Is Adjuvant Chemotherapy Necessary for All Patients with pT3N0 Rectal Cancer after Upfront Surgery? A Multicenter Retrospective Study

Kyong-Min Kang; Ho Yung Lee; Hong-min Ahn; Heung-Kwon Oh; Duck-Woo Kim; Sung-Bum Kang; Dong Woon Lee; Sung Chan Park; Jae Hwan Oh; Min Jung Kim; Ji Won Park; Seung-Bum Ryoo; Seung-Yong Jeong; Kyu Joo Park

doi:10.4143/crt.2025.1308

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Original Article Is Adjuvant Chemotherapy Necessary for All Patients with pT3N0 Rectal Cancer after Upfront Surgery? A Multicenter Retrospective Study: Kyong-Min Kang¹, Ho Yung Lee¹, Hong-min Ahn¹, Heung-Kwon Oh¹, Duck-Woo Kim¹, Sung-Bum Kang¹, Dong Woon Lee², Sung Chan Park², Jae Hwan Oh², Min Jung Kim³, Ji Won Park³, Seung-Bum Ryoo³, Seung-Yong Jeong³, Kyu Joo Park³; DOI: https://doi.org/10.4143/crt.2025.1308
Published online: May 4, 2026

¹Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

²Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea

³Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

Correspondence: Duck-Woo Kim, Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea
Tel: 82-31-787-7101 E-mail: kdw@snubh.org

• Received: November 27, 2025 • Accepted: April 30, 2026

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

Purpose
The role of adjuvant chemotherapy (ACT) in pathologic T3N0 (pT3N0) rectal cancer, which has a favorable prognosis, remains controversial because high-risk groups for recurrence are not well defined. This study investigated prognostic factors for survival in this patient group and evaluated the benefit of ACT based on these factors.
Materials and Methods
This retrospective study analyzed 352 patients with pT3N0 rectal cancer who underwent upfront radical surgery at three referral hospitals between November 2003 and December 2020. A multivariable Cox regression model was used to identify the prognostic factors for 5-year recurrence-free survival (RFS). Patients were categorized as high or low risk based on these factors, and survival outcomes were compared between those who received ACT and those who did not, using the log-rank test.
Results
Median follow-up was 52.8 months. One hundred ninety-three patients (54.8%) received ACT. Multivariable analysis revealed that ACT, circumferential resection margin (CRM) ≤ 2 mm, vascular invasion, and perineural invasion were independent predictors of 5-year RFS. In patients with ≥ 1 risk factor, ACT significantly improved RFS (92.5% vs. 72.8%; hazard ratio [HR], 0.247; 95% confidence interval [CI], 0.090 to 0.683; p < 0.01). In those without risk factors, no significant benefit was observed (98.0% vs. 91.6%; HR, 0.272; 95% CI, 0.057 to 1.313; p=0.082).
Conclusion
This study identified CRM ≤ 2 mm, vascular invasion, and perineural invasion as high-risk features for recurrence in pT3N0 rectal cancer. ACT improved RFS only in patients with these features. While these findings support risk-based ACT administration in this patient population, further validation of our risk stratification system is needed.
Key words: Rectal neoplasms, Risk factors, Drug therapy

Introduction

Patients with pathologic T3N0 (pT3N0) rectal cancer have a favorable prognosis among the locally advanced rectal cancer (LARC) population, which generally refers to cT3-4 and/or node-positive disease without distant metastasis. A pooled analysis reported 5-year overall survival (OS) of 75% and disease-free survival of 65%, compared with 65% and 54% for T4N0 disease and 44%-60% and 36%-48% for T3N+ disease, respectively [1]. Following the standardization of total mesorectal excision (TME), which substantially reduced local recurrence and improved cancer-related survival in LARC, the local recurrence rate in pT3N0 rectal cancer has declined to approximately 10% [2-4]. These favorable outcomes have fostered speculation about the existence of a low-risk subgroup in whom adjuvant therapy could be safely omitted without compromising oncologic outcomes [5,6].

In contrast to colon cancer, where high-risk features are well defined, no consistent risk stratification system has been developed for pT3N0 rectal cancer, despite multiple attempts to identify prognostic factors to guide adjuvant treatment [6-11]. Since the adoption of TME and the standardization of preoperative chemoradiotherapy for T3 and more advanced disease, such investigative efforts have been limited [7,11,12]. Consequently, representative guidelines have extrapolated evidence from colon cancer adjuvant trials to inform adjuvant chemotherapy (ACT) recommendations in rectal cancer [13]. Defining a subgroup of patients with pT3N0 rectal cancer in whom favorable outcomes can be achieved with surgery alone could refine treatment guidelines and mitigate overtreatment.

Therefore, this study aimed to identify the predictive factors associated with survival in patients with pT3N0 rectal cancer treated with upfront radical resection and evaluate the oncologic benefit of ACT according to these factors.

Materials and Methods

1. Patients and treatment

This multicenter, retrospective cohort study included patients with rectal cancer who underwent surgical resection at three referral hospitals between November 2003 and December 2020. The inclusion criteria were as follows: (1) no neoadjuvant therapy, (2) standard radical resection, (3) histologically confirmed T3N0 rectal adenocarcinoma, (4) tumor location within 15 cm from the anal verge, as determined by endoscopic assessment, and (5) R0 resection. The exclusion criteria were (1) distant metastasis, (2) history of other malignancy, (3) hereditary colorectal cancer syndromes, (4) emergency surgery, and (5) adjuvant radiotherapy or chemoradiotherapy.

All patients underwent preoperative staging with digital rectal examination, carcinoembryonic antigen testing, colonoscopy, abdominopelvic computed tomography (CT), chest CT, and anorectal magnetic resonance imaging. Most patients with cT3-4 or node-positive rectal cancer received neoadjuvant chemoradiotherapy, whereas upfront surgery was generally performed for cT1-2N0 disease. Among patients with cT3-4 or clinically node-positive disease, upfront surgery was considered in selected cases, such as tumors located in the upper rectum, a high likelihood of requiring permanent stoma formation, or the presence of significant comorbidities or frailty that made neoadjuvant treatment less suitable. For indeterminate cases, treatment was decided by a multidisciplinary team comprising a colorectal surgeon, radiation oncologist, medical oncologist, radiologist, and pathologist and finalized after comprehensive consultation with the patient, taking into account their overall health status and the potential risks and benefits of each option. All patients underwent standardized radical resections based on conventional surgical oncologic principles [14]. The administration of ACT was determined by the attending physician according to the pathologic stage and the patient’s condition. For pT3N0 disease with high-risk features for systemic recurrence, defined per the National Comprehensive Cancer Network (NCCN) guidelines [15], postoperative 5-fluorouracil–based chemotherapy with or without oxaliplatin was recommended [16]. Oxaliplatin was excluded from the chemotherapy regimen for elderly or fragile patients, or for those with only one high-risk factor. Pathologic staging was performed using the American Joint Committee on Cancer (AJCC) TNM staging system versions applicable at the time of the respective cases, ranging from the 6th to the 8th editions. Lymphatic invasion and vascular invasion were distinguished in the pathologic reports of this study cohort [17]. Lymphatic invasion was defined as the presence of tumor cells within thin-walled spaces lined by endothelial cells, lacking an identifiable muscular coat or intraluminal red blood cells. On the other hand, vascular invasion was defined as tumor cells present within the vessels, showing relatively thick walls containing smooth muscle or an elastic lamina, often accompanied by intraluminal red blood cells. In cases where differentiation is difficult, D2-40 monoclonal antibody-immunostained slides, a lymphatic-specific endothelial marker, were screened for identification. Follow-up consisted of physical examination and carcinoembryonic antigen testing every 3 months for 2 years, then every 6 months for 5-8 years. Chest, abdominal, and pelvic CT scans were performed every 3-6 months for 2 years, then every 6-12 months thereafter. Colonoscopy was performed every 1-2 years, and positron emission tomography–CT was reserved for suspected recurrence.

2. Analysis

Demographic and clinicopathologic data were obtained from the electronic medical records. Recurrence-free survival (RFS) was defined as the interval from surgery to recurrence, and OS as the interval from surgery to last follow-up or death. Recurrence was identified radiologically or confirmed histologically.

Categorical variables were analyzed using Fisher’s exact test or Pearson’s chi-squared test. Patients with missing data were excluded from the analysis. Independent prognostic factors were identified using a multivariable Cox regression model. Survival outcomes were estimated using Kaplan-Meier curves and compared with log-rank tests. All statistical tests were two-sided, with p < 0.05 considered statistically significant. Analyses were performed with SPSS ver. 27 (IBM Corp.) and R ver. 4.4.1 (R Core Team, R Foundation for Statistical Computing).

Results

A total of 352 patients with pT3N0 rectal cancer were included in the analysis. Of these, 193 patients (54.8%) received ACT, while the other 159 patients (45.2%) were followed up without adjuvant therapy. Circumferential resection margin (CRM) was significantly more common in the observation group, while perineural invasion (PNI) was significantly more prevalent in the ACT group. No significant differences were observed between the two groups for the remaining variables (Table 1). The median follow-up duration was 52.8 months (interquartile range, 32.4 to 67.2 months). During follow-up, 25 patients (7.1%) experienced recurrence, including four (1.1%) with loco-regional failure and 21 (6.0%) with distant failure. The cumulative 5-year RFS rate was 91.7%. A total of 55 deaths (15.6%) were recorded, yielding a cumulative 5-year OS rate of 81.8%. When stratified by treatment group, loco-regional failure was observed in one patient (0.5%) in the ACT group and three patients (1.9%) in the observation group (hazard ratio [HR], 0.271; 95% confidence interval [CI], 0.028 to 2.629; p=0.260). Distant failure occurred in seven patients (3.6%) in the ACT group and 14 patients (8.8%) in the observation group (HR, 0.390; 95% CI, 0.153 to 0.991; p=0.048).

Variables with p < 0.05 in the univariable analysis for 5-year RFS, including ACT, CRM, vascular invasion, and perineural invasion, were incorporated into the multivariable model. Multivariable analysis identified ACT (HR, 0.235; 95% CI, 0.097 to 0.567; p=0.001), CRM > 2 mm (HR, 0.270; 95% CI, 0.109 to 0.668; p=0.005), vascular invasion (HR, 5.055; 95% CI, 2.035 to 12.558; p=0.001), and PNI (HR, 3.092; 95% CI, 1.347 to 7.099; p=0.008) as significant predictors for 5-year RFS (Table 2). Variables with p < 0.05 in the univariable analysis for 5-year OS, including age, ACT, and CRM, were incorporated into the multivariable model. Age ≥ 70 years (HR, 2.948; 95% CI, 1.442 to 6.025; p=0.003), ACT (HR, 0.213; 95% CI, 0.112 to 0.404; p < 0.001), and CRM > 2 mm (HR, 0.387; 95% CI, 0.204 to 0.736; p=0.004) were independent prognostic factors for 5-year OS (Table 3).

To assess the efficacy of ACT, patients were stratified into two risk groups: those with ≥ 1 risk factor were designated as high risk, and those without as low risk. The effect of ACT was evaluated within each subgroup. In the high-risk group for RFS, the cumulative 5-year RFS rate was 92.5% in patients who received ACT and 72.8% in those who did not (HR, 0.247; 95% CI, 0.090 to 0.683; p < 0.01) (Fig. 1A). In the low-risk group, the cumulative 5-year RFS rate was 98.0% with ACT and 91.6% without ACT (HR, 0.272; 95% CI, 0.057 to 1.313; p=0.082) (Fig. 1B). In the high-risk group for OS, the cumulative 5-year OS rate was 89.0% with ACT and 61.7% without ACT (HR, 0.230; 95% CI, 0.117 to 0.450; p < 0.01) (Fig. 2A). In the low-risk group, the cumulative 5-year OS rate was 98.0% with ACT and 88.2% without ACT (HR, 0.152; 95% CI, 0.028 to 0.781; p=0.024) (Fig. 2B).

A sensitivity analysis was performed using a 1 mm cutoff for CRM. CRM ≤ 1 mm was observed in one patient (0.5%) in the ACT group and in nine patients (5.7%) in the observation group. Multivariable analysis identified ACT (HR, 0.280; 95% CI, 0.110 to 0.713; p=0.008), CRM > 1 mm (HR, 0.194; 95% CI, 0.051 to 0.735; p=0.016), and vascular invasion (HR, 4.398; 95% CI, 1.776 to 10.891; p=0.001) as significant predictors for 5-year RFS (S1 Table). Age ≥ 70 years (HR, 3.069; 95% CI, 1.498 to 6.285; p=0.002), ACT (HR, 0.233; 95% CI, 0.122 to 0.448; p < 0.001), and CRM > 1 mm (HR, 0.162; 95% CI, 0.068 to 0.389; p < 0.001) were independent prognostic factors for 5-year OS (S2 Table).

The benefit of ACT across different risk groups was assessed based on the risk factors identified in this analysis. In the high-risk group for RFS, the cumulative 5-year RFS rate was 92.0% in patients who received ACT and 46.3% in those who did not (HR, 0.122; 95% CI, 0.026 to 0.578; p=0.008) (S3A Fig.). In the low-risk group, the cumulative 5-year RFS rate was 96.1% with ACT and 91.2% without ACT (HR, 0.505; 95% CI, 0.180 to 1.420; p=0.195) (S3B Fig.). In the high-risk group for OS, the cumulative 5-year OS rate was 88.8% with ACT and 61.0% without ACT (HR, 0.230; 95% CI, 0.117 to 0.450; p < 0.001) (S4A Fig.). In the low-risk group, the cumulative 5-year OS rate was 98.1% with ACT and 88.7% without ACT (HR, 0.127; 95% CI, 0.015 to 1.091; p=0.060) (S4B Fig.).

A subgroup analysis categorized by age (≥ 70 years vs. < 70 years) was performed. In patients aged < 70 years, the 5-year OS rate was 96.7% in the ACT group compared with 85.6% in the observation group (HR, 0.191; 95% CI, 0.045 to 0.922; p=0.039) (S5A Fig.). In patients aged ≥ 70 years, the 5-year OS rate was 89.6% in the ACT group compared with 61.5% in the observation group (HR, 0.215; 95% CI, 0.116 to 0.438; p < 0.001) (S5B Fig.).

After stratifying patients by risk within each age group, ACT was associated with a significantly improved RFS in the high-risk subgroup (95.0% vs. 64.3%; HR, 0.126; 95% CI, 0.024 to 0.652; p=0.014) (S6A Fig.), whereas no significant benefit was observed in the low-risk subgroup (97.1% vs. 89.2%; HR, 0.340; 95% CI, 0.035 to 3.271; p=0.350) (S6B Fig.) among patients aged < 70 years. In contrast, among patients aged ≥ 70 years, ACT was not significantly associated with RFS in either the high-risk subgroup (90.1% vs. 78.1%; HR, 0.421; 95% CI, 0.112 to 1.577; p=0.199) (S7A Fig.) or the low-risk subgroup (98.4% vs. 92.9%; HR, 0.233; 95% CI, 0.026 to 2.087; p=0.193) (S7B Fig.).

All ACT regimens in this study were 5-fluorouracil–based, with or without oxaliplatin. Subgroup analysis was performed to compare RFS according to regimen type. Recurrence was observed in six of the 143 patients (4.2%) who received non-oxaliplatin-based ACT, in two of the 50 patients (4%) who received oxaliplatin-based ACT, and in 17 of the 159 patients (10.7%) in the observation group (S8 Table). In the high-risk group, both oxaliplatin-based and non-oxaliplatin-based ACT significantly improved 5-year RFS compared with observation (94.3% and 90.9% vs. 72.8%; p=0.01 and p=0.037, respectively) (S9A Fig.). However, no significant difference in 5-year RFS was detected between the two ACT groups (94.3% vs. 90.9%, p=0.543) (S9A Fig.). In the low-risk group, no significant differences in 5-year RFS were observed among the observation, non-oxaliplatin-based ACT, and oxaliplatin-based ACT groups (91.6%, 97.8%, and 100.0%, respectively; p=0.215) (S9B Fig.).

Discussion

This study demonstrated that ACT significantly improved 5-year RFS in the high-risk subgroup of patients with pT3N0 rectal cancer, defined by CRM ≤ 2 mm, vascular invasion, or perineural invasion. While this high-risk classification system, derived from a multicenter real-world cohort in Korea, may help inform ACT decision-making, further validation of these findings is warranted, given the retrospective and nonrandomized design of this study. Earlier studies reported relatively favorable outcomes in pT3N0 rectal cancer. Gunderson et al. [18] observed a 5-year OS of 75% in patients with pT3N0 tumors, compared with 65% in those with pT4N0 tumors. Similarly, a retrospective study reported a 10-year RFS of 87% in pT3N0 disease [8]. Based on such results, several researchers [2,5,6] have questioned the consistent benefit of adjuvant therapy in this subgroup. However, a validated system for defining high-risk patients has been lacking. Although retrospective studies [4,6,10] suggested ACT is more beneficial for high-risk patients compared with low-risk patients, variation in the definition of risk features, likely reflecting heterogeneity in populations and data sources, has limited their clinical utility. Moreover, the types of adjuvant therapy administered varied significantly across these studies, and none specifically focused on the isolated effect of chemotherapy in the adjuvant setting based on risk stratification.

In this study, CRM ≤ 2 mm, vascular invasion, and PNI emerged as high-risk features for 5-year RFS. CRM status is a well-established prognostic factor in colorectal cancer [2,11]. Consistent with prior findings, this study confirmed that CRM ≤ 2 mm was associated with poor oncologic outcomes in pT3N0 rectal cancer. Eriksen et al. [19] analyzed 1,676 patients with pathologic T3 rectal cancer who underwent upfront radical resection and demonstrated a strong association between threatened CRM and both local recurrence and distant metastasis, reinforcing its prognostic value. The European Society for Medical Oncology guidelines recommend adjuvant therapy for patients with rectal cancer with CRM ≤ 2 mm who did not undergo preoperative chemoradiotherapy [11]. In stage II colorectal cancer, retrieval of < 12 lymph nodes (LNs) is considered a major prognostic indicator [11,20]. A retrospective study of 6,793 patients in the Danish Colorectal Cancer Group registry reported that among stage I-II patients treated with radical resection alone, those with ≥ 12 retrieved LNs had significantly higher 5-year OS than those with fewer than 12 [21]. In contrast, the present study did not find a significant association between inadequate LN sampling and survival, likely due to the small proportion of patients with < 12 LNs (7.7%). Although representative guidelines [15,20] identify lymphovascular invasion (LVI) as an adverse prognostic factor for colorectal cancer and recommend factoring it into decision-making for adjuvant therapy, its significance in stage II disease remains debated [22,23]. In this study, vascular invasion was significantly associated with reduced RFS, whereas lymphatic invasion showed no correlation. A prospective multicenter study found that isolated LVI had no effect on the outcomes in node-negative rectal cancer after radical resection [23]. PNI has also been identified as an unfavorable prognostic factor in rectal cancer [22,24,25]. Lee et al. [22] and Peng et al. [25] reported that PNI independently predicted recurrence in patients with pT3N0 rectal cancer and recommended ACT, consistent with the findings of this study. Although previous studies have identified the prognostic role of CRM involvement, vascular invasion, and PNI in colorectal cancer, the present study specifically focused on patients with pT3N0 rectal cancer undergoing upfront surgery and further stratified them according to these risk factors to evaluate the impact of ACT.

We adopted a 2 mm cutoff for CRM based on prior studies that have adopted this cutoff [26,27] rather than the commonly used 1 mm cutoff for margin positivity [15], as the number of patients with CRM ≤ 1 mm in our cohort was limited. In the sensitivity analysis, using the 1 mm cutoff for CRM, PNI slightly lost its status as a risk factor, while other high-risk features remained consistent. Furthermore, ACT did not show a statistically significant benefit in OS in the low-risk group. As further reflected in the differences observed in this analysis, the findings concerning the proposed risk stratification system and the potential OS benefit of ACT in the low-risk group in the primary analysis should be interpreted with caution, given the small number of events and the observational design of the present study. Nevertheless, the 2 mm cutoff for CRM might offer the potential benefit of including a broader range of patients who could benefit from ACT, including those with marginally positive margins.

Several studies have reported limited efficacy of ACT in elderly patients with colorectal cancer [28]. In the age-stratified analysis, ACT was associated with significantly improved OS in both patients aged < 70 years and ≥ 70 years. When evaluating the effect of ACT on RFS, the benefit was observed only in patients aged < 70 years with high-risk features. In contrast, no statistically significant benefit was seen in patients aged ≥ 70 years, regardless of risk classification. However, absolute differences in RFS between the ACT and observation groups were observed even in the absence of statistical significance, including 12% in high-risk patients aged ≥ 70 years and 7.9% in low-risk patients aged < 70 years. Given the limited sample size in the subgroup analyses and the observational nature of this study, definitive conclusions regarding the age-stratified benefit of ACT cannot be drawn, and the findings should therefore be interpreted with caution.

Patients with pT3N0 rectal cancer who undergo upfront surgery without neoadjuvant therapy are often those initially staged as cT1-2 or borderline cT3 on preoperative magnetic resonance imaging (MRI). This cohort may represent a relatively more favorable subset of T3 disease, which may influence the overall prognosis of pT3N0 patients and potentially affect the interpretation of treatment effects, including the impact of ACT. However, in the present cohort, patients with more advanced clinical features were also substantially represented, with cT3-4 and clinically node-positive disease accounting for 56.9% and 40.2% of the study population, respectively. In addition, the distribution of these clinical staging variables was comparable between the observation and ACT groups (Table 1). Furthermore, neither clinical T stage nor clinical N stage was significantly associated with RFS or OS (Tables 2 and 3). Nevertheless, given the retrospective nature of this study and the inherent variability of MRI-based staging, the potential impact of selection bias should be taken into account.

Within our cohort, neoadjuvant radiotherapy was omitted in patients with LARC who would otherwise be candidates for this approach, particularly when permanent stoma formation was anticipated or in those with significant comorbidities or frailty rendering neoadjuvant treatment less suitable. Although not statistically significant, factors that are commonly considered primary clinical criteria for radiotherapy, such as cT3-4 disease and low- to mid-rectal tumor location, were more frequently observed in the observation group, suggesting a potential imbalance in indications for radiotherapy. In this context, the poorer outcomes in the observation group may not be solely attributable to the absence of ACT, but may also be influenced by the omission of indicated radiotherapy. In our analysis, loco-regional failure was infrequent in both groups and did not differ significantly between groups, whereas a statistically significant difference was observed for distant failure. These findings suggest that the observed differences in oncologic outcomes may not be primarily explained by excess loco-regional failure in the observation group. Instead, the observed pattern appears to be more closely associated with distant failure, which may be consistent with the systemic effects of ACT. However, given the small number of recurrence events, the statistical power of these analyses is limited, and the results should be interpreted with caution.

Among 193 patients who received ACT in this study, 50 (25.9%) were treated with an oxaliplatin-containing regimen, and the remainder received fluoropyrimidine monotherapy. Fluoropyrimidines are the only agents with proven survival benefit in patients with pathologic stage II/III rectal cancer undergoing upfront surgery [29]. Oxaliplatin-based ACT is frequently used in this population, but its administration is based on evidence extrapolated from colon cancer trials [30]. Our subgroup analysis demonstrated that ACT conferred a significant benefit in the high-risk group compared with the low-risk group, irrespective of the regimen. However, oxaliplatin-containing therapy did not provide additional survival benefit over fluoropyrimidine alone. While these findings indicate that routine oxaliplatin use may not provide additional benefit in high-risk patients with pT3N0 rectal cancer treated with upfront surgery, this result comes from an exploratory analysis and warrants confirmation in larger prospective studies.

The study has some limitations. First, its retrospective design and reliance on an administrative database are responsible for inherent biases, including incomplete data and limited available variables. Missing data precluded evaluation of molecular markers, such as microsatellite instability, that may influence chemotherapy effectiveness [31]. Although preoperative obstruction and perforation are also clinically important oncologic risk factors, these conditions were often associated with patients requiring emergency surgery or those preferentially treated with neoadjuvant therapy due to their high-risk features, resulting in their underrepresentation in our upfront surgery cohort. In addition, within the patients managed with elective upfront surgery, a reliable analysis of these variables was not feasible because of a substantial amount of missing data. Second, although ACT did not achieve statistical significance, the Kaplan-Meier curves show an absolute difference of approximately 7% in 5-year RFS in the low-risk group, suggesting that the observed differences are not negligible. Given the very small number of events and the limited sample size in this subgroup, the lack of statistical significance may more likely reflect low statistical power rather than the absence of a true treatment effect. Therefore, clinically meaningful benefits of ACT cannot be completely excluded. Third, the present study spans multiple AJCC editions. During the earlier period (2003-2009), tumor deposits were not classified as N1c according to AJCC 6th edition criteria, which may have led to an underestimation of nodal disease in some patients. Fourth, the present study focused on high-risk patients who did not undergo neoadjuvant therapy. Additional studies are needed to assess whether similar benefits are observed in patients receiving preoperative concurrent chemoradiotherapy. Fifth, although the NCCN guidelines [15] recommend that postoperative systemic chemotherapy with radiation may also be considered for patients with pT3N0 rectal cancer after upfront surgery, the 61 patients who met the eligibility criteria but received adjuvant radiotherapy during the study period were excluded from the analysis, as their inclusion could have confounded the evaluation of the potential effects of ACT.

This study identified CRM ≤ 2 mm, vascular invasion, and PNI as risk factors for adverse long-term outcomes in patients with pT3N0 rectal cancer. ACT was associated with improved survival in the high-risk group defined by these features, and no statistically significant benefit was observed in the low-risk group, supporting a tailored approach to adjuvant treatment after upfront radical resection. However, the retrospective nature of the study, along with the relatively low event rates and small subgroup sizes, warrants cautious interpretation. Randomized controlled trials with larger cohorts, stratified by these high-risk factors, could help clarify the role of ACT following upfront surgery in this population.

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

CRT_25-1308_S1_Table.pdf

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CRT_25-1308_S8_Table.pdf

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NOTES

Ethical Statement

The institutional review board of each participating hospital (Seoul National University Bundang Hospital No. B-2508-988-103) approved this study and waived the need for informed consent owing to its retrospective design and minimal risk of identification.

Author Contributions

Conceived and designed the analysis: Kang KM, Kim DW.

Collected the data: Kang KM, Lee HY, Ahn HM, Oh HK, Kim DW, Kang SB, Lee DW, Park SC, Oh JH, Kim MJ, Park JW, Ryoo SB, Jeong SY, Park KJ.

Contributed data or analysis tools: Kang KM, Kim DW.

Performed the analysis: Kang KM, Kim DW.

Wrote the paper: Kang KM, Lee HY, Ahn HM, Oh HK, Kim DW, Kang SB, Lee DW, Park SC, Oh JH, Kim MJ, Park JW, Ryoo SB, Jeong SY, Park KJ.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Acknowledgments

The authors acknowledge support from the National R&D Program for Cancer Control through the National Cancer Center funded by the Ministry of Health & Welfare, Republic of Korea (HA22C0042). This support was in the form of general research resources and did not involve any direct financial assistance for this specific study.

Fig. 1.

Kaplan-Meier curves of 5-year recurrence-free survival for patients in the adjuvant chemotherapy (ACT) and observation groups. The Kaplan-Meier curves are shown for subgroups: with ≥ 1 risk factor for recurrence-free survival (A) and without risk factors (B). CI, confidence interval; HR, hazard ratio.

Fig. 2.

Kaplan-Meier curves of 5-year overall survival for patients in the adjuvant chemotherapy (ACT) and observation groups. The Kaplan-Meier curves are shown for subgroups: with ≥ 1 risk factor for overall survival (A) and without risk factors (B). CI, confidence interval; HR, hazard ratio.

Table 1.

Clinicopathologic characteristics of the participants

Characteristic	Adjuvant therapy		p-value
Characteristic	Observation (n=159)	Chemotherapy (n=193)	p-value
Age at operation (yr)			0.084
< 70	50 (31.4)	79 (40.9)
≥ 70	109 (68.6)	114 (59.1)
Sex			0.989
Male	104 (65.4)	125 (64.8)
Female	55 (34.6)	68 (35.2)
ASA score			0.341
1-2	141 (88.7)	178 (92.2)
3-4	18 (11.3)	15 (7.8)
Preoperative CEA (ng/mL)			0.786
≤ 5	128 (80.5)	152 (78.8)
> 5	31 (19.5)	41 (21.2)
Distance from anal verge (cm)			0.078
Low to mid (≤ 10)	117 (73.6)	124 (64.2)
Upper (> 10)	42 (26.4)	69 (35.8)
Gross type			0.749
Fungating	117 (73.6)	146 (75.6)
Infiltrative	42 (26.4)	47 (24.4)
Tumor size (cm)			0.557
< 5	74 (46.5)	97 (50.3)
≥ 5	85 (53.5)	96 (49.7)
cT stage			0.413
1	22 (13.8)	27 (14.0)
2	41 (25.8)	63 (32.6)
3	83 (52.2)	93 (48.2)
4	13 (8.2)	10 (5.2)
cN stage			0.564
Negative	98 (61.6)	112 (58.0)
Positive	61 (38.4)	81 (42.0)
CRM (mm)			0.043
≤ 2	23 (14.5)	14 (7.3)
> 2	136 (85.5)	179 (92.7)
Histology			0.862
WD, MD	157 (98.7)	189 (97.9)
PD, MC	2 (1.3)	4 (2.1)
No. of harvested LNs			0.184
< 12	16 (10.1)	11 (5.7)
≥ 12	143 (89.9)	182 (94.3)
Lymphatic invasion			0.111
Negative	138 (86.8)	154 (79.8)
Positive	21 (13.2)	39 (20.2)
Vascular invasion			0.229
Negative	145 (91.2)	167 (86.5)
Positive	14 (8.8)	26 (13.5)
Perineural invasion			< 0.001
Negative	134 (84.3)	129 (66.8)
Positive	25 (15.7)	64 (33.2)

Values are presented as number (%). ASA, American Society of Anesthesiologists; CEA, carcinoembryonic antigen; CRM, circumferential resection margin; LN, lymph node; MC, mucinous carcinoma; MD, moderately differentiated; PD, poorly differentiated; WD, well-differentiated.

Table 2.

Univariable and multivariable analyses of factors associated with 5-year recurrence-free survival

Characteristic	Univariable analysis		Multivariable analysis
Characteristic	HR (95% CI)	p-value	HR (95% CI)	p-value
Age at operation (yr)
< 70	1
≥ 70	0.783 (0.355-1.725)	0.544	-	-
Sex
Male	1
Female	0.358 (0.123-1.044)	0.060	-	-
ASA score
1-2	1
3-4	1.414 (0.423-4.728)	0.574	-	-
Distance from anal verge (cm)
Low to mid (≤ 10)	1
Upper (> 10)	1.407 (0.630-3.123)	0.407	-	-
Preoperative CEA (ng/mL)
≤ 5	1
> 5	1.707 (0.712-4.088)	0.230	-	-
cT stage
1-2	1
3-4	0.774 (0.353-1.696)	0.522	-	-
cN stage
Negative	1
Positive	0.609 (0.254-1.458)	0.266	-	-
Adjuvant therapy
Observation	1		1
Chemotherapy	0.341 (0.147-0.790)	0.012	0.235 (0.097-0.567)	0.001
Histology
WD, MD	1
PD, MC	0.048 (0.001-11,413.664)	0.631	-	-
Gross type
Fungating	1
Infiltrative	2.051 (0.921-4.567)	0.079	-	-
Tumor size (cm)
< 5	1
≥ 5	0.579 (0.256-1.310)	0.223	-	-
No. of harvested LNs
< 12	1
≥ 12	2.183 (0.295-16.142)	0.444	-	-
CRM (mm)
≤ 2	1		1
> 2	0.228 (0.095-0.548)	0.001	0.270 (0.109-0.668)	0.005
Lymphatic invasion
Negative	1
Positive	1.023 (0.351-2.982)	0.966	-	-
Vascular invasion
Negative	1		1
Positive	3.598 (1.500-8.629)	0.004	5.055 (2.035-12.558)	0.001
Perineural invasion
Negative	1		1
Positive	2.601 (1.180-5.731)	0.018	3.092 (1.347-7.099)	0.008

ASA, American Society of Anesthesiologists; CEA, carcinoembryonic antigen; CI, confidence interval; CRM, circumferential resection margin; HR, hazard ratio; LN, lymph node; MC, mucinous carcinoma; MD, moderately differentiated; PD, poorly differentiated; WD, well-differentiated.

Table 3.

Univariable and multivariable analyses of factors associated with 5-year overall survival

Characteristic	Univariable analysis		Multivariable analysis
Characteristic	HR (95% CI)	p-value	HR (95% CI)	p-value
Age at operation (yr)
< 70	1		1
≥ 70	3.175 (1.554-6.486)	0.002	2.948 (1.442-6.025)	0.003
Sex
Male	1
Female	0.784 (0.438-1.403)	0.412	-	-
ASA score
1-2	1
3-4	1.862 (0.879-3.944)	0.105	-	-
Distance from anal verge (cm)
Low to mid (≤ 10)	1
Upper (> 10)	1.028 (0.585-1.806)	0.923	-	-
Preoperative CEA (ng/mL)
≤ 5	1
> 5	1.736 (0.970-3.108)	0.063	-	-
cT stage
1-2	1
3-4	1.024 (0.597-1.841)	0.581	-	-
cN stage
Negative	1
Positive	0.740 (0.417-1.310)	0.301	-	-
Adjuvant therapy
Observation	1		1
Chemotherapy	0.203 (0.107-0.384)	0.001	0.213 (0.112-0.404)	0.001
Histology
WD, MD	1
PD, MC	0.048 (0.001-172.957)	0.468	-	-
Gross type
Fungating	1
Infiltrative	1.514 (0.862-2.661)	0.149	-	-
Tumor size (cm)
< 5	1
≥ 5	1.280 (0.753-2.176)	0.362	-	-
No. of harvested LNs
< 12	1
≥ 12	0.772 (0.331-1.804)	0.550	-	-
CRM (mm)
≤ 2	1		1
> 2	0.332 (0.175-0.631)	0.001	0.387 (0.204-0.736)	0.004
Lymphatic invasion
Negative	1
Positive	1.378 (0.711-2.669)	0.342	-	-
Vascular invasion
Negative	1
Positive	1.511 (0.713-3.200)	0.281	-	-
Perineural invasion
Negative	1
Positive	1.343 (0.750-2.404)	0.321	-	-

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Is Adjuvant Chemotherapy Necessary for All Patients with pT3N0 Rectal Cancer after Upfront Surgery? A Multicenter Retrospective Study

DOI: https://doi.org/10.4143/crt.2025.1308

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Abstract
Introduction
Materials and Methods
Results
Discussion
Electronic Supplementary Material
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REFERENCES

Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A Real-World, Retrospective Study

Is Adjuvant Chemotherapy Necessary for All Patients with pT3N0 Rectal Cancer after Upfront Surgery? A Multicenter Retrospective Study

Fig. 1. Kaplan-Meier curves of 5-year recurrence-free survival for patients in the adjuvant chemotherapy (ACT) and observation groups. The Kaplan-Meier curves are shown for subgroups: with ≥ 1 risk factor for recurrence-free survival (A) and without risk factors (B). CI, confidence interval; HR, hazard ratio.

Fig. 2. Kaplan-Meier curves of 5-year overall survival for patients in the adjuvant chemotherapy (ACT) and observation groups. The Kaplan-Meier curves are shown for subgroups: with ≥ 1 risk factor for overall survival (A) and without risk factors (B). CI, confidence interval; HR, hazard ratio.

Fig. 1.

Fig. 2.

Is Adjuvant Chemotherapy Necessary for All Patients with pT3N0 Rectal Cancer after Upfront Surgery? A Multicenter Retrospective Study

Characteristic	Adjuvant therapy		p-value
Characteristic	Observation (n=159)	Chemotherapy (n=193)	p-value
Age at operation (yr)			0.084
< 70	50 (31.4)	79 (40.9)
≥ 70	109 (68.6)	114 (59.1)
Sex			0.989
Male	104 (65.4)	125 (64.8)
Female	55 (34.6)	68 (35.2)
ASA score			0.341
1-2	141 (88.7)	178 (92.2)
3-4	18 (11.3)	15 (7.8)
Preoperative CEA (ng/mL)			0.786
≤ 5	128 (80.5)	152 (78.8)
> 5	31 (19.5)	41 (21.2)
Distance from anal verge (cm)			0.078
Low to mid (≤ 10)	117 (73.6)	124 (64.2)
Upper (> 10)	42 (26.4)	69 (35.8)
Gross type			0.749
Fungating	117 (73.6)	146 (75.6)
Infiltrative	42 (26.4)	47 (24.4)
Tumor size (cm)			0.557
< 5	74 (46.5)	97 (50.3)
≥ 5	85 (53.5)	96 (49.7)
cT stage			0.413
1	22 (13.8)	27 (14.0)
2	41 (25.8)	63 (32.6)
3	83 (52.2)	93 (48.2)
4	13 (8.2)	10 (5.2)
cN stage			0.564
Negative	98 (61.6)	112 (58.0)
Positive	61 (38.4)	81 (42.0)
CRM (mm)			0.043
≤ 2	23 (14.5)	14 (7.3)
> 2	136 (85.5)	179 (92.7)
Histology			0.862
WD, MD	157 (98.7)	189 (97.9)
PD, MC	2 (1.3)	4 (2.1)
No. of harvested LNs			0.184
< 12	16 (10.1)	11 (5.7)
≥ 12	143 (89.9)	182 (94.3)
Lymphatic invasion			0.111
Negative	138 (86.8)	154 (79.8)
Positive	21 (13.2)	39 (20.2)
Vascular invasion			0.229
Negative	145 (91.2)	167 (86.5)
Positive	14 (8.8)	26 (13.5)
Perineural invasion			< 0.001
Negative	134 (84.3)	129 (66.8)
Positive	25 (15.7)	64 (33.2)

Characteristic	Univariable analysis		Multivariable analysis
Characteristic	HR (95% CI)	p-value	HR (95% CI)	p-value
Age at operation (yr)
< 70	1
≥ 70	0.783 (0.355-1.725)	0.544	-	-
Sex
Male	1
Female	0.358 (0.123-1.044)	0.060	-	-
ASA score
1-2	1
3-4	1.414 (0.423-4.728)	0.574	-	-
Distance from anal verge (cm)
Low to mid (≤ 10)	1
Upper (> 10)	1.407 (0.630-3.123)	0.407	-	-
Preoperative CEA (ng/mL)
≤ 5	1
> 5	1.707 (0.712-4.088)	0.230	-	-
cT stage
1-2	1
3-4	0.774 (0.353-1.696)	0.522	-	-
cN stage
Negative	1
Positive	0.609 (0.254-1.458)	0.266	-	-
Adjuvant therapy
Observation	1		1
Chemotherapy	0.341 (0.147-0.790)	0.012	0.235 (0.097-0.567)	0.001
Histology
WD, MD	1
PD, MC	0.048 (0.001-11,413.664)	0.631	-	-
Gross type
Fungating	1
Infiltrative	2.051 (0.921-4.567)	0.079	-	-
Tumor size (cm)
< 5	1
≥ 5	0.579 (0.256-1.310)	0.223	-	-
No. of harvested LNs
< 12	1
≥ 12	2.183 (0.295-16.142)	0.444	-	-
CRM (mm)
≤ 2	1		1
> 2	0.228 (0.095-0.548)	0.001	0.270 (0.109-0.668)	0.005
Lymphatic invasion
Negative	1
Positive	1.023 (0.351-2.982)	0.966	-	-
Vascular invasion
Negative	1		1
Positive	3.598 (1.500-8.629)	0.004	5.055 (2.035-12.558)	0.001
Perineural invasion
Negative	1		1
Positive	2.601 (1.180-5.731)	0.018	3.092 (1.347-7.099)	0.008

Characteristic	Univariable analysis		Multivariable analysis
Characteristic	HR (95% CI)	p-value	HR (95% CI)	p-value
Age at operation (yr)
< 70	1		1
≥ 70	3.175 (1.554-6.486)	0.002	2.948 (1.442-6.025)	0.003
Sex
Male	1
Female	0.784 (0.438-1.403)	0.412	-	-
ASA score
1-2	1
3-4	1.862 (0.879-3.944)	0.105	-	-
Distance from anal verge (cm)
Low to mid (≤ 10)	1
Upper (> 10)	1.028 (0.585-1.806)	0.923	-	-
Preoperative CEA (ng/mL)
≤ 5	1
> 5	1.736 (0.970-3.108)	0.063	-	-
cT stage
1-2	1
3-4	1.024 (0.597-1.841)	0.581	-	-
cN stage
Negative	1
Positive	0.740 (0.417-1.310)	0.301	-	-
Adjuvant therapy
Observation	1		1
Chemotherapy	0.203 (0.107-0.384)	0.001	0.213 (0.112-0.404)	0.001
Histology
WD, MD	1
PD, MC	0.048 (0.001-172.957)	0.468	-	-
Gross type
Fungating	1
Infiltrative	1.514 (0.862-2.661)	0.149	-	-
Tumor size (cm)
< 5	1
≥ 5	1.280 (0.753-2.176)	0.362	-	-
No. of harvested LNs
< 12	1
≥ 12	0.772 (0.331-1.804)	0.550	-	-
CRM (mm)
≤ 2	1		1
> 2	0.332 (0.175-0.631)	0.001	0.387 (0.204-0.736)	0.004
Lymphatic invasion
Negative	1
Positive	1.378 (0.711-2.669)	0.342	-	-
Vascular invasion
Negative	1
Positive	1.511 (0.713-3.200)	0.281	-	-
Perineural invasion
Negative	1
Positive	1.343 (0.750-2.404)	0.321	-	-

Table 1. Clinicopathologic characteristics of the participants

Table 2. Univariable and multivariable analyses of factors associated with 5-year recurrence-free survival

Table 3. Univariable and multivariable analyses of factors associated with 5-year overall survival