Impact of neoadjuvant chemotherapy vs. upfront surgery on survival in early-onset colorectal cancer—a single centre experience

Introduction

Colorectal cancer (CRC) remains a leading cause of cancer morbidity and mortality worldwide. While the incidence is decreasing in older adults owing to improved screening and treatment, it is increasing among younger adults under the age of 50 years (1). CRC in younger patients under age 50 has been termed early-onset colorectal cancer (EO-CRC). A US-based study reported that the prevalence of EO-CRC increased by 1.9% per year between 2011 and 2019, with the steepest rise (3.8% per year) in the 20–29 years age group; these patients were predominantly female and commonly presented with abdominal pain and hematochezia (1,2). In China, EO-CRC incidence rose by approximately 140% from 1990 to 2017, with patients presenting at more advanced local stages, a predilection for the left colon/rectum, and a higher male incidence linked to alcohol consumption, smoking, and low whole-grain dietary intake (3-5).

This EO-CRC group is distinguished by unique clinical and molecular characteristics (6), driven by distinct environmental (diet and lifestyle), genetic, and potentially immunological risk factors; including gut microbiota dysbiosis and chronic inflammation (7,8), necessitating tailored therapeutic approaches moving beyond one-size-fits-all strategies for older CRC patients (9). Traditional treatment strategies for locally advanced rectal and colon cancers involve surgical resection as the primary curative intervention. However, neoadjuvant therapy (chemotherapy alone or in combination with radiotherapy), has increasingly been adopted, especially in rectal cancer to improve tumour downstaging, reduce local recurrence, and enhance sphincter preservation, even in early onset disease (10-12). Recent advances in total neoadjuvant therapy (TNT) have further improved outcomes for locally advanced rectal cancer, though data specific to EO-CRC remain limited (13).

Despite advances in the understanding of EO-CRC epidemiology and biology, critical gaps remain in defining the optimal sequence of multimodal therapies for this population. The National Comprehensive Cancer Network (NCCN) 2024 guidelines (14) dictate surgical resection alone for stage I disease and surgical resection and systemic chemotherapy for stage II and III disease, with adjuvant radiation therapy for rectal cancer (15,16). Notably, these guidelines are predominantly based on studies and randomized controlled trials (RCTs) enrolling patients over 50 years of age, with limited data on younger patients (17), particularly the comparative impact of upfront surgery (UFS) versus neoadjuvant chemotherapy (NAC) on survival outcomes and treatment-related toxicity. This subgroup, despite recorded better survival outcomes and chemotherapy tolerability, due to their distinct clinical and molecular characteristics, tends to be overtreated and therefore, prone to unnecessary long term treatment toxicities and quality-of-life impacts, which warrant close monitoring (18). Additionally, the utility of pathological downstaging as a surrogate marker for long-term prognosis in EO-CRC has not been fully elucidated, and tumor location (colon vs. rectal), a key clinical determinant of neoadjuvant therapy selection, has not been rigorously evaluated as a confounder in comparative analyses of UFS and NAC for EO-CRC.

This retrospective cohort study aims to compare the oncological and survival outcomes of patients with locally advanced stage III/IV EO-CRC treated with UFS versus those who received NAC followed by radical surgery. We hypothesize that NAC contributes to improved pathological downstaging and disease-free survival (DFS) without increasing perioperative morbidity in this population. Understanding these differences could refine personalized treatment strategies and improve evidence based clinical decision-making in these understudied patient groups. We present this article in accordance with the STROBE reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0006/rc).

Methods

Study design and population

This is a population-based, retrospective cohort study of patients surgically treated for early onset locally advanced colon and rectal cancer in a single centre, The Second Affiliated Hospital of Chongqing Medical University, based in Chongqing, China between January 2018 and December 2023. The patients were then categorized into two groups based on the initial treatment modality; those who were treated with NAC prior to surgery and those who went through UFS. Inclusion criteria were age more than 18 years and less than 50 years at diagnosis, advanced clinical stage III and IV CRC, and availability of complete clinical and follow-up data. Exclusion criteria were non-primary CRC, history of other malignancies, incomplete or missing follow-up data.

Patients with clinically or pathologically confirmed stage III and IV CRC were selected for inclusion in this study. We focused on clinical stage III and IV CRC, confirmed with computed tomography (CT) and magnetic resonance imaging (MRI) scans, in this advanced disease cohort due to the distinct clinical management choices and prognostic considerations associated with these stages, where treatment sequencing decisions between neoadjuvant therapy and UFS are most clinically relevant. Treatment allocation was determined by a multidisciplinary team (MDT) consisting of gastrointestinal surgeons, medical oncologists, and radiation oncologists in accordance with NCCN 2024 CRC guidelines. Decisions were based on tumor location, clinical stage, resectability, and patient performance status, following institutional protocols and NCCN guidelines. NAC was recommended for patients with locally advanced rectal cancer (T3/T4, low rectal), stage IV EO-CRC with resectable distant metastases, or high-risk stage III colon cancer (poorly differentiated histology, lymphovascular invasion, or perineural invasion). Conversely, patients with obstructive symptoms or those treated in the earlier years of the study period [2018–2020] were more likely to undergo UFS, reflecting evolving institutional practices. UFS was the standard of care for non-high-risk stage III colon cancer and non-locally advanced rectal cancer (T1/T2). All treatment decisions were additionally guided by pre-operative imaging (CT/MRI), tumor location, and patient performance status.

Neoadjuvant and postoperative chemotherapy regimens were in accordance with NCCN 2024 guidelines: included FOLFOX (folinic acid + fluorouracil + oxaliplatin), FOLFIRI (folinic acid + fluorouracil + irinotecan), FOLFOXIRI (folinic acid + fluorouracil + oxaliplatin + irinotecan), and CAPOX/ XELOX (capecitabine + oxaliplatin), were typically administered based on tumor staging, pathology type, and patient health status. In high-risk cases, radiotherapy and targeted therapies such as anti-epidermal growth factor receptor (EGFR) (cetuximab) or anti-vascular endothelial growth factor (VEGF) (bevacizumab) antibodies were also added. The number of neoadjuvant cycles varied based on tumor response and patient tolerance. In high-risk cases, radiotherapy (long-course: 45–50.4 Gy in 25–28 fractions; or short-course: 25 Gy in 5 fractions) and targeted therapies such as anti-EGFR (cetuximab) or anti-VEGF (bevacizumab) were added. TNT, defined as delivery of all planned chemotherapy and radiotherapy prior to surgery. No patients in the NAC group were unable to proceed to surgical resection due to neoadjuvant therapy-related adverse events. Adverse events were also recorded and graded.

Adjuvant chemotherapy regimens were similar to neoadjuvant regimens and were administered postoperatively based on pathological findings and patient recovery. Postoperative immunotherapy refers to treatment with immune checkpoint inhibitors (anti-PD-1 antibodies: pembrolizumab or nivolumab), which were administered only to patients with confirmed microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status.

Follow-up was via outpatient clinic and telephone follow-ups. Follow-up time was till August 31, 2025.

Data collection

The study retrospectively identified and utilized data from the institutional electronic medical records. Demographics, lifestyle factors (smoking, alcohol consumption), tumor characteristics such as location, histology, and stage; left-sided colon was defined as the descending colon, right-sided colon was defined as the cecum and ascending colon; treatment details (surgical type, neoadjuvant regimen, post-surgical chemotherapy regimen, length of hospital stay-calculated from surgical date to discharge) and postoperative outcomes were collected. Tumour location was then subcategorized anatomically. Metastatic status was recorded at two time points: synchronous metastases identified around surgery, and metachronous metastases detected during follow-up, with detailed sites specified (e.g., liver, lung, peritoneum).

Outcome measures

The primary outcome was pathological tumour downstaging, defined as a reduction in tumor stage from clinical preoperative assessment to pathological postoperative staging according to American Joint Committee on Cancer (AJCC) 8th edition criteria. For the UFS group, pathological downstaging may occur due to overestimation of clinical stage at diagnosis or, rarely, spontaneous tumor regression; this is acknowledged as a limitation of clinical staging modalities.

The resection margin distance (cm) was a secondary surgical outcome, defined as the linear distance from the nearest tumor cell to the resected surgical margin. This is reported to highlight cases where surgical quality may be compromised, though such cases were infrequent.

Secondary outcomes include: (I) DFS, which was defined as the time from surgery or primary tumor resection if stage IV to the first documented recurrence, metastasis or death from any cause; (II) overall survival (OS), defined as the time from surgery to death from any cause or last follow-up; (III) cancer-specific survival (CSS), defined as the time from surgery to death due to CRC; (IV) treatment-related adverse events, including surgical complications within 30 days, were recorded. And last, patterns of recurrence and metastasis site distribution.

Statistical analysis

Continuous variables were represented as mean ± standard deviation or median with interquartile range and compared using Student’s t-test or Mann-Whitney U tests as appropriate. Categorical variables were presented as counts and percentages, with group comparisons performed via Chi-squared or Fisher’s exact tests.

Survival analyses were conducted using Kaplan-Meier, with differences between treatment groups and tumor locations assessed by log-rank tests. Multivariable Cox proportional hazards models adjusted for potential confounders including age, sex, comorbidities, tumor location, histology, and baseline stage. Interaction terms between treatment modality and tumor location were included to evaluate effect modification. Propensity score matching (PSM) was applied to reduce selection bias, matching patients in neoadjuvant and UFS groups based on baseline characteristics including age, sex, tumor location, clinical stage, and comorbidities. Tumor location was specifically included due to the significant baseline imbalance in rectal cancer proportion between groups. Sensitivity analyses were performed to assess the robustness of findings. Survival analyses were repeated excluding stage IV patients to assess whether results were driven by metastatic cases. Statistical significance was set at P<0.05. Analyses were performed using IBM SPSS Statistics for Windows, Version 28.0 (IBM Corp., Armonk, NY, USA) and Python 3.9.12.

Ethical considerations

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of The Second Affiliated Hospital of Chongqing Medical University (No. 2026EC079). Written informed consent to participate in the study was waived due to retrospective data use and anonymization of patient identifiers.

Results

Baseline characteristics and treatments

A total of 249 patients with early CRC, by our definition—age less than 50 years, who underwent surgical treatment at our centre, were identified. After extensive exclusion, a total of 162 patients were included in this study, which were then divided into the UFS group (n=133, 82.1%) and the NAC group (n=29, 17.9%), based on whether or not they received preoperative NAC (Figure 1). A comparison of baseline characteristics between the two groups revealed no statistically significant differences in age distribution, gender, smoking, drinking, or family history, indicating generally balanced baseline characteristics. The mean age was 41.03±6.82 years in the UFS group, and 40.48±8.79 years in the NAC group, sex distribution (male: 45.9% UFS vs. 58.6% NAC; female: 54.1% UFS vs. 41.4% NAC; P=0.21), smoking status (P=0.83), and alcohol use (P=0.47).

Figure 1 Flowchart of EO-CRC patients from 2018–2023. EO-CRC, early-onset colorectal cancer.

Presenting symptoms were comparable, except for abdominal pain which was more frequent in UFS group (42.1% vs. 17.2%, P=0.01). Body mass index and family history showed no significant differences (see Table 1).

Treatment and surgical details

Various chemotherapy regimens were used in NAC (FOLFOX 48.3%, CAPOX 20.7%, FOLFOXIRI 31%). the range number of cycles was 4–6 cycles (12–18 weeks total). TNT was administered to 4/29 (13.8%) patients with low rectal T3/T4 tumors in the NAC group. Neoadjuvant Radiotherapy was admistered to 5 patients (17.2%) in the NAC group, all of whom had advanced rectal cancer. Among these, long-course chemoradiotherapy (45–50.4 Gy with concurrent chemotherapy) was given to 10 patients (76.9%), and short-course radiotherapy (25 Gy in 5 fractions) was given to 3 patients (23.1%). Neoadjuvant radiotherapy regimen and cycles were not available. Postoperative immunotherapy was slightly more common in NAC (19.5% vs. 34.5%, P=0.08) but not statistically significant (Table 2). Adverse events during neoadjuvant treatment were not available; no patients in our cohort were unable to proceed to surgery due to NAC-related toxicity.

Surgical approach, and perioperative details were similar across groups with no significant differences in surgical methods, resection margin, or blood transfusions. Surgery approach was predominantly laparoscopic in both groups (~84.2% UFS, 86.2% NAC; P=0.96). Stoma creation rates did not differ significantly (21.1% UFS vs. 27.6% NAC, P=0.44). Postoperative complications within 30 days were similar between groups (14.3% UFS vs. 24.1% NAC; P=0.18), with most being Clavien-Dindo grade I–II; the overall difference was not statistically significant. Adjuvant treatments, recurrence, and metachronous metastases were also similar with no significant differences. Length of hospital stay was comparable (median 12 days UFS vs. 14 days NAC; P=0.31).

Adjuvant chemotherapy regimens were similar between groups, with FOLFOX being most commonly used (56.4% UFS vs. 51.7% NAC; P=0.71). In Table 2, we have merged CAPOX and XELOX as they represent the same regimen (capecitabine + oxaliplatin). Postoperative immunotherapy (anti-PD-1 antibodies) was administered to 26 patients (19.5%) in the UFS group and 10 patients (34.5%) in the NAC group. According to institutional policy during the study period, immunotherapy was indicated only for patients with confirmed MSI-H or dMMR status; however, due to the retrospective nature of this study, complete MSI testing records were not available for all patients to verify adherence to this policy. The high observed rate of immunotherapy use may reflect off-label utilization, particularly in the earlier years of the cohort, or incomplete documentation.

Pathological outcomes

In regard to tumour characteristics, there was a significant difference in tumour location (P=0.002), with the neoadjuvant group having markedly more rectal tumors (75.9% vs. 43.6%, P=0.002), especially low rectal tumours (22.6% vs. 55.2%). Preoperative clinical stage distribution and lymph node involvement are similar. Clinical stage distribution among the two groups was: (71.4% vs. 65.5%) stage III and (28.6% vs. 34.5%) stage IV, P=0.53. Pathological staging (reduction from clinical to pathological stage) differs significantly (P<0.001), with lower stages more frequent in NAC group (P=0.004). In the UFS group, downstaging likely reflects overestimation of clinical stage at diagnosis, a well-recognized limitation of CT/MRI in CRC staging (e.g., clinically node-positive patients found to be node-negative on pathology) rather than true biological regression.

Resection margin distance was recorded in the pathology reports as the linear distance from the nearest tumor cell to the closest surgical margin. The mean margin distance was 4.48 cm in the UFS group and 3.58 cm in the NAC group, but not statistically significant (P=0.18). However, due to the retrospective nature of the data, it was not consistently specified whether this distance referred to the radial (circumferential), proximal, or distal margin. Therefore, formal classification of R0 (microscopically margin-negative) vs. R1 (microscopically margin-positive) resection according to standardized criteria could not be reliably performed.

Histological types differ (P=0.02) with more signet ring (2.3% vs. 6.9%), less adenocarcinoma types in NAC (54.9% vs. 55.2%), compared to UFS. Pathological differentiation and invasion patterns did not differ significantly, though more undifferentiated tumours in the neoadjuvant group (6% vs. 24.1%). Lymph node involvement was comparable (63.9% UFS vs. 58.6% NAC, P=0.59). Metastasis at diagnosis and synchronous metastasis sites were also similar, although liver metastasis shows borderline significance (P=0.055) (Table 3).

Survival outcomes

Median DFS was 21 months, and OS was 35 months.

Overall pathological downstaging was observed in 43 of the cohort (34 UFS vs. 9 NAC; P=0.55). DFS and OS events were not statistically different between groups before PSM (52 vs. 13; P=0.57 and 56 vs. 13; P=0.79, respectively). Recurrence rates and metachronous metastasis showed no significant difference (Tables 4,5).

After PSM to adjust for baseline differences (1:1 matching including age, sex, tumor location, clinical T stage, clinical N stage, and comorbidities), NAC was associated with significantly higher pathological downstaging (22/45 NAC vs. 23/45 UFS, P=0.001), and better DFS (22/45 vs. 23/45, P=0.005) and OS (22/33 vs. 11/33, P=0.001). Though recurrence was slightly higher in NAC post-matching (21/33 vs. 23/33, P=0.001), metachronous metastasis rates remained comparable (P=0.49) (Tables 4,5; Figures 2,3).

Figure 2 Kaplan-Meier curves for DFS by treatment group. DFS, disease-free survival.

Figure 3 Kaplan-Meier curves for OS by treatment group. OS, overall survival.

Multivariate Cox regression analysis

On multivariable Cox regression analysis controlling for key clinicopathological variables, the treatment group (NAC vs. US) was not an independent predictor of either DFS [hazard ratio (HR) =1.18, 95% confidence interval (CI): 0.64–2.18, P=0.58] or OS (HR =0.99, 95% CI: 0.53–1.81, P=0.98). Tumor location was also not an independent predictor of DFS (HR =1.15, 95% CI: 0.70–1.90, P=0.56) and OS (HR =1.39, 95% CI: 0.87–2.25, P=0.16).

Significant independent predictors of worse DFS included higher preoperative stage (HR =2.84, 95% CI: 1.72–4.67, P<0.001), nodal involvement (N stage, HR =1.56, 95% CI: 1.16–2.09, P=0.003), invasion (HR =1.59, 95% CI: 1.24–2.03, P<0.001), and synchronous metastases to the liver (HR =2.49, 95% CI: 1.35–4.58, P=0.003) or lungs (HR =5.22, 95% CI: 2.12–12.86, P<0.001).

For OS, significant predictors included preoperative stage (HR =1.65, 95% CI: 1.02–2.67, P=0.03), T stage (HR =1.44, 95% CI: 1.00–2.08, P=0.05), invasion (HR =1.26, 95% CI: 1.00–1.59, P=0.04), and postoperative stage (HR =1.86, 95% CI: 1.14–3.02, P=0.01) (Tables 6,7).

Discussion

This study evaluated the impact of neoadjuvant therapy compared to UFS on pathological downstaging, survival outcomes, and treatment-related morbidity in early-onset, locally advanced stage III/IV CRC patients, a cohort for whom optimal treatment sequences remain debated.

Our findings underline the potential of NAC to improve pathological response and survival in EO-CRC compared to UFS, after PSM, demonstrate that NAC is associated with significantly higher pathological downstaging rates and improved DFS and OS in EO-CRC compared to UFS, supporting the potential role of NAC in multimodal treatment strategies for selected EO-CRC patients. However, it does not independently improve DFS or OS compared to UFS after adjustment for confounders. This aligns with existing literature advocating NAC benefits in locally advanced CRC (19,20), and extend this evidence to the understudied EO-CRC cohort, while confirming the safety of NAC. The higher downstaging rates translate into better oncological control, reducing recurrence and improving DFS and OS post-matching (21). These results support the growing evidence that neoadjuvant approaches confer oncological benefits while preserving safety in this distinct patient population.

The lack of independent NAC effect in regression models indicates the influence of tumour biology and stage on survival, emphasising NAC as part of a multimodal, individualised treatment strategy rather than a standalone determinant, and the lack of survival benefit suggests that factors beyond tumour shrinkage, including disease biology and treatment selection biases, may influence outcomes. The predominance of rectal tumours in NAC group aligns with current guidelines and clinical practice favoring preoperative chemotherapy in rectal cancer (22), and recent literature suggesting that factors beyond tumor shrinkage such as genomic profiles, host immunity, and treatment selection biases, may influence long-term outcomes (23) .

NAC is a standard strategy for locally advanced rectal cancer to reduce local recurrence, facilitate R0 resection, and improve sphincter preservation; this clinical practice explains the overrepresentation of rectal/low rectal tumors in the NAC group, and our PSM adjustment for tumor location minimizes the selection bias inherent to this retrospective cohort. However, its benefit for OS in colon cancer is less defined and under investigation (21). Our cohort essentially compares a group selected for NAC based on specific clinical features (e.g., rectal location) to a broader group treated with UFS. On multivariable analysis, preoperative stage, nodal involvement, lymphovascular invasion, and synchronous metastases emerged as independent predictors of worse DFS and OS. These findings are consistent with established prognostic factors in CRC (24,25), and highlights the importance of accurate staging and risk stratification in EO-CRC. The results of the PSM analysis; the NAC group exhibited a pathological downstaging rate (P=0.001), while dramatic, must be interpreted with extreme caution due to the very small size of the NAC cohort (n=29), which makes creating a robust matched sample challenging. Importantly, pathological downstaging in the UFS group which was observed in 34 (25.6%) patients, was attributable to the well-recognized limitation of pre-operative cross-sectional imaging (CT/MRI) in accurately assessing tumor T and N stage, rather than clinical staging error; this phenomenon is common in CRC and highlights the gold standard role of pathological staging in refining clinical assessment.

There have been various contradictions to the prognosis in EO-CRC patients. Some studies show that high-risk stage III EO-CRC patients have an overall negative prognosis, that is significantly higher relapse rate, though receiving more intensive adjuvant chemotherapy (26). Other studies show they had better CSS rates (27). This could be due to differences in age cutoff for the definition of EO-CRC (45 or 50 years). A recent study compared the prognostic implications of adjuvant chemotherapy between stage 2–3 EO-CRC and late-onset CRC patients, and found that age had no significant impact on the prognosis between both cohorts, and stage 3 showed poor OS despite intensive adjuvant therapy (28).

The improved pathological downstaging observed aligns with prior studies demonstrating the efficacy of neoadjuvant chemoradiotherapy, particularly in rectal cancer, to reduce tumor burden and facilitate margin-negative resections (13,19,20). However, the translation of downstaging or margin-negative resections into long-term survival advantages has been sparsely reported. Our study aims to contribute to the current knowledge by showing concomitant improvements in both DFS and OS, highlighting the potential prognostic relevance in early-onset patients who may have unique tumor biology (6).

The neoadjuvant regimens in our study varied (FOLFOX, CAPOX, FOLFOXIRI), and radiotherapy was administered to 44.8% of NAC patients, all of whom had rectal cancer. Additionally, the number of chemotherapy cycles ranged from 4 to 6, reflecting real-world clinical practice where treatment is tailored to tumor response and patient tolerance. While this heterogeneity limits direct comparison with a uniform treatment protocol, it reflects the pragmatic reality of clinical decision-making in a tertiary referral center. Additionally, contrary to concerns that neoadjuvant therapy might increase surgical morbidity, our analysis showed similar complication rates between groups, consistent with other investigations highlighting the safety of contemporary multimodal regimens (13,29). In the issue of chemotherapy or chemoradiotherapy, a study compared the efficacy and safety of NAC with neoadjuvant chemoradiotherapy in rectal cancer, and demonstrated that NAC with CAPOX achieved similar pathological complete response (pCR) and downstaging rates and lower perioperative metastasis compared to neoadjuvant chemoradiotherapy (30). This finding supports the feasibility of neoadjuvant treatment without compromising short-term surgical outcomes.

Standard adjuvant chemotherapy regimens have widely been demonstrated to effectively control tumour progression, especially for advanced diseases highlighted by multiple metastases, and stage 3 and T4-stage diseases (31). Though some studies show that stage 2–3 EO-CRC patients do not get an OS benefit from NCCN guideline-driven therapy and are therefore over treated (17). A study comparing EO-CRC patients compared with LOCRC (50–65 years and patients >65 years) patients with metastatic CRC treated with FOLFOX, EO-CRC had a higher incidence of nausea and vomiting (69.3% vs. 57.6% vs. 60.4%; P=0.02), severe abdominal pain (8.4% vs. 3.4% vs. 3.5%; P=0.02), and severe anaemia (6.1% vs. 1.0% vs. 1.5%; P<0.001) post administration. Severe abdominal pain was associated with poorer OS (HR =2.24, 95% CI: 1.23–4.09; P=0.008), which could be due to distinct genomic profiles and higher intensity chemotherapy increasing the risk of adverse events (32).

Histological subtypes have been shown to significantly influence postoperative survival in EO-CRC. They frequently exhibit mucinous, signet-ring cells, poorly differentiated tumours, and increased lymph node metastasis, which are associated with poorer prognoses compared to tubular adenocarcinoma (33). In our cohort, the NAC group had a higher proportion of signet ring cell carcinoma (6.9% vs. 2.3%), which may reflect more aggressive biology driving the decision for preoperative therapy. Several studies have demonstrated that mucinous adenocarcinoma may exhibit lower sensitivity to standard postoperative chemotherapy regimens (such as FOLFOX and CAPOX), therefore warranting the need for exploring new therapeutic strategies (34). The prevalence of MSI-H in unselected EO-CRC populations is typically 10–15% (35,36), suggesting that some patients in our cohort also may have received immunotherapy without biomarker confirmation. This represents a limitation and highlights the need for prospective biomarker-directed treatment protocols.

Our findings support the integration of NAC into treatment strategies for selected EO-CRC patients, particularly those with locally advanced rectal cancer or high-risk features. The improved downstaging and survival outcomes after matching suggest that NAC may confer oncological benefits without increasing perioperative morbidity. However, the lack of independent effect in regression models emphasizes that NAC is not a substitute for careful patient selection based on tumor biology, stage, and molecular profile. The growing incidence of EO-CRC (1,5) underscores the urgent need for age-specific evidence to guide treatment decisions.

Various nomograms and risk stratification models have been developed to screen out patients with high-risk EO-CRC, which may benefit from chemotherapy based on OS and independent prognostic factors. High-grade staging and pathology, elevated CEA levels, unmarried patients, etc., have been shown to have worse outcomes based on robust accuracy in determining CSS in EO-CRC patients (37-39).

Nevertheless, several limitations should be acknowledged. First, the retrospective design inherently risks selection bias, despite adjustments with propensity matching, and missing data on molecular biomarkers limited our ability to explore predictive factors fully. Second, the follow-up duration—2 years, while adequate for early outcomes, may be insufficient to capture all late recurrences characteristic of colorectal malignancies. Third, the sample size constrained subgroup analyses by tumor location, the lack of toxicity data, and molecular characterisation warrant cautious interpretation. Fourth, the absence of molecular data (e.g., KRAS/NRAS/BRAF, CMS classification) prevents us from identifying biological subtypes that might be more responsive to NAC. Fifth, the heterogeneity of neoadjuvant regimens, cycles, and inclusion of radiotherapy precludes definitive conclusions about optimal protocol. Sixth, pathological margin assessment was limited by non-standardized reporting; margin distances were recorded in centimeters without consistent specification of margin location (radial vs. longitudinal), preventing reliable R0/R1 classification.

Despite these limitations, our study has several key strengths that enhance the clinical relevance of our findings. First, we focused on locally advanced stage III/IV EO-CRC, a high-risk subgroup where treatment sequencing decisions (NAC vs. UFS) are most clinically impactful and for which data is scarce. Second, we adjusted PSM for primary tumor location, a critical confounder in NAC-UFS comparisons for CRC and strengthening the validity of our survival analyses. Third, we confirmed the safety of NAC in EO-CRC (no increased perioperative morbidity, no surgery delay/failure due to adverse effects), which is a key consideration for the younger patient population where treatment-related toxicity is a major concern. Fourth, our study is the first to report post-PSM survival benefits of NAC in a Chinese EO-CRC cohort, as EO-CRC in China exhibits unique epidemiological features (e.g., higher male incidence, left-sided/rectal predilection, links to alcohol/smoking) compared to Western cohorts.

Future prospective studies with larger cohorts and integration of comprehensive molecular profiling are essential to validate these observations and refine patient selection for neoadjuvant therapy. The question of which patients with CRC truly benefit from NAC remains open and should be addressed in prospective, randomized controlled trials that incorporate robust biomarker profiling to guide patient selection. Moreover, exploring quality-of-life outcomes and long-term functional results would provide a more holistic assessment of treatment impact.

In conclusion, our study supports the oncological benefit and safety of neoadjuvant therapy in early-onset locally advanced CRC, encouraging its consideration in personalized treatment planning. The promising rates of pathological downstaging in the NAC group warrant further investigation. These findings contribute valuable evidence toward optimizing multidisciplinary management strategies in this increasingly prevalent patient group.

Conclusions

In this cohort study, NAC was associated with better downstaging, and better survival outcomes than UFS in EO-CRC patients. These findings support current trends toward tailored perioperative treatment in EO-CRC, balancing UFS and neoadjuvant approaches based on patient and tumor characteristics.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0006/rc

Data Sharing Statement: Available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0006/dss

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0006/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0006/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 was approved by the Institutional Review Board of The Second Affiliated Hospital of Chongqing Medical University (No. 2026EC079). Written informed consent to participate in the study was waived due to retrospective data use and anonymization of patient identifiers.

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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