Patterns of recurrence and outcomes of poor responders to neoadjuvant long-course chemoradiotherapy for rectal cancer

Introduction

Locally advanced rectal cancer (LARC) remains a major global health challenge, with its management evolving significantly over the past few decades to balance tumor control, sphincter preservation, and quality of life. Neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery and adjuvant chemotherapy has become the standard of care for LARC (1). This multimodal strategy aims to downstage and downgrade tumors, increase the chance of sphincter-preserving surgery, and reduce the risk of locoregional recurrence (2,3). Moreover, in recent years, neoadjuvant treatment regimens have been continuously optimized, and the tumor regression effect in the overall population has become increasingly better (4-6).

However, the therapeutic response to nCRT is highly heterogeneous among patients. Previous studies have indicated that tumor regression grading (TRG) after nCRT was a prognostic factor in LARC (7-10). Approximately 15–30% of LARC patients achieve a pathological complete response (pCR), a state associated with excellent prognosis (11,12). While about 20% of LARC patients exhibits poor tumor regression (e.g., TRG 3, as defined in this study) (13). Yet their specific recurrence patterns and long-term outcomes remain insufficiently characterized.

Existing literature has primarily focused on outcomes of good responders or the general LARC population, with limited attention to poor responders to nCRT. This knowledge gap has critical clinical implications: without clear data on how and where recurrence occurs in this subgroup, follow-up strategies may be suboptimal, leading to delayed detection of recurrent disease. The findings of this study seek to provide evidence-based guidance for optimizing follow-up protocols and treatment adherence in this high-risk patient population. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1065/rc).

Methods

Study population

The present retrospective study included consecutive patients diagnosed with LARC who received neoadjuvant long-course chemoradiotherapy (LCCRT) and surgery at our hospital between July 2013 and August 2023. A total of 1,184 patients were identified. TRG was assessed according to the 7th edition of the American Joint Committee on Cancer Staging Manual and College of American Pathologists guidelines, as modified by Ryan et al. (14). A 4-point TRG system (0–3) was used. TRG0 was defined as complete pathological response with no residual tumor cells. TRG1 was defined as near-complete regression with only focal residual cancer cells. TRG2 was defined as moderate regression with prominent residual tumor. TRG3 was defined as minimal regression with extensive residual disease. All TRG scoring was performed independently by two specialized pathologists. The distribution of TRG grades is as follows: TRG 0: n=269 (22.7%); TRG 1: n=237 (20.0%); TRG 2: n=543 (45.9%); TRG 3: n=135 (11.4%). Eligibility criteria were as follows: (I) histologically confirmed adenocarcinoma of the rectum and rectal magnetic resonance imaging (MRI) confirmed locally advanced disease; (II) completion of neoadjuvant LCCRT as initial treatment; (III) underwent total mesorectal excision (TME) surgery, with postoperative pathology confirming a TRG of 3; (IV) complete clinical, pathological, and follow-up data available. Patients with distant metastases at initial diagnosis or those who discontinued treatment due to severe adverse events were excluded from the analysis. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Review Board of Fudan University Shanghai Cancer Center. All patients provided written informed consent for their data to be used in the study.

Treatment protocols

Data collection and outcome measures

Clinicopathological characteristics and survival outcomes data were extracted from electronic medical records, including age, gender, tumor location, MRI-based extramural vascular invasion (EMVI), surgical approach (open or laparoscopic surgery), postoperative pathological stage, perineural invasion, pathological lymphovascular invasion, circumferential resection margin (CRM, less than 1 mm was defined as positive), RAS and BRAF status, mismatch repair (MMR) status, and adjuvant chemotherapy.

Follow-up

All patients underwent regular post-surgical follow-up. During the first 2 years, carcinoembryonic antigen (CEA) measurements and clinical evaluations were performed every 3–6 months, while abdominal/pelvic computed tomography (CT) or MRI, plus chest CT was conducted every 6 months. From years 3 to 5, CT/MRI imaging was performed annually, with CEA measurements and clinical evaluations still every 6 months. Annual imaging and CEA assessments were continued after 5 years. Median follow-up duration was defined as the time interval from the date of surgical resection to the last documented follow-up or death.

Statistical analysis

Statistical analyses were conducted using IBM SPSS Statistics software (Version 25.0; IBM Corp., Armonk, NY, USA) and R version 4.5.1. Categorical variables were summarized as counts and percentages, with intergroup comparisons performed using the Chi-squared (χ²) test or Fisher’s exact test, as deemed appropriate based on expected cell frequencies. Continuous variables were expressed as either medians or means ± standard deviations, and group comparisons were undertaken using the independent samples t-test or Mann-Whitney U test, respectively. Survival curves were constructed using the Kaplan-Meier method, and differences in survival were assessed using the log-rank test. Multivariate Cox regression analysis was performed using variables with a P value <0.05 in univariate analysis. Variable selection was performed using the ‘enter method’. A two-tailed P value <0.05 was considered statistically significant.

Results

Patient characteristics

A total of 135 patients who met the study inclusion criteria were enrolled in the final analysis. MMR status was available for 125 patients, including 4 cases of deficient mismatch repair (dMMR) and 121 cases of proficient mismatch repair (pMMR). CRM was positive (≤1 mm) in 14 patients (10.4%) and negative in 121 patients (89.6%), with all patients achieving a negative distal resection margin. Detailed patient baseline characteristics and clinicopathological data were shown in Table 1. Notably, a total of 19 patients did not receive adjuvant chemotherapy, with the specific reasons clearly clarified as follows: 5 patients declined adjuvant chemotherapy due to personal willingness; 4 patients opted for traditional Chinese medicine treatment instead of standard adjuvant chemotherapy; 2 patients were unable to receive adjuvant chemotherapy due to postoperative intestinal obstruction; 1 patient had contraindications to chemotherapy due to angina pectoris; 1 patient was enrolled in our center’s clinical trial and randomized to the follow-up observation group without adjuvant chemotherapy on account of a postoperative pathological stage of ypI; the reasons for non-receipt of adjuvant chemotherapy remained unclear for the remaining 6 patients despite our best efforts of investigation. Detailed comparison of baseline clinicopathological characteristics between patients with or without adjuvant chemotherapy shown in Table S1.

Disease recurrence patterns

The median duration of follow-up for all patients was 45 months. During the follow-up period, disease recurrence was documented in 65 patients (48.1%), with diverse recurrence patterns observed. The median time to recurrence (TTR) was 16.1 months [interquartile range (IQR) 11.1–25.3; range, 2.2–79.6 months] (Figure 1A). The distribution of TTR was right-skewed, with the majority of recurrences occurring within the first two years: 32.3% occurred within 12 months, 58.5% within 18 months, 72.3% within 24 months, and 86.2% within 36 months. Only one patient (1.5%) experienced recurrence beyond 60 months (Figure 1B). The Kaplan-Meier estimated median disease-free survival (DFS) for the entire cohort was 41.7 months [95% CI 31.2–not reached] (Figure 1C). Specifically, locoregional recurrence was observed in 12 patients (18.5% of recurrent cases). Distant metastasis was identified in 30 patients, including 19 cases (29.2% of recurrent cases) of lung metastasis, 8 cases (12.3% of recurrent cases) of liver metastasis, and 3 cases (4.6% of recurrent cases) of metastasis to other distant sites (e.g., bone, peritoneal cavity). Additionally, 13 patients (20.0% of recurrent cases) presented with multiple-site recurrence (simultaneous locoregional and distant recurrence or metastases to multiple distant organs), and the recurrence site remained unknown in 10 patients (15.4% of recurrent cases) due to limited diagnostic evidence or rapid disease progression. Median TTR was shortest for liver metastasis (15.1 months; IQR 10.4–33.5), followed by lung metastasis (14.7; IQR 10.7–21.9 months) and locoregional recurrence (18.9; IQR 14.9–27.0 months). No statistically significant difference in TTR was observed across the three major recurrence sites (P=0.90) (Figure 1D).

Figure 1 Recurrence time, distribution of recurrence sites, and disease-free survival in the study cohort. (A) Distribution of time to recurrence; (B) cumulative proportion of recurrences over time; (C) Kaplan-Meier curve showing the median DFS of the entire cohort; (D) Kaplan-Meier curve showing the median DFS by recurrence site. DFS, disease-free survival.

Survival outcomes

The 5-year OS and 3-year DFS were 56.8% and 53.1%, respectively. For the correlation between MMR status and recurrence patterns, all 4 dMMR patients remained free of disease recurrence during the follow-up period. Univariate analysis was performed to explore the association between potential clinical-pathological factors and survival outcomes. Mid-upper rectal cancers had significantly superior DFS and OS compared to low rectal cancers [OS: hazard ratio (HR) =0.300, 95% CI: 0.147–0.612, P=0.001; DFS: HR =0.551, 95% CI: 0.330–0.919, P=0.02]. Patients with high rectal tumors (>5 cm; n=61) had superior OS and DFS compared with those with low rectal tumors (≤5 cm; n=74) (log-rank OS: P<0.001, DFS: P=0.02) (Figure 2A,2B). Lymphovascular invasion (VI) was found to be significantly correlated with adverse survival outcomes (OS: HR =2.405, 95% CI: 1.257–4.604, P=0.008; DFS: HR =1.782, 95% CI: 1.038–3.059, P=0.04). Patients with lymphovascular invasion had poor OS and DFS compared with those without lymphovascular invasion (log-rank OS: P=0.006, DFS: P=0.03) (Figure 2C,2D). Positive CRM was significantly associated with poor outcomes (DFS: HR =4.321, 95% CI: 2.318–8.057, P<0.001; OS: HR =5.960, 95% CI: 3.015–11.781, P<0.001). Patients with positive CRM had poor OS and DFS compared with those with negative CRM (log-rank OS: P<0.001, DFS: P<0.001) (Figure 3A,3B).

Figure 2 Kaplan-Meier survival curve for survival analysis in LARC patients with poor responders to nCRT. (A) OS according to tumor location; (B) DFS according to tumor location; (C) OS according to lymphovascular invasion; (D) DFS according to lymphovascular invasion. DFS, disease-free survival; LARC, locally advanced rectal cancer; nCRT, neoadjuvant chemoradiotherapy; OS, overall survival.

Figure 3 Kaplan-Meier survival curve for survival analysis in LARC patients with poor responders to nCRT. (A) OS according to CRM status; (B) DFS according to CRM status; (C) OS according to adjuvant chemotherapy; (D) DFS according to adjuvant chemotherapy. CRM, circumferential resection margin; DFS, disease-free survival; LARC, locally advanced rectal cancer; nCRT, neoadjuvant chemoradiotherapy; OS, overall survival.

Patients who received adjuvant chemotherapy after initial treatment exhibited a notably longer OS than those who were not administered adjuvant chemotherapy (HR =0.326, 95% CI: 0.153–0.694, P=0.004), though the association between adjuvant chemotherapy and DFS failed to attain statistical significance in the univariate analysis (HR =0.600, 95% CI: 0.303–1.188, P=0.14). Adjuvant chemotherapy can improve OS but not DFS (log-rank OS: P=0.002, DFS: P=0.16) (Figure 3C,3D). To adjust for potential confounding factors and identify independent prognostic factors, a multivariate Cox proportional hazards regression model was constructed. The results demonstrated that adjuvant chemotherapy was an independent protective factor for OS (HR = 0.333, 95% CI: 0.141–0.789, P=0.01) (Table 2). In addition, multivariate analysis showed that CRM (OS: HR =5.943, 95% CI: 2.895–12.200, P<0.001; DFS: HR =3.661, 95% CI: 1.927–6.955, P<0.001) and distance from the anal verge (OS: HR =0.303, 95% CI: 0.147–0.627, P=0.001; DFS: HR =0.590, 95% CI: 0.352–0.988, P=0.045) were independent prognostic factors in these patients (Tables 2,3).

Discussion

This retrospective study of 135 poor responders to nCRT at our center fills a critical knowledge gap by characterizing recurrence patterns and survival outcomes in this high-risk subgroup of LARC patients. The 48.1% recurrence rate over a median 45-month follow-up confirms the aggressive nature of disease in poor responders. This rate is consistent with a previous report (15). The predominance of lung metastasis (29.2% of recurrent cases) over liver metastasis (12.3%) is consonant with existing literature on rectal cancer metastatic patterns (16). Rectal cancer (especially low rectal cancer) has a well-documented higher propensity for pulmonary metastasis due to its dual venous drainage. The predominance of lung metastasis in our cohort has direct implications for follow-up. It strongly suggests that more frequent chest CT should be considered in the post-treatment surveillance of poor responders. Unlike abdominal imaging (e.g., abdominal ultrasound or CT), which is typically included in standard follow-up (17), while chest CT is sometimes underutilized or performed less frequently. Our data highlight that more frequent chest CT (may be every 3–6 months) may lead to early detection of lung metastases, which are more amenable to curative-intent interventions (e.g., surgical resection, radiofrequency ablation or stereotactic body radiation therapy) if identified promptly.

Adjuvant chemotherapy has been well-established in the management of patients with high-risk stage II or stage III colon cancer. However, its clinical value in patients with LARC who have undergone nCRT followed by surgery remains unclear. Notably, findings from the landmark EORTC 22921 trial demonstrated that adjuvant chemotherapy administered after nCRT did not yield significant improvements in long-term outcomes for this patient population (3). Despite their poor response to nCRT, adjuvant chemotherapy emerged as an independent protective factor for OS. This finding is particularly notable given the ongoing debate about the value of adjuvant chemotherapy in patients with minimal neoadjuvant response. Poor responders to nCRT may be inherently resistant to systemic therapy (18,19), making adjuvant treatment ineffective. However, our results contradict this notion, demonstrating that adjuvant chemotherapy reduces the risk of death in this subgroup. This suggests that the lack of response to nCRT does not equate to resistance to all systemic agents. Adjuvant chemotherapy may target residual microscopic disease that persists despite neoadjuvant therapy. The discrepancy between OS benefit and non-significant DFS improvement may reflect delayed recurrence detection or effective salvage therapy for recurrent disease in the adjuvant-treated cohort, though longer follow-up is needed to clarify this distinction. This finding mandates strict adherence to adjuvant chemotherapy in patients with TRG 3, even when nCRT fails to induce tumor regression. This recommendation is particularly relevant given that treatment abandonment is common in poor responders due to perceived futility. Certainly, the phenomenon of adjuvant treatment effect reduction after neoadjuvant systemic therapy warrants special attention in the era of total neoadjuvant therapy.

Several limitations of this study warrant consideration when interpreting our findings. First, its retrospective observational design and relatively small sample size inherently introduce biases, most notably selection bias, which may affect the causal inferences drawn from our analyses. Our exclusive focus on TRG 3 poor responders (with no good responder cohorts included for comparison) precluded investigating whether superior local response correlates with improved distant disease control, a key prognostic association worthy of further study. Second, the single-center cohort restricts the generalizability of our findings to broader patient populations, as treatment protocols, surgical techniques, and follow-up practices may vary across institutions. Third, the definition of poor response as tumor regression grade 3 is based on TRG classification system modified by Ryan et al., which may limit direct cross-study comparisons with research adopting other TRG grading systems (e.g., Mandard, Dworak), as each system has distinct grading criteria and numerical definitions for tumor regression. Fourth, our institutional database lacks detailed records of the specific cause of death for included patients, precluding the calculation of rectal cancer-specific survival and generation of corresponding curves. Fifth, systematic data on the modality of recurrence detection (e.g., routine periodic imaging vs. symptomatic presentation) and detailed records of salvage surgery decision-making for recurrent patients were unavailable. This precluded an analysis of whether periodic post-treatment imaging surveillance is associated with an increased likelihood of curative-intent salvage surgery. In addition, in our cohort, patients who received adjuvant chemotherapy generally had better postoperative performance status, no severe complications, and no comorbidities precluding systemic therapy. Conversely, most patients not receiving adjuvant chemotherapy had poor performance status, severe postoperative complications, or significant comorbidities. These baseline health differences may confound the observed survival benefit of adjuvant chemotherapy, as healthier patients typically have better prognoses independent of treatment.

Conclusions

Poor responders to neoadjuvant long-course CRT in LARC face a high risk of recurrence, with lung metastasis being the most common distant failure site. Regular chest CT should be prioritized in their follow-up to enable early detection of lung metastases. Despite minimal response to neoadjuvant therapy, adjuvant chemotherapy significantly improves overall survival, emphasizing the need for strict adherence to standardized post-treatment protocols.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1065/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1065/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1065/prf

Funding: This work was supported by the National Natural Science Foundation of China (grant Nos. 82403343, 82573254 and 82373090), Shanghai Youth Technological Talent Program-Yangfan Program (No. 24YF2705800), Explorer Program of Science and Technology Commission of Shanghai Municipality (No. 25TS1403400), and Shanghai Municipal Natural Science Foundation (No. 25ZR1401062). The funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1065/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. The study protocol was approved by the Institutional Review Board of Fudan University Shanghai Cancer Center. All patients provided written informed consent for their data to be used in the study.

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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