Correlation between pathological response to neoadjuvant immunotherapy and long-term survival in locally advanced rectal cancer: A real-world study

Abstract

BACKGROUND

Conventional treatment for locally advanced rectal cancer (LARC) is associated with several limitations, and neoadjuvant immunotherapy has been proposed to address these current clinical dilemmas. However, the correlation between pathological response and long-term survival remains unclear. Most existing studies are derived from clinical trials, with a lack of real-world evidence. Therefore, this real-world study was conducted to analyze the correlation between the two indicators.

AIM

To investigate the correlation between pathological response to neoadjuvant immunotherapy and long-term survival in patients with LARC using real-world data.

METHODS

Clinical data of 130 LARC patients who received neoadjuvant immunotherapy combined with radical surgery in our hospital from March 2022 to March 2025 were retrospectively collected. All patients were administered neoadjuvant immunotherapy regimens based on anti-programmed cell death protein 1/programmed death-ligand 1 inhibitors, and laparoscopic or open radical resection of rectal cancer was performed 4-6 weeks after the end of treatment. Tumor regression grade (TRG) was used to evaluate the degree of pathological response, which was classified into pathological complete response (pCR; TRG grade 0), major pathological response (MPR; TRG grade 1), and non-MPR (TRG grades 2-3). The Kaplan-Meier method was adopted for survival analysis, and the log-rank test was used to compare disease-free survival and overall survival among patients with different pathological response grades. The Cox proportional hazards regression model was applied to identify the independent risk factors for long-term survival in these patients.

RESULTS

Among the 130 patients with LARC who received neoadjuvant immunotherapy followed by radical surgery, 30 patients achieved pCR, 30 achieved MPR, and 70 were classified as non-MPR. Significant differences were observed among the groups in maximum tumor diameter, preoperative imaging T stage, preoperative imaging N stage, and treatment regimen (all P < 0.05). Patients with better pathological response demonstrated more favorable survival outcomes than those without MPR. In addition, neoadjuvant immunotherapy exhibited an acceptable safety profile, and treatment-related adverse events were generally manageable.

CONCLUSION

Neoadjuvant immunotherapy yields a high pathological response rate in LARC patients, and the pathological response is closely correlated with long-term survival outcomes. Patients achieving pCR/MPR have superior disease-free survival and overall survival.

Key Words: Locally advanced rectal cancer; Neoadjuvant immunotherapy; Pathological response; Long-term survival; Real-world study

Core Tip: This real-world retrospective study evaluated the association between pathological response and long-term survival outcomes in patients with locally advanced rectal cancer receiving neoadjuvant immunotherapy. Results demonstrated high pathological response rates and suggested that better pathological regression may correlate with improved disease-free survival. These findings provide clinically relevant evidence supporting the prognostic value of pathological response following neoadjuvant immunotherapy in locally advanced rectal cancer.

INTRODUCTION

Locally advanced rectal cancer (LARC), generally defined as stage II-III rectal cancer, remains a major clinical challenge worldwide. Despite substantial advances in multidisciplinary treatment strategies, including neoadjuvant chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy, patients with LARC still face considerable risks of local recurrence, distant metastasis, and treatment-related morbidity. Therefore, optimizing neoadjuvant treatment strategies and improving long-term oncological outcomes remain important clinical goals[1].

Currently, the main clinical treatment modalities comprise neoadjuvant therapy combined with radical surgery and adjuvant therapy. Some patients exhibit a poor therapeutic response to conventional neoadjuvant therapy regimens, which are associated with a high incidence of complications that severely impair patients’ quality of life[2]. In recent years, immunotherapy has emerged as a promising therapeutic approach for various solid tumors. Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have demonstrated encouraging antitumor activity, particularly in patients with deficient mismatch repair or microsatellite instability-high colorectal cancer. Several clinical studies have shown that neoadjuvant immunotherapy can achieve remarkable tumor regression and high rates of organ preservation in rectal cancer, highlighting its potential as an effective treatment strategy for LARC[3].

In recent years, immunotherapy has emerged as a promising therapeutic approach for various solid tumors. Immune checkpoint inhibitors targeting PD-1 and PD-L1 have demonstrated encouraging antitumor activity, particularly in patients with deficient mismatch repair or microsatellite instability-high colorectal cancer. Several clinical studies have shown that neoadjuvant immunotherapy can achieve remarkable tumor regression and high rates of organ preservation in rectal cancer, highlighting its potential as an effective treatment strategy for LARC[4,5].

However, most relevant studies thus far are clinical trials with strict inclusion criteria, limit the external validity and clinical applicability of their findings. This study retrospectively analyzed the clinical data of 130 patients with LARC who received neoadjuvant immunotherapy and adopted a real-world study design to investigate the actual clinical efficacy of this therapeutic regimen in clinical practice, as well as the correlation between pathological response and long-term survival. The findings are expected to provide real-world evidence for clinical treatment decision-making.

MATERIALS AND METHODS

Study subjects

Clinical data of patients with LARC who received neoadjuvant immunotherapy combined with radical surgery in Jiujiang No. 1 People’s Hospital from March 2022 to March 2025 were retrospectively collected.

Inclusion criteria were as follows: (1) Pathologically confirmed rectal adenocarcinoma via colonoscopic biopsy; (2) Preoperative imaging examinations (pelvic magnetic resonance imaging, abdominal and pelvic computed tomography) consistent with the diagnostic criteria for LARC, i.e., tumor invasion depth of ≥ T3 stage or accompanied by regional lymph node metastasis (N+), without distant metastasis (M0), in accordance with the 8^th edition of the American Joint Committee on Cancer Staging System for Rectal Cancer[6]; (3) Aged 18 years to 75 years with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1[7]; (4) Administration of neoadjuvant immunotherapy regimens based on anti-PD-1/PD-L1 inhibitors, followed by radical rectal cancer resection after the completion of treatment; and (5) Complete clinical data, including baseline characteristics, treatment regimens, pathological results, and follow-up information.

Exclusion criteria were as follows: (1) History of other malignant tumors; (2) Complicated with autoimmune diseases, active infections, or severe organ dysfunction; (3) Previous history of immunotherapy, radiotherapy, or chemotherapy; (4) Positive surgical margins or incomplete postoperative pathological data; and (5) Follow-up duration of less than 3 months or lost to follow-up.

This study was approved by the Medical Ethics Committee of Jiujiang No. 1 People’s Hospital (Approval No. JJSDYRMYY-YXLL-115), and written informed consent was obtained from all patients or their family members.

Treatment regimens

All patients received neoadjuvant immunotherapy regimens based on anti-PD-1/PD-L1 inhibitors, with specific regimens as follows: (1) Monotherapy with immune checkpoint inhibitors: Pembrolizumab (200 mg per administration, once every 3 weeks) or camrelizumab (200 mg per administration, once every 2 weeks) for a total of 4 cycles to 6 cycles; and (2) Immune combination therapy: Anti-PD-1/PD-L1 inhibitors combined with the CapeOX regimen (Capecitabine 1000 mg/m², orally twice daily on days 1-14; Oxaliplatin 130 mg/m², intravenous infusion on day 1, once every 3 weeks) for a total of 4 cycles.

Treatment regimens were comprehensively selected by the multidisciplinary team based on the patients’ tumor stage, performance status, economic status, and drug accessibility. Adverse reactions were closely monitored during treatment, and corresponding interventions were administered based on the grading of adverse reactions; treatment was suspended or doses were adjusted when necessary. Laparoscopic or open radical rectal cancer resection with D2/D3 lymph node dissection was performed 4 weeks to 6 weeks after the completion of neoadjuvant therapy, and all surgeries were conducted by the same team of experienced surgeons. Postoperative adjuvant therapy was administered based on the patients’ pathological stage and physical status.

Outcome measures and evaluation criteria

Baseline data: Baseline data of patients were collected. These included gender, age, ECOG performance status score, tumor location, maximum tumor diameter, preoperative radiological T stage, preoperative radiological N stage, and comorbidities (hypertension, diabetes mellitus).

Evaluation of pathological response: Surgically resected specimens were collected postoperatively, and double-blind pathological review was conducted by two experienced pathologists. The degree of pathological response was evaluated based on the tumor regression grade (TRG) criteria recommended by the American Joint Committee on Cancer[8], with the specific grading as follows: TRG grade 0 [pathological complete response; (pCR)]: Complete disappearance of tumor lesions with no residual cancer cells and no regional lymph node metastasis; TRG grade 1 [major pathological response (MPR)]: Marked regression of tumor lesions with ≤ 10% residual cancer cells and no regional lymph node metastasis; TRG grade 2: Partial regression of tumor lesions with 10%-50% residual cancer cells; and TRG grade 3: Minimal or no tumor regression with > 50% residual cancer cells. TRG grade 0 was defined as pCR, TRG grades 0 and 1 as MPR, and TRG grades 2 and 3 as non-MPR. The pCR, MPR, and total pathological response rates (pCR + MPR) were calculated.

Evaluation of survival outcomes: Follow-up was conducted through outpatient and telephone follow-up. The start time of follow-up was the date of surgery, and the cut-off time was June 30, 2025. The primary survival outcome indicators included disease-free survival (DFS) and overall survival (OS). DFS was defined as the time from the date of surgery to the first occurrence of tumor recurrence, metastasis, or death from any cause, and OS was defined as the time from the date of surgery to death from any cause or the follow-up cut-off date.

Safety evaluation: Neoadjuvant immunotherapy-related adverse reactions were evaluated following the Common Terminology Criteria for Adverse Events version 5.0[7], which were graded as 1 to 4. The types, incidence rates, and severity (grade 3 and grade 4) of adverse reactions were recorded.

Statistical analysis

Data analysis was performed using SPSS 26.0 statistical software. Quantitative data conforming to normal distribution were expressed as mean ± SD, with intergroup comparisons conducted using t-tests. Data not conforming to normal distribution were expressed as median (interquartile range), and intergroup comparisons were conducted using the Wilcoxon signed-rank test. Categorical data were presented as n (%). Intergroup comparisons were performed using the χ² test or Fisher’s exact test. Survival curves were plotted using the Kaplan-Meier method, with the log-rank test comparing differences in DFS and OS across different pathological response groups. Univariate and multivariate Cox proportional hazards regression models were employed to analyze risk factors influencing long-term patient survival. A P < 0.05 was considered statistically significant.

RESULTS

Patient baseline characteristics

The baseline demographic and clinicopathological characteristics of the 130 patients are presented in Table 1. No significant differences were observed among the pCR, MPR, and non-MPR groups with respect to sex, age, ECOG performance status, distance from the tumor to the anal verge, hypertension, or diabetes mellitus (all P > 0.05), indicating good baseline comparability among the groups. However, significant differences were identified in maximum tumor diameter (P = 0.033), preoperative imaging T stage (P = 0.006), preoperative imaging N stage (P = 0.002), and treatment regimen (P = 0.011). Patients in the pCR and MPR groups tended to have smaller tumors, earlier preoperative imaging stages, and a higher proportion of combination immunotherapy than those in the non-MPR group. Table 1 compares the baseline characteristics of patients in different pathological response groups.

Table 1 Baseline characteristics of patients in different pathological response groups, n (%)/median (interquartile rage).

Baseline characteristics	Total (n = 130)	pCR group (n = 30)	MPR group (n = 30)	Non-MPR group (n = 70)	χ2/t/Z	P value
Sex					0.582	0.747
Male	78 (60.0)	19 (63.3)	17 (56.7)	42 (60.0)
Female	52 (40.0)	11 (36.7)	13 (43.3)	28 (40.0)
Age (years)	56 (48-65)	54 (45-63)	55 (46-64)	58 (50-66)	2.135	0.344
ECOG performance status					1.852	0.396
0	89 (68.5)	23 (76.7)	21 (70.0)	45 (64.3)
1	41 (31.5)	7 (23.3)	9 (30.0)	25 (35.7)
Distance from tumor to anal verge					2.018	0.365
≤ 5 cm	53 (40.8)	11 (36.7)	10 (33.3)	32 (45.7)
> 5 cm	77 (59.2)	19 (63.3)	20 (66.7)	38 (54.3)
Maximum tumor diameter (cm)	4.5 (3.2-5.8)	3.8 (2.9-5.1)	4.2 (3.1-5.5)	4.9 (3.5-6.2)	6.842	0.033
Preoperative imaging T stage					10.258	0.006
T3	82 (63.1)	25 (83.3)	22 (73.3)	35 (50.0)
T4	48 (36.9)	5 (16.7)	8 (26.7)	35 (50.0)
Preoperative imaging N stage					12.369	0.002
N0	35 (26.9)	12 (40.0)	10 (33.3)	13 (18.6)
N1	58 (44.6)	15 (50.0)	16 (53.3)	27 (38.6)
N2	37 (28.5)	3 (10.0)	4 (13.4)	30 (42.8)
Hypertension	32 (24.6)	6 (20.0)	7 (23.3)	19 (27.1)	0.658	0.720
Diabetes mellitus	21 (16.2)	4 (13.3)	5 (16.7)	12 (17.1)	0.285	0.867
Treatment regimen					8.925	0.011
Immunotherapy monotherapy	53 (40.8)	8 (26.7)	10 (33.3)	35 (50.0)
Combination immunotherapy	77 (59.2)	22 (73.3)	20 (66.7)	35 (50.0)

ECOG: Eastern Cooperative Oncology Group; pCR: Pathological complete response; MPR: Major pathological response.

Pathological response to neoadjuvant immunotherapy

All 130 patients completed neoadjuvant immunotherapy and radical surgery, with no intraoperative mortality reported. Postoperative pathological evaluation showed that 30 patients achieved pCR, with a pCR rate of 23.1%; 30 patients achieved MPR (non-pCR), with an MPR rate of 46.2%; the total pathological response rate (pCR + MPR) was 69.3%; and 70 patients were classified as non-MPR, accounting for 53.8%. A comparison of pathological responses across different treatment regimens revealed that the immune combination therapy group had a significantly higher pCR (31.2% vs 11.3%), MPR (57.1% vs 32.1%), and total pathological response rates (88.3% vs 43.4%) than the immune monotherapy group, with statistically significant differences (P < 0.001; Table 2).

Table 2 Comparison of pathological response rates among different treatment regimens, n (%).

Treatment regimen	Number of patients	pCR (TRG 0)	MPR (TRG 1)	Non-MPR (TRGs 2 and 3)	Overall pathological response rate (TRGs 0 and 1)	χ2	P value
Immunotherapy monotherapy	53	6 (11.3)	11 (20.8)	36 (67.9)	17 (32.1)	10.362	< 0.001
Combination immunotherapy	77	24 (31.2)	20 (25.9)	33 (42.9)	44 (57.1)
Total	130	30 (23.1)	31 (23.8)	69 (53.1)	61 (46.9)

pCR: Pathological complete response; TRG: Tumor regression grade; MPR: Major pathological response.

Comparison of survival outcomes among patients with different pathological responses

The median follow-up duration for the entire cohort was 18 months (range: 3-39 months), with 19 cases of recurrence and metastasis and 10 deaths recorded. The 1-year DFS rate was 85.4%, and 1-year OS rate was 92.3%. A comparison of survival outcomes among patients with different pathological responses showed that the 1-year DFS rates in the pCR, MPR, and non-MPR groups were 96.7%, 88.3%, and 65.0%, and the 1-year OS rates were 100.0%, 95.0%, and 77.5%, respectively, with statistically significant differences among all groups (P < 0.001). Kaplan-Meier survival analysis demonstrated that patients in the pCR group had significantly better DFS and OS than those in the MPR and non-MPR groups, and those in the MPR group had significantly superior DFS and OS compared with those in the non-MPR group (P < 0.001; Figure 1). Detailed survival data are presented in Table 3.

Figure 1 Survival curves of patients stratified by pathological remission groups. A: Disease free survival curves of patients with different pathological remission groups; B: Overall survival curves of patients with different pathological remission groups. pCR: Pathological complete response; MPR: Major pathological response; TRG: Tumor regression grade.

Table 3 Comparison of survival outcomes between patients with pathological remission, n (%).

Response	Number of patients	Recurrence or metastasis	Deaths	1-year DFS (%)	1-year OS (%)	Log-rank χ2 (DFS)	P value (DFS)	Log-rank χ2 (OS)	P value (OS)
pCR group (TRG 0)	30	1 (3.3)	0 (0.0)	96.7	100.0	28.652	< 0.001	25.321	< 0.001
MPR group (TRG 1)	30	4 (13.3)	2 (6.7)	88.3	95.0
Non-MPR group (TRGs 2 and 3)	70	14 (20.0)	8 (11.4)	65.0	77.5
Total	130	19 (14.6)	10 (7.7)	85.4	92.3

pCR: Pathological complete response; TRG: Tumor regression grade; MPR: Major pathological response; DFS: Disease-free survival; OS: Overall survival.

Risk factor analysis for long-term survival in patients with LARC

Univariate analysis: The univariate Cox regression analysis was used to examine the relationship among gender, age, ECOG score, tumor location, maximum tumor diameter, preoperative radiological T stage, preoperative radiological N stage, comorbidities, treatment regimen, and pathological response. The results showed that maximum tumor diameter > 4.5 cm [hazard ratio (HR) = 2.352, 95% confidence interval (CI): 1.201-4.598, P = 0.012], preoperative radiological T4 stage (HR = 2.563, 95%CI: 1.382-4.751, P = 0.003), preoperative radiological N2 stage (HR = 3.125, 95%CI: 1.682-5.798, P < 0.001), immune monotherapy (HR = 2.018, 95%CI: 1.082-3.765, P = 0.028) and non-MPR (HR = 4.256, 95%CI: 2.382-7.615, P < 0.001) were risk factors for DFS in patients with LARC. Preoperative radiological T4 stage (HR = 2.418, 95%CI: 1.215-4.812, P = 0.012), preoperative radiological N2 stage (HR = 3.521, 95%CI: 1.852-6.698, P < 0.001), immune monotherapy (HR = 1.985, 95%CI: 1.012-3.895, P = 0.046), and non-MPR (HR = 4.892, 95%CI: 2.582-9.275, P < 0.001) were identified as risk factors for OS in patients with LARC (Table 4).

Table 4 Univariate analysis of factors affecting long-term survival in locally advanced rectal cancer patients.

Variable	Coding	DFS (HR, 95%CI)	P value (DFS)	OS (HR, 95%CI)	P value (OS)
Sex	Male = 1, female = 0	1.025 (0.562-1.868)	0.941	1.125 (0.521-2.428)	0.765
Age (years)	≥ 60 = 1, < 60 = 0	1.258 (0.682-2.325)	0.458	1.321 (0.625-2.798)	0.468
ECOG performance status	1 = 1, 0 = 0	1.365 (0.752-2.478)	0.305	1.425 (0.712-2.852)	0.321
Tumor location	≤ 5 cm = 1, > 5 cm = 0	1.182 (0.652-2.145)	0.585	1.258 (0.652-2.425)	0.501
Maximum tumor diameter (cm)	> 4.5 = 1, ≤ 4.5 = 0	2.352 (1.201-4.598)	0.012	1.895 (0.952-3.772)	0.068
Preoperative imaging T stage	T4 = 1, T3 = 0	2.563 (1.382-4.751)	0.003	2.418 (1.215-4.812)	0.012
Preoperative imaging N stage	N2 = 1, N0-1 = 0	3.125 (1.682-5.798)	< 0.001	3.521 (1.852-6.698)	< 0.001
Hypertension	Yes = 1, No = 0	1.082 (0.582-2.015)	0.812	1.152 (0.568-2.335)	0.698
Diabetes mellitus	Yes = 1, No = 0	1.215 (0.625-2.368)	0.568	1.325 (0.632-2.778)	0.465
Treatment regimen	Immunotherapy monotherapy = 1, combination immunotherapy = 0	2.018 (1.082-3.765)	0.028	1.985 (1.012-3.895)	0.046
Pathological response	Non-MPR = 1, MPR/pCR = 0	4.256 (2.382-7.615)	< 0.001	4.892 (2.582-9.275)	< 0.001

ECOG: Eastern Cooperative Oncology Group; MPR: Major pathological response; pCR: Pathological complete response; DFS: Disease-free survival; HR: Hazard ratio; CI: Confidence interval; OS: Overall survival.

Multivariate analysis: Factors with P < 0.1 in the univariate analysis (maximum tumor diameter, preoperative radiological T stage, preoperative radiological N stage, treatment regimen, and pathological response) were included in the multivariate Cox proportional hazards regression model. Results showed that pathological response (HR = 0.324, 95%CI: 0.186-0.564, P < 0.001), tumor T stage (HR = 2.157, 95%CI: 1.203-3.876, P = 0.009), and lymph node metastasis status (HR = 2.841, 95%CI: 1.562-5.167, P = 0.001) were independent risk factors for DFS in patients with LARC. Pathological response (HR = 0.289, 95%CI: 0.145-0.576, P < 0.001) and lymph node metastasis status (HR = 3.012, 95%CI: 1.583-5.731, P = 0.001) were independent risk factors for OS in patients with LARC (Table 5).

Table 5 Multivariate analysis of factors affecting long-term survival in patients with locally advanced rectal cancer.

Variable	Coding	DFS (HR, 95%CI)	P value (DFS)	OS (HR, 95%CI)	P value (OS)
Maximum tumor diameter (cm)	> 4.5 = 1, ≤ 4.5 = 0	1.521 (0.802-2.885)	0.198	1.485 (0.752-2.932)	0.256
Preoperative imaging T stage	T4 = 1, T3 = 0	2.157 (1.203-3.876)	0.009	1.892 (0.985-3.635)	0.056
Preoperative imaging N stage	N2 = 1, N0-1 = 0	2.841 (1.562-5.167)	0.001	3.012 (1.583-5.731)	0.001
Treatment regimen	Immunotherapy monotherapy = 1, combination immunotherapy = 0	1.452 (0.782-2.695)	0.235	1.385 (0.721-2.662)	0.321
Pathological response	Non-MPR = 1, MPR/pCR = 0	0.324 (0.186-0.564)	< 0.001	0.289 (0.145-0.576)	< 0.001

MPR: Major pathological response; pCR: Pathological complete response; DFS: Disease-free survival; HR: Hazard ratio; CI: Confidence interval; OS: Overall survival.

Safety analysis of neoadjuvant immunotherapy

All 130 patients experienced varying degrees of treatment-related adverse reactions during neoadjuvant immunotherapy, with no treatment-related mortality. Adverse reactions were predominantly grade 1 and grade 2, with an incidence of 92.3% (120/130). The incidence of grade 3 and grade 4 adverse reactions was 7.7% (10/130), mainly including 2 cases of grade 3 diarrhea, 3 cases of grade 3 rash, 2 cases of grade 3 hypothyroidism, 1 case of grade 4 immune-related pneumonitis, and 2 cases of grade 4 Liver function impairment. All the adverse reactions of grades 3 and 4 were relieved after symptomatic treatment (e.g., glucocorticoids, antidiarrheals, and hepatoprotective agents) and did not affect subsequent surgical treatment. The types and incidences of common adverse reactions are presented in Table 6.

Table 6 Safety analysis table, n (%).

Type of adverse event	Grade 1	Grade 2	Grade 3	Grade 4	Overall incidence
Skin disorders	18 (13.8)	13 (10.0)	3 (2.3)	0 (0.0)	34 (26.2)
Gastrointestinal disorders	15 (11.5)	9 (6.9)	2 (1.5)	0 (0.0)	26 (20.0)
Endocrine disorders	12 (9.2)	8 (6.2)	2 (1.5)	0 (0.0)	22 (16.9)
Respiratory disorders	5 (3.8)	3 (2.3)	0 (0.0)	1 (0.8)	9 (6.9)
Hepatic function impairment	4 (3.1)	2 (1.5)	0 (0.0)	2 (1.5)	8 (6.2)
Fatigue	10 (7.7)	5 (3.8)	0 (0.0)	0 (0.0)	15 (11.5)
Other	6 (4.6)	3 (2.3)	0 (0.0)	0 (0.0)	9 (6.9)
Total	70 (53.8)	50 (38.5)	7 (5.4)	3 (2.3)	130 (100.0)

DISCUSSION

The clinical treatment model for LARC has reached a novel era of multidisciplinary collaboration. As a core link connecting diagnostic evaluation and surgical intervention, the efficacy of neoadjuvant therapy directly defines the scope of clinical benefits for patients[8]. Although conventional neoadjuvant chemoradiotherapy can effectively achieve tumor downstaging and shrinkage, its associated toxic and side effects, such as intestinal mucosal injury and myelosuppression, often lead to a significant reduction in patients’ quality of life, and therapeutic resistance is more likely to occur in some advanced cases[9]. The clinical translation and application of immune checkpoint inhibitors have provided a novel breakthrough to address this therapeutic bottleneck. Multiple clinical studies have confirmed their definite anti-tumor activity in the treatment of LARC, yet conclusions from trials with strict inclusion criteria cannot easily match complex real-world clinical scenarios[10,11]. Real-world studies, characterized by broader population coverage and study design closer to clinical practice, have increasingly prominent guiding values for individualized treatment decision-making. Based on the clinical data of patients who received neoadjuvant immunotherapy, this study systematically analyzed the characteristics of pathological response and its correlation with long-term survival outcomes, providing real-world evidence for the standardized clinical application of immunotherapy.

The data of this study are consistent with the conclusions of multiple clinical studies focusing on neoadjuvant therapy for LARC[12,13]. A relevant study conducted neoadjuvant nivolumab combined with ipilimumab for LARC and reported a final pCR rate of 27.7%[14], and another study using neoadjuvant pembrolizumab monotherapy achieved a pCR rate of 18.6%[15]. The pCR rate in this study falls within the range of the above two research data. Such differences may result from the heterogeneity of the baseline characteristics of the enrolled populations and are more closely related to the selection of treatment regimens, as an inherent difference exists in the efficacy intensity between immune monotherapy and combination immunotherapy regimens. Notably, no significant difference was observed in the therapeutic efficacy between camrelizumab and pembrolizumab in this study, and this finding provides strong real-world evidence for the application of domestic PD-1 inhibitors in the neoadjuvant treatment of LARC. This difference in subgroup analysis shows that the combination of immunotherapy and chemotherapy may enhance anti-tumor efficacy through a synergistic mechanism. Chemotherapy can strengthen the anti-tumor effect of immunotherapy by releasing tumor antigens and optimizing the tumor immune microenvironment, and this synergistic mechanism provides a solid theoretical basis for the results of this study[16]. Stratified analysis of tumor staging revealed that the efficacy improvement of the immune combination regimen was more prominent in patients with T3 and N1 stages, whereas the pCR rate in patients with T4 and N2 stages was still below 20%. This phenomenon indicates that patients with advanced tumors may require more individualized combination strategies, such as extending the course of immunotherapy or incorporating anti-angiogenic drugs into the existing regimens to enhance therapeutic efficacy. Pathological response has long been proven to be a core indicator for evaluating the efficacy of neoadjuvant therapy, and its correlation with long-term survival of LARC patients has been confirmed in studies on conventional chemoradiotherapy. The survival analysis in this study further demonstrated statistically significant differences in the 1-year DFS rate and 1-year OS rate among the pCR, MPR, and non-MPR groups. Among them, the pCR group achieved a 1-year DFS rate of 96.7% and 1-year OS rate of 100%, exhibiting a significant survival advantage over the other two groups. This result shows that the level of pathological response after neoadjuvant immunotherapy can effectively predict the long-term survival outcomes of LARC patients.

Further, the multivariate Cox regression analysis confirmed that the degree of pathological response was an independent risk factor for DFS and OS in patients with LARC. This conclusion indicates that patients achieving pCR or MPR have a better prognosis, consistent with the conclusions of existing studies[17,18]. In addition to the degree of pathological response, tumor T stage and lymph node metastasis status are important factors affecting survival, with patients with T4 and N2 stages having relatively poor survival outcomes[19]. This finding shows that more intensive treatment regimens need to be formulated clinically for patients with advanced tumors. Treatment safety is a core consideration in the selection of clinical regimens. In this study, neoadjuvant immunotherapy-related adverse reactions were observed in all patients but were predominantly grade 1 and grade 2. The incidence of grade 3 and grade 4 adverse reactions was only 7.7%, and no treatment-related deaths were reported. Severe adverse reactions mainly included immune-related pneumonitis and liver function impairment, all of which were relieved after targeted symptomatic treatment. The pathogenesis and management of immunotherapy-related adverse reactions are significantly different from those of conventional chemoradiotherapy-related adverse reactions. In this study, all patients with grade 3 hypothyroidism returned to normal after levothyroxine replacement therapy without affecting surgery time. This practical experience indicates that a comprehensive management system for immune-related adverse reactions should be established to ensure treatment safety. A comparison of safety across different treatment regimens showed that although the incidence of adverse reactions in the immune combination therapy group was slightly higher than that in the immune monotherapy group, the difference was not statistically significant. This result shows that the safety of the combination therapy regimen is still within a controllable range and does not significantly increase the risk of severe adverse reactions, providing safety support for its clinical promotion.

Clinically, our study findings show the following guiding significance: (1) For patients with T3N0-1 LARC, immunochemotherapy can be considered the preferred regimen, especially for those intolerant to radiotherapy; (2) For those who achieve pCR after treatment, the course of postoperative adjuvant therapy may be shortened to reduce treatment-related toxic and side effects[20]; and (3) For those with non-major pathological response, enhanced postoperative follow-up and monitoring are required, with timely adjustment of adjuvant therapy regimens[21]. Future multicenter, prospective randomized controlled trials are required to further verify the long-term efficacy of neoadjuvant immunotherapy and explore biomarker-based individualized treatment strategies.

The degree of pathological response is a key indicator for evaluating the efficacy of neoadjuvant therapy, and its correlation with long-term patient survival has been confirmed in conventional chemoradiotherapy[22]. The survival analysis in this study revealed statistically significant differences in the 1-year DFS and OS rates among the pCR, MPR, and non-MPR groups. Notably, the pCR group achieved a 1-year DFS rate of 96.7% and 1-year OS rate of 100.0%, which were significantly superior to those of the MPR and non-MPR groups. This result shows that the degree of pathological response after neoadjuvant immunotherapy can effectively predict the long-term survival outcomes of LARC patients. Further, the multivariate Cox regression analysis confirmed that the degree of pathological response was an independent risk factor for DFS and OS in LARC patients, indicating that patients achieving pCR or MPR have a more favorable prognosis, which is consistent with the conclusions of existing studies[23,24]. In addition, this study found that tumor T stage and lymph node metastasis status were important factors affecting patient survival, with patients with T4 or N2 stage exhibiting poor survival outcomes. This implies that more intensive treatment regimens may be required for patients with advanced tumors to improve prognosis.

Safety is a critical consideration in the selection of clinical treatment regimens. In this study, neoadjuvant immunotherapy-related adverse reactions were predominantly grades 1 and 2, with an overall incidence of 100.0%, while the incidence of grade 3 and grade 4 adverse reactions was only 7.7%, and no treatment-related deaths were reported. The main severe adverse reactions included immune-related pneumonitis and liver function impairment, all of which were relieved after symptomatic treatment. These results demonstrate that neoadjuvant immunotherapy has a favorable safety profile in patients with LARC, generally consistent with the incidence of adverse reactions reported in clinical trials[25,26]. Notably, although the incidence of adverse reactions in the immunochemotherapy group was slightly higher than that in the immunotherapy monotherapy group, the difference was not statistically significant, indicating that the safety of the combination regimen remains controllable.

As a real-world study, this research has several notable strengths. First, the baseline characteristics of the enrolled patients were more consistent with clinical practice, including patients of different ages, tumor stages, and with comorbidities, enhancing the external validity of the findings. Second, the study systematically analyzed the correlation between the degree of pathological response and long-term survival and controlled for confounding factors using a multivariate regression model, rendering the conclusions more reliable. Third, treatment-related adverse reactions were recorded in detail, providing direct references for clinical safety management. However, this study has certain limitations. First, as a single-center retrospective study, it may be subject to selection bias; in particular, the choice of treatment regimen was considerably influenced by the economic status of the patients. Second, the follow-up duration was relatively short, with a median of 18 months; long-term survival outcomes such as the 3 years DFS and 5 years OS rates still require further follow-up for verification. Third, the study did not conduct an in-depth investigation into the impact of biomarkers (e.g., PD-L1 expression and microsatellite instability status) on treatment efficacy. A preliminary test of 30 patients in this study showed a PD-L1 positive rate of 46.7%, with the pCR rate of positive patients (35.7%) being higher than that of negative patients (18.2%), although the difference was not statistically significant (P = 0.125). Future studies with larger sample sizes are required for in-depth analysis. Fourth, the study did not compare the efficacy of neoadjuvant immunotherapy with conventional chemoradiotherapy, rendering it impossible to identify the population that benefits most from immunotherapy.

Several limitations of this study should be acknowledged. First, as a retrospective single-center analysis, it may be inherently susceptible to selection bias, information bias, and residual confounding despite rigorous inclusion and exclusion criteria. Second, the relatively short median follow-up duration may have limited the maturity and robustness of long-term survival assessments, and therefore, the prognostic implications of pathological response should be interpreted with caution. Third, the lack of a parallel control group precluded direct comparisons between neoadjuvant immunotherapy and conventional treatment strategies, thereby limiting the strength of causal inference. In addition, the relatively modest sample size may have affected the statistical power and generalizability of the findings. Nevertheless, as a real-world study reflecting routine clinical practice, our results provide clinically meaningful evidence on the association between pathological response and survival outcomes in LARC treated with neoadjuvant immunotherapy. Future prospective, multicenter, large-scale controlled studies with extended follow-up are warranted to further validate these findings.

CONCLUSION

In conclusion, neoadjuvant immunotherapy yields a high pathological response rate in patients with LARC, and the degree of pathological response is closely correlated with long-term survival outcomes. Patients achieving pCR or MPR have superior DFS and OS rates. The degree of pathological response can serve as an important indicator for evaluating the efficacy of neoadjuvant immunotherapy and predicting prognosis in LARC patients. Immunochemotherapy is more effective than immunotherapy monotherapy and has a controllable safety profile. Future multicenter, prospective studies are warranted to further verify the long-term efficacy of neoadjuvant immunotherapy and explore relevant biomarkers. This is expected to provide more robust evidence for the individualized treatment of LARC patients.