision or radical resection. The cohort was stratified into preoperative RT (n=106), postoperative RT (n=355), and no RT (n=16,500) groups.

The inclusion criteria were as follows: (I) patients with stage I RC who received surgery but did not undergo chemotherapy; (II) the rectum was the only site of cancer onset; and (III) a known treatment sequence consisting of “radiation before surgery” (preoperative RT), “radiation after surgery” (postoperative RT), or “no radiation” (no RT). Exclusion criteria included: (I) unknown surgery status; (II) RT other than beam radiation, such as radioactive implants (includes brachytherapy), radioisotopes, combination of beam with implants or isotopes, recommendations with unknown administration and radiation methods where the source or method is not otherwise specified (NOS); (III) unknown race recode or median household income or tumor size; (IV) survival months flag display incomplete; and (V) unknown causes of death.

Outcomes and baseline clinical characteristics

The follow-up of the patients was from the date of cancer diagnosis until death or censored on December 31, 2023, whichever came first. We chose overall survival (OS) as primary endpoints. OS was defined as the time between the initial diagnosis of RC and death from all causes or the last follow-up. Survival status and duration were extracted from SEER mortality records. Baseline clinical characteristics included RT status, age at diagnosis, sex, year of diagnosis, stage at diagnosis, race/ethnicity, histologic type, surgical type, tumor size, and median household income. Local excision was performed either through traditional open surgery or via transanal endoscopic microsurgery (TEM). Radical resection for RC involved the complete removal of the rectum and surrounding lymph nodes, through procedures such as low anterior resection (LAR) or abdominoperineal resection (APR), with TME being a critical component to ensure thorough clearance of cancerous tissue.

Statistical analysis

R software (version 4.3.1) was used for statistical analyses, and P<0.05 (two-tailed) was considered to indicate statistical significance. Number and percentage (N, %) were used to describe the categorical data, and the Chi-squared test was used to compare the difference between development and validation sets. The Kaplan-Meier (KM) method was used to evaluate OS, and any differences in survival were evaluated with a stratified log-rank test. To assess the independent prognostic role of preoperative RT, we performed multivariable Cox proportional hazards regression on the entire unmatched cohort, adjusting for clinically relevant confounders identified a priori: age at diagnosis, sex, year of diagnosis, T stage, race/ethnicity, histologic type, tumor size, median household income, and surgical approach (local excision vs. radical resection). The hazard ratio (HR) with 95% confidence interval (CI) and the corresponding P value were calculated to evaluate the independent association of RT with OS. PSM was used to calculate the propensity score of each research object and select individuals from the control group with the same or similar propensity scores as the treatment group, thereby matching them to validate the robustness of the findings. The nearest neighbor matching method was used with a caliper width set to 0.25 times the standard deviation of the propensity score, and a 1:1 matching ratio was applied. After adjusting for age, sex, year of diagnosis, stage at diagnosis, race, histologic type, surgical type, tumor size, and income, we repeated the Cox regression analysis in the matched cohort without further covariate adjustment. All statistical tests were two-tailed, and a P<0.05 was considered statistically significant.

In the SEER database, only a small portion of patients with chemotherapy status marked as “none/unknown” had an unknown chemotherapy status. The study described “no/unknown” directly as no chemotherapy to avoid ambiguity, a common approach in SEER database articles that did not substantially affect research outcomes. For the type and version of the stage classification system, data from 2004 to 2010 were categorized using the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system 6^th edition; from 2010 to 2015, the AJCC TNM staging system 7^th edition was applied; from 2016 to 2017, the SEER Combined Stage Group was utilized; and from 2018 to 2021, the extent of disease (EOD) 2018 stage group was employed. In this study, most RC staging was based on imaging-based clinical staging. In a few cases, the clinical TNM staging was adjusted to pathological staging due to considerations related to the surgical situation.

Results

Demographics and clinical characteristics

Based on the inclusion criteria, data were extracted from the SEER database for 16,961 cases of stage I RC patients diagnosed between 2004 and 2021, all of whom received surgery and did not undergo chemotherapy. Please refer to Figure 1 for the specific screening procedures. The basic characteristics of the no RT group, preoperative RT group, and postoperative RT group are shown in Table 1.

Figure 1 The flowchart of patient selection. ICD-O-3, International Classification of Diseases for Oncology, 3rd Edition; RT, radiotherapy; SEER, Surveillance, Epidemiology, and End Results; WHO, World Health Organization.

PSM analysis

Significant differences were detected between the groups in terms of age, race, year of diagnosis, histologic type, T stage, surgery, tumor size, and income (Table 1). In terms of treatment modalities, the majority of patients who did not receive chemotherapy opted not to undergo RT. Only a small fraction of the total included data involved patients undergoing preoperative or postoperative RT. To balance confounding factors, PSM analysis was conducted on the no RT group and the preoperative RT group. After PSM analysis, all confounders were well balanced (Figure 2, Table 2).

Figure 2 Standardized mean difference analysis (A) and probability density analysis (B) for PSM. (A) The curves of the two matched groups exhibit a high degree of overlap within the PS value range, indicating that the baseline characteristics between the groups are well balanced. 0, no RT; 1, preoperative RT. (B) Before adjustment, there were significant differences between the groups. After adjustment, the differences between the groups nearly disappeared. PS, propensity score; PSM, propensity score matching; RT, radiotherapy; T, tumor.

KM analysis of the impact of preoperative RT on 5-year OS in stage I RC patients

According to KM survival curves and Log-rank analysis, before PMS analysis, no RT might be more beneficial for the 5-year OS rate. The 5-year OS rates were as follows: no RT, 79.7%; preoperative RT, 61.9%; postoperative RT, 65.9% (P<0.001; Figure 3A). After PMS analysis, preoperative RT and no RT had no significant impact on survival (75.8% vs. 62.5%, P=0.10; Figure 3B).

Figure 3 KM analysis of the impact of preoperative RT on OS in (A) total patients before PSM, (B) total patients after PSM, (C) T1N0M0 patients after PSM, and (D) T2N0M0 patients after PSM. KM, Kaplan-Meier; OS, overall survival; PSM, propensity score matching; RT, radiotherapy.

Multivariate Cox regression analysis of factors influencing OS in stage I RC patients

Before PSM analysis, multivariate regression analysis indicated that age, sex, year of diagnosis, histologic type, T stage, RT, surgery, tumor size, and income significantly affected OS (Table 3). After PSM analysis, multivariate analysis revealed that age ≥65 years (HR =5.18; 95% CI: 3.15–8.51; P<0.001) and preoperative RT (HR =1.56; 95% CI: 1.07–2.26; P=0.02) were associated with poorer OS (Table 4).

Analysis the impact of preoperative RT on OS in T1N0M0 and T2N0M0 RC patients

PSM analysis was performed separately on T1N0M0 (Table S1 and Figure S1) and T2N0M0 (Table S2 and Figure S2) data, followed by survival analysis. KM survival analysis (Figure 3C,3D) showed that preoperative RT remained unbeneficial for T1N0M0 RC patients (87.5% vs. 62.5%, P=0.08) and T2N0M0 (72.2% vs. 61.7%, P=0.34). Multivariate Cox regression analysis (Figure 4) indicated that preoperative RT had no significant impact on the OS of T2N0M0 patients (HR =1.545; 95% CI: 0.975–2.45; P=0.06), and even had a markedly detrimental effect on T1N0M0 patients (HR =2.122; 95% CI: 1.014–4.44; P=0.046).

Figure 4 Multivariate Cox regression analysis of factors influencing OS in (A) T1N0M0 and (B) T2N0M0 patients after PSM. CI, confidence interval; HR, hazard ratio; OS, overall survival; PSM, propensity score matching; RT, radiotherapy.

Subgroup analysis of different types of surgery

PSM analysis was performed separately on patients undergoing local excision (Table S3 and Figure S3) and radical resection (Table S4 and Figure S4). After PSM analysis, KM analysis showed that preoperative RT did not provide a significant benefit over no RT for RC patients who underwent local excision (P=0.93; Figure S5) and radical resection (P=0.06; Figure S6). Subgroup analysis by type of surgery indicated that preoperative RT also had no significant advantage over no RT for RC patients who underwent local excision (HR =1.073; 95% CI: 0.399–2.881; P=0.89; Figure 5), and even had a significant negative impact on the OS of patients who underwent radical resection (HR =1.877; 95% CI: 1.229–2.866; P=0.004; Figure 5).

Figure 5 Multivariate Cox regression analysis of factors influencing OS in patients undergoing (A) local excision and (B) radical resection after PSM. CI, confidence interval; HR, hazard ratio; OS, overall survival; PSM, propensity score matching; T, tumor; RT, radiotherapy.

Discussion

This retrospective study undertook a statistical analysis of surgically treated stage I RC patients, aiming to explore the impact of preoperative RT on their survival. The results of this study indicate that for stage I RC patients who did not undergo chemotherapy, abstaining from RT appeared more advantageous for survival, regardless of whether patients received local excision or radical resection.

A recent multicenter, population-based Dutch national cross-sectional cohort study suggested that with routine use of magnetic resonance imaging and the continued improvement of the quality of RC surgery, neoadjuvant RT may safely be omitted for most cases of localized RC (19). In this cross-sectional study of 2,775 patients with colorectal cancer, the decreased use of neoadjuvant RT from 87% to 37% was not associated with the local regional recurrence rate (5.8% vs. 5.5%). The OS improved from 79.6% to 86.4%. Our study also found that for T1N0M0 patients, omitting RT was more beneficial for OS compared to preoperative RT (87.5% vs. 62.5%). This suggests that overtreatment in early-stage RC, especially in T1N0M0 patients, may be associated with higher mortality.

Preoperative RT in early-stage RC patients may lead to radiation proctitis, cystitis, and intestinal perforation, which negatively impact patient survival. Additionally, RT itself carries the risk of secondary malignancies. For early-stage RC patients who would not undergo chemotherapy, preoperative RT should not be performed.

The European Society for Medical Oncology (ESMO) recommends that for RC patients with T1N0M0, local resection surgery is the preferred treatment (20). Local excisional procedures such as TEM are appropriate as a single modality for early cancers (cT1N0 without adverse features like G3, V1, L1) (21,22). Bach et al.’s research indicates that short-course RT followed by TEM can achieve long-term outcomes comparable to those of radical surgery for early-stage RC, provided it is applied to a select group of biologically favorable tumors (18). ACOSOG Z6041 (16) and URBINO (17) trials emphasized the importance of neoadjuvant radiochemotherapy or short-course RT combined with local excision. However, the results of our study indicate that preoperative RT had no significant advantage over no RT, regardless of whether patients underwent local excision or radical resection. Furthermore, the type of surgery has no significant impact on the survival of early-stage RC. This suggests that, given the functional preservation offered by local excision, it should be recommended for both T1N0M0 and T2N0M0 cases. However, larger randomized studies, such as the ongoing STAR-TREC study, are needed to more precisely determine whether to choose neoadjuvant RT when opting for local excision.

Limitations

Our investigation has several limitations that merit acknowledgement. First, the retrospective nature of SEER-derived data inherently constrained our ability to adjust for confounding variables. Second, despite rigorous PSM, residual selection bias may persist due to unobserved covariates. Third, temporal variations in TNM staging criteria could introduce classification heterogeneity; however, our analyses suggested a minimal impact on early-stage categorization. Fourth, the focus on OS neglected critical quality-of-life metrics, which are essential for comprehensively assessing patient-reported outcomes and functional recovery. Finally, the historical cohort’s lack of access to contemporary diagnostic modalities [e.g., high-resolution magnetic resonance imaging (MRI)] and advanced radiation delivery systems may limit the extrapolation to current clinical practice.

Conclusions

This study concluded that for early-stage RC patients who would not undergo chemotherapy, giving up RT seemed to be more beneficial for OS, regardless of whether patients received local excision or radical resection. Further clinical trials are urgently warranted to explore the optimal treatment approach for early-stage RC. In addition, among patients with T2N0M0 disease who were candidates for local excision, preoperative RT failed to demonstrate any survival benefits. Notably, it was significantly associated with a pronounced decrease in OS in patients with T1N0M0 disease.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2570/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2570/prf

Funding: This study was supported by the Chongqing Science & Technology Bureau and Health Commission Project (2021ZY023879).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2570/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. This 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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