Sage Journals: Discover world-class research

Abstract

Background

Local advanced rectal cancer (LARC) patients who achieved pathological complete response (pCR) after neoadjuvant chemoradiotherapy (NCRT) generally have a favorable prognosis. This retrospective study aimed to evaluate the prognostic value of magnetic resonance imaging (MRI) parameters and neutrophil-to-lymphocyte ratio (NLR) in LARC patients with pCR.

Methods

Between 2015 and 2019, 180 LARC patients who achieved pCR after NCRT and surgery were included. MRI parameters and NLR were evaluated as potential predictors for 5-year overall survival (OS) and disease-free survival (DFS) using the Kaplan–Meier and COX regression analysis.

Results

With a median follow-up time of 68.3 months, the 5-year OS and DFS rates were 94.2% and 91.4%, respectively. Thirteen patients (7.2%) died, 2 (1.1%) experienced local recurrence, and 15 (8.3%) experienced distant metastases. Pretreatment MRI parameters and NLR were correlated with 5-year OS and DFS in pCR patients in the univariate analysis. The multivariate analysis identified baseline EMVI and NLR as independent predictors for 5-year OS and DFS (all P < .05). Patients in the low-risk group (EMVI-negative and/or NLR ≤ 2.8, n = 159, 88.3%) had a more favorable 5-year DFS compared to those in the high-risk group (EMVI-positive and NLR > 2.8, n = 21, 11.7%) (95.6% vs 59.4%, P < .001), with similar findings for 5-year OS (97.4% vs 70.6%, P < .001).

Conclusions

This study showed that MRI parameters and NLR were associated with long-term prognosis in patients with pCR. These findings could aid in stratifying pCR patients and guide subsequent treatment and follow-up strategies.

Keywords

local advanced rectal cancer neoadjuvant chemoradiotherapy magnetic resonance imaging neutrophil-to-lymphocyte ratio pathological complete response

Introduction

Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths worldwide.¹ Neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC).² After NCRT, tumor cells exhibit varied responses to therapy, and the degree of response is closely related to prognosis, as demonstrated by several studies.^3,4 Pathological complete response (pCR), the optimal treatment response, is characterized as the absence of residual tumor cells in the primary tumor and lymph nodes. Approximately 20% of patients achieved pCR following NCRT and surgery.^3,4 A pooled analysis of 3105 LARC patients indicated that the 5-year disease-free survival (DFS) was 83.3% in the pCR group and 65.6% in the non-pCR group (P < .001).³ Thus, pCR is frequently used as the primary endpoint in current clinical research of LARC.⁵

Despite the association of pCR with favorable long-term prognosis, recurrence still occurs in some patients. Limited studies have investigated the prognostic factors of pCR patients. Furthermore, the benefits of adjuvant chemotherapy in pCR patients remain contentious.⁶ In pCR patients, therapeutic and follow-up strategies may differ based on distinct prognostic factors. Therefore, identifying pCR patients at high risk of recurrence is crucial for optimizing clinical management.

Magnetic resonance imaging (MRI) offers unique advantages by providing accurate images of soft tissue structures in the mesorectum, establishing itself as the standard for clinical staging of LARC.⁷ The current American Joint Committee on Cancer (AJCC) staging system for LARC encompasses a heterogeneous group of tumors in stages II-III, and the prognosis of LARC correlates significantly with parameters such as the depth of extramural invasion, extramural venous invasion (EMVI) and involvement of the mesorectal fascia (MRF).⁸ These parameters have demonstrated prognostic relevance in LARC patients after NCRT,⁸ guiding risk-adapted treatment strategies as recommended by the European Society for Medical Oncology (ESMO).⁷ Previous data indicated that MRI-defined low-risk LARC patients exhibited a pCR rate exceeding 30% following NCRT, contrasting with lower rates observed in those categorized as MRI-defined high-risk LARC.^9,10 However, few studies have focused on the prognostic value of baseline MRI parameters in LARC patients with pCR.

Cellular inflammation components, known for their dual roles in the promotion or containment of tumors, have been proven to correlate with prognosis in various solid malignancies, including rectal cancer.¹¹ The neutrophil-to-lymphocyte ratio (NLR) is a widely utilized and economical biomarker for predicting tumor prognosis¹¹ A meta-analysis reported that NLR was an independent clinical predictor of overall survival (OS) and DFS in patients with rectal cancer undergoing curative surgery.¹² Moreover, elevated baseline NLR was associated with poor prognosis in LARC patients treated with NCRT.¹³ Nevertheless, the prognostic effect of NLR on LARC patients with a pCR status after NCRT remains unclear.

Therefore, we conducted a study to evaluate the prognostic value of MRI parameters and NLR in patients who achieve pCR after NCRT and surgery.

Materials and Methods

Patients Selection

Retrospectively, all patients diagnosed with histologically confirmed rectal adenocarcinoma who received NCRT at our center from January 2015 to November 2019 were eligible for inclusion in this study. The inclusion criteria were as follows: (1) patients who underwent pelvic MRI before NCRT, (2) clinical stage was cT3-4 or lymph node-positive, (3) lower edge of the tumor no more than 10 cm from the anal edge, (4) received NCRT in our center, (5) pathologically diagnosed ypT0N0 after surgery, (6) older than or equal to 18 years old, and (7) had an Eastern Cooperative Oncology Group score of less than 2. The exclusion criteria were as follows: (1) the presence of a second primary cancer that may affect the prognosis, and (2) loss to follow-up after surgery. Additionally, eight patients with ypT0 who underwent local excision to preserve anal function and remained regional recurrence-free within 2 years after surgery were also included in this analysis. Venous blood samples of patients were collected at baseline.

This study was approved by the ethics committee of Peking University Cancer Hospital (2025YJZ28), and the requirement for obtaining informed patient consent was waived. The reporting of this study conforms to the STROBE guidelines.¹⁴ All patient details have been de-identified.

MRI Assessment

A pelvic diagnostic or simulation high-resolution MRI in the supine position before NCRT was necessary, requiring a three-dimensional T2-weighted sequence, especially in axial scanning. The slice thickness was 3-5 mm. Axial scanning should be angulated perpendicular to the rectal tumor axis.¹⁵ The cT stage, T3 substage, cN stage, EMVI, MRF status, and tumor length and thickness were evaluated based on the ESMO and European Society of Gastrointestinal and Abdominal Radiology consensus meeting guidelines.^7,15 The distance from the lower edge of the tumor to the anus less than 5 cm is defined as “low”, and 5-10 cm is defined as “middle”.

Evaluation of tumor regression using MRI is recommended 5-12 weeks after NCRT before surgery.

Neoadjuvant Treatment

Patients underwent computed tomography (CT) and MRI simulation using contrast-enhanced CT with a 5 mm slice thickness in the supine position, secured with a thermoplastic film. A full bladder and an empty rectum were maintained to ensure consistency in the positioning of the rectal tumor and to protect the intestine. Simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) was performed in all patients with prescription doses for the planning gross tumor volume (PGTV) of 50-50.6 Gy and planning target volume (PTV) of 41.8-45 Gy, respectively, in 22-25 fractions. Detailed contouring procedures have been previously described.¹⁶

Patients received capecitabine with or without oxaliplatin as concurrent chemotherapy. With comprehensive informed consent regarding the benefits and risks, induction or consolidation chemotherapy (XELOX regimen) was implemented in some cases.

All patients were informed about the risks and benefits of NCRT and provided written informed consent to treatment.

Surgical and Postoperative Treatment

After NCRT, a multidisciplinary team developed the following treatment strategies. Patients were recommended for surgery, predominantly TME. Local excision was considered in specific cases to preserve organ function, based on mutual decision-making between physicians and patients.

A pCR was defined by the absence of tumor cells in the primary tumor and lymph nodes. The assessment of surgical specimens was conducted independently by two senior pathologists using a standardized protocol.¹⁷

Adjuvant chemotherapy was recommended according to National Comprehensive Cancer Network guidelines. XELOX (oxaliplatin and capecitabine) and FOLFOX (oxaliplatin, leucovorin, and 5-FU) were preferred, while capecitabine monotherapy was an alternative.

Follow-up

After radical surgery, patients were advised to regular follow-up at 3-month intervals for the first 2 years, 6-month intervals for 3 to 5 years, and annually thereafter. Follow-up assessments included symptoms, physical examination, blood tests, and CT examinations of the thorax, abdomen, and pelvis.

Statistical Analysis

Data were collected and analyzed using the Statistical Package for the Social Sciences (IBM Corp. SPSS Statistics for Windows, v.22.0, Armonk, NY, USA). The optimal cut-off values for NLR, tumor length, and thickness were determined using the X-tile software version 3.6.1 (Yale University, New Haven CT, USA).¹⁸ Student’s t-test was used to compare differences in continuous data, and the Chi-square or Fisher’s test for categorical data. OS was defined as the date from radical surgery to death from any cause. DFS was defined as the date from radical surgery to any type of locoregional recurrence, distant metastasis, or death for any reason. OS and DFS analyses were performed using the Kaplan–Meier method, and the results were compared using the log-rank test. The Cox regression model was used for univariate and multivariate analysis. Variables with a P-value of < 0.05 in univariate analyses were included in multivariate analyses.

Results

Patient Characteristics

A total of 180 LARC patients with pCR after NCRT were included in this analysis. The baseline clinical characteristics and treatment patterns of patients are summarized in Table 1. The median age was 59 (range: 31-82) years, 122 (67.8%) patients were male, 87 (48.3%) patients were diagnosed with low rectal cancer, and 46 (25.6%) patients had elevated CEA levels. The mean baseline NLR was 2.6.

Table 1.

Characteristics of Patients With Pathological Complete Response (n = 180).

Characteristics	Numbers	Proportion (%)
Age, median(range), years	59 (31-82)
Sex
Male	122	67.8
Female	58	32.2
ECOG performance
0	130	72.2
1	50	27.8
Preoperative CEA
≤5 ng/mL	124	68.9
>5 ng/mL	46	25.6
Unknown/missing	10	5.5
Tumor location
Low	87	48.3
Middle	93	51.7
Tumor differentiation
Well-differentiated	18	10.0
Moderately differentiated	141	78.3
Poorly differentiated	10	5.6
Others	11	6.1
cT category
T2	8	4.4
T3a-b	127	70.6
T3c-d	11	6.1
T4	34	18.9
cN category
N0	6	3.3
N+	174	96.7
Lateral pelvic lymph node
positive	41	22.8
negative	139	77.2
Baseline NLR
Mean (SD)	2.6 (1.3)
MRF
Positive	66	36.7
Negative	114	63.3
EMVI
Positive	70	38.9
Negative	110	61.1
MRI-defined tumor length (mm)
Mean (SD)	46.6 (16.0)
MRI-defined tumor thickness (mm)
Mean (SD)	15.3 (5.4)
Induction chemotherapy or consolidation chemotherapy
Yes	30	16.7
No	150	83.3
Surgery
APR	63	35.0
LAR	106	58.9
Hartmann	3	1.7
Local excision	8	4.4
Adjuvant chemotherapy
Yes	64	35.6
No	105	58.3
Unknown/missing	11	6.1
Mismatch repair
proficient mismatch repair.	7	3.9
deficient mismatch repair	0	0.0
Unknown/missing	173	96.1
RAS/RAF
Wild-type	6	3.3
Mutation-type	4	2.2
Unknown/missing	170	94.5

Abbreviations: ECOG: Eastern Cooperative Oncology Group; CEA: Carcinoembryonic antigen; NLR: neutrophil-to-lymphocyte ratio; MRI: magnetic resonance imaging; MRF: mesorectal fasciae; EMVI: extramural venous invasion; APR: abdominoperineal resection; LAR: low anterior resection.

In terms of pretreatment MRI parameters, 34 (18.9%) patients were diagnosed with clinical T4, 174 (96.7%) patients had clinical N+, 66 (36.7%) patients were MRF-positive, and 70 (38.9%) patients were EMVI-positive.

Outcomes in Patients with pCR

The median follow-up time was 68.3 months (range: 21.2-108.4 months). Among 180 patients, the 5-year OS was 94.2% (Figure 1A), the 5-year DFS was 91.4% (Figure 1B), the 5-year local recurrence-free survival was 93.7% (Figure 1C), and the 5-year distant metastasis-free survival (DMFS) was 91.4% (Figure 1D). During the follow-up period, 13 patients (7.2%) died and 15 patients (8.3%) experienced tumor recurrence. Local regional recurrence occurred in 2 patients (1.1%) in the left pelvic wall, both of whom were combined with distant metastases. Among 15 patients (8.3%) who suffered distant metastases, 5 had pulmonary metastases, 2 had liver metastases, 1 had brain metastases, 1 had peritoneal metastases, 1 had retroperitoneal lymph nodes, and 5 had multiple organ metastases (3 of 5 involved the lung, and 2 of 5 involved the liver) when they first diagnosed with distant metastases.

Figure 1.

Kaplan‒Meier Survival Curves for Overall Survival (A), Disease-free Survival (B), Local Recurrence-free Survival (C), and Distant Metastasis-Free Survival (D) in Patients With Pathological Complete Response.

Association Between MRI Parameter and Survival Outcomes

We analyzed the impact of MRI characteristics on 5-year OS and DFS. The X-Tile software identified the optimal cut-off value of MRI-defined tumor length as 64 mm for 5-year OS and DFS. Patients were classified into the group with tumor length ≤ 64 mm (n = 160, 88.9%) and the group with tumor length > 64 mm (n = 20, 11.1%). The tumor length ≤ 64 mm group had significantly better 5-year OS (95.4% vs 85.0%, P = .001) and DFS (93.0% vs 79.7%, P = .008) compared to the group with tumor length > 64 mm. Similarly, the tumor thickness > 20 mm (n = 20, 11.1%) patients had worse 5-year OS (85.0% vs 95.4%, P = .001) and DFS (79.7% vs 93.0%, P = .007) compared to those with tumor thickness ≤ 20 mm (n = 160, 88.9%).

In addition, patients with MRF-negative status had significantly better outcomes than those with MRF-positive status in terms of 5-year OS (96.3% vs 90.8%, P = .012,) and 5-year DFS (94.6% vs 85.8%, P = .023). EMVI-negative patients also had a better 5-year OS (99.0% vs 87.0%, P < .001) and DFS compared to EMVI-positive patients (96.3% vs 84.0%, P = .002).

The 5-year OS was 94.2% and 94.1% in patients with cT2-3 and cT4 (P = .081), and the corresponding DFS was 92.3% and 87.4% (P = .193). Patients with cN + had a similar 5-year OS (94.0% vs 100.0%, P = .513) and DFS (91.7% vs 83.3%, P = .424) compared to cN0.

Association Between NLR Level with Survival Outcomes

According to the X-Tile software, the optimal cut-off value for NLR level was 2.8 for 5-year OS and 2.8 for 5-year DFS. Therefore, patients were categorized into low-NLR (NLR ≤ 2.8, n = 121, 67.2%) and high-NLR (NLR > 2.8, n = 59, 32.8%) groups.

The 5-year OS rates in the low-NLR and high-NLR groups were 96.6% and 89.3% (P = .016). The 5-year DFS rates in the low-NLR and high-NLR groups were 95.0% and 83.7% (P = .029).

Univariate and Multivariate Analysis for Survival Outcomes

The results of the univariate and multivariate analyses of OS are presented in Table 2. In the univariate analysis, MRF negative, EMVI negative, tumor length ≤ 64 mm, tumor thickness ≤ 20 mm and a low baseline NLR were associated with better OS (all P < .05). The multivariate analysis identified EMVI-negative (hazard ratio [HR], 0.092; 95% confidence interval [CI], 0.020-0.417; P = .002) and low baseline NLR (HR, 0.220; 95%CI, 0.071-0.680; P = .009) were proven to be independent predictors for better OS.

Table 2.

Univariate and Multivariate Analysis for Overall Survival in Patients With Pathological Complete Response.

Parameters	Univariate analysis		Multivariate analysis
Parameters	HR (95% CI)	P-Value	HR (95% CI)	P-Value
Age		0.895
>59 vs ≤ 59 year	0.929 (0.312-2.766)
Sex		0.390
Female vs Male	0.568 (0.156-2.065)
ECOG performance		0.822
1 vs 0	1.145 (0.352-3.722)
Preoperative CEA		0.225
>5 ng/mL vs ≤ 5 ng/mL	2.035 (0.646-6.414)
Tumor location		0.836
Middle vs Low	1.122 (0.376-3.344)
Tumor differentiation		0.458
Well-differentiated	1
Moderately differentiated	0.504 (0.108-2.342)
Poorly differentiated	1.619 (0.225-11.666)
Others	0.000 (0.000-NA)
cT category		0.093
T2-T3	1
T4	2.610 (0.853-7.985)
cN category		0.665
N0 vs N+	0.047 (0.000-46798.752)
Lateral pelvic lymph node		0.472
Negative vs Positive	0.649 (0.200-2.108)
MRF		0.020		0.666
Negative vs Positive	0.247 (0.076-0.803)		0.737 (0.184-2.955)
EMVI		0.004		0.002
Negative vs Positive	0.108 (0.024-0.488)		0.092 (0.020-0.417)
MRI-defined tumor length (mm)		0.004		0.599
>64 mm vs ≤ 64 mm	5.111 (1.670-15.643)		1.671 (0.246-11.340)
MRI-defined tumor thickness (mm)		0.003		0.611
>20 mm vs ≤ 20 mm	5.519 (1.805-16.878)		1.610 (0.257-10.083)
Induction or consolidation chemotherapy		0.430
Yes vs No	0.439 (0.057-3.385)
Surgery		0.374
APR	1
LAR	0.365 (0.119-1.118)
Hartmann	0.000 (0.000-NA)
Local excision	0.000 (0.000-NA)
Adjuvant chemotherapy		0.278
Yes vs No	1.830 (0.614-5.449)
Baseline NLR		0.024		0.009
≤2.8 vs > 2.8	0.276 (0.090-0.846)		0.220 (0.071-0.680)

Abbreviations: HR: hazard ratio; CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; CEA: carcinoembryonic antigen; MRI: magnetic resonance imaging; MRF: mesorectal fasciae; EMVI: extramural venous invasion; APR: abdominoperineal resection; LAR: low anterior resection; NLR: neutrophil-to-lymphocyte ratio. The bold indicated statistical significance, with P < 0.05.

Similarly, the results of the univariate and multivariate analyses of DFS are presented in Table 3. The univariate analysis revealed MRF-negative, EMVI-negative, tumor length ≤ 64 mm, tumor thickness ≤ 20 mm, and a low baseline NLR were correlated with increased DFS (all P < 0.05). Multivariate analysis confirmed that EMVI-negative (HR, 0.179; 95%CI, 0.057-0.558; P = .003) and low baseline NLR (HR, 0.295, 95%CI, 0.109-0.799; P = .016) were independent predictors for better DFS.

Table 3.

Univariate and Multivariate Analysis for Disease-free Survival in Patients With Pathological Complete Response.

Parameters	Univariate analysis		Multivariate analysis
Parameters	HR (95%CI)	P-Value	HR (95%CI)	P-Value
Age		0.864
>59 vs ≤ 59 year	1.090 (0.409-2.903)
Sex		0.217
Female vs Male	0.453 (0.129-1.592)
ECOG performance		0.730
1 vs 0	1.205 (0.418-3.467)
Preoperative CEA		0.075
>5 ng/mL vs ≤ 5 ng/mL	2.510 (0.910-6.924)
Tumor location		0.902
Middle vs Low	0.940 (0.353-2.507)
Tumor differentiation		0.634
Well-differentiated	1
Moderately differentiated	0.760 (0.170-3.395)
Poorly differentiated	2.047 (0.288-14.549)
Others	0.000 (0.000-NA)
cT category		0.201
T2-T3	1
T4	1.992 (0..692-5.734)
cN category		0.437
N0 vs N+	2.233 (0.295-16.925)
Lateral pelvic lymph node		0.155
Negative vs Positive	0.480 (0.174-1.321)
MRF		0.030		0.579
Negative vs Positive	0.327 (0.119-0.899)		0.713 (0.216-2.356)
EMVI		0.006		0.003
Negative vs Positive	0.202 (0.065-0.627)		0.179 (0.057-0.558)
MRI-defined tumor length (mm)		0.014		0.631
>64 mm vs ≤ 64 mm	3.769 (1.309-10.854)		1.499 (0.288-7.801)
MRI-defined tumor thickness (mm)		0.012		0.748
>20 mm vs ≤ 20 mm	3.894 (1.352-11.213)		1.459 (0.301-7.075)
Induction or consolidation chemotherapy		0.586
Yes vs No	0.664 (0.152-2.904)
Surgery		0.197
APR	1
LAR	0.327 (0.119-0.900)
Hartmann	0.000 (0.000-NA)
Local excision	0.000 (0.000-NA)
Adjuvant chemotherapy		0.343
Yes vs No	1.608 (0.603-4.284)
Baseline NLR		0.037		0.016
≤2.8 vs > 2.8	0.349 (0.130-0.939)		0.295 (0.109-0.799)

Risk Stratification in Patients with pCR

Based on the results of the multivariate analysis, patients were categorized into low-risk (EMVI-negative and/or NLR ≤ 2.8) and high-risk (EMVI-positive and NLR > 2.8). Therefore, patients were divided into a low-risk (n = 159, 88.3%) group and a high-risk (n = 21, 11.7%) group. The patients with pCR in the low-risk group demonstrated significantly better 5-year OS than those in the high-risk group (97.4% vs 70.6%, P < .001; Figure 2A), as well as in 5-year DFS (95.6% vs 59.4%, P < .001; Figure 2B).

Figure 2.

Kaplan‒Meier Survival Curves for Overall Survival (A) and Disease-Free Survival (B) in the Low-Risk and High-Risk Groups in Patients With Pathological Complete Response.

Discussion

While most previous research has focused on identifying clinical predictors associated with achieving pCR in LRAC patients after NCRT and has demonstrated that pCR predicted a favorable long-term prognosis, few studies have analyzed prognostic factors specifically in patients with pCR. Focusing on the pCR subgroup, our research revealed that pretreatment MRI parameters and baseline NLR were correlated with prognosis in pCR patients after NCRT in the univariate analysis. In the multivariate analysis, high NLR levels (> 2.8) and EMVI-positive status were independent predictors for poorer OS and DFS. pCR patients categorized in the low-risk group (EMVI-negative and/or NLR ≤2.8) exhibited a more favorable 5-year DFS compared to those in the high-risk group (EMVI-positive and NLR > 2.8) (95.6% vs 59.4%, P < .001), with consistent findings for 5-year OS (97.4% vs 70.6%, P < .001). Therefore, these findings underscore the potential utility of pretreatment MRI parameters and NLR in guiding treatment decisions and clinical follow-up strategies for patients who achieve pCR after NCRT.

After NCRT, patients achieving pCR often exhibit excellent oncological outcomes. In a study including 242 patients with pCR after NCRT, Jiang et al.¹⁹ reported the 5-year OS and DMFS were 94.7% and 88.9%, respectively. A pooled analysis of 3105 LARC patients who achieved pCR after NCRT indicated that the 5-year crude DFS was 83.3%, higher than the 65.6% observed in those who did not achieve pCR, which highlights the significant benefit of achieving pCR.³ Consistent with these findings, our study showed that patients who achieved pCR had an ideal 5-year DFS (91.4%) and OS (94.2%). However, a minority of pCR patients still develop tumor recurrence. Park et al.⁴ found that the 5-year recurrence-free survival of pCR patients was 90.5%, with a 5-year distant metastasis rate of 7.0% and no local recurrence occurred within 5 years. These results revealed that the recurrence pattern in pCR patients was predominantly distant metastasis. In a study of 195 LARC patients with pCR, 3 had local recurrence and 15 had distant metastasis (including 7 lung metastases).²⁰ Our research corroborates these findings, emphasizing the necessity of routine monitoring of distant areas, especially the lungs, in pCR patients after NCRT.

The role of adjuvant chemotherapy in pCR patients after NCRT remains significantly controversial. Some studies have demonstrated that pCR patients can still benefit from adjuvant chemotherapy, with the OS of those who received adjuvant chemotherapy being superior to those who did not.^6,21 Conversely, other studies proposed that adjuvant chemotherapy can be safely omitted in pCR patients, as it failed to confirm survival advantages.^22,23 Therefore, the identification of reliable prognostic markers for stratifying pCR patients could potentially resolve this ongoing dispute, and serve to guide follow-up strategies. Based on the risk stratification of our findings, low-risk pCR patients may potentially benefit from the omission of chemotherapy to avoid treatment toxicity, and a reduction in the costs of follow-up examinations. In contrast, high-risk patients may still require adjuvant chemotherapy or at least more frequent follow-up. Furthermore, our study found pCR patients with only EMVI-positive or high NLR still exhibited a favorable prognosis. An interesting perspective emerging from our findings is that a single risk factor may be insufficient to accurately discriminate the prognosis of pCR patients and the presence of multiple adverse characteristics may lead to truly poor prognosis, which need large sample size study to prove. These findings not only enhance our comprehension of pCR patient management but also provide valuable insights for the direction of future research.

To the best of our knowledge, few studies have investigated the relationship between MRI parameters and long-term prognosis in LARC patients achieving pCR. MRI plays a crucial role in assessing tumors, and its parameters are associated with prognosis in LARC. Among MRI parameters, EMVI positivity has been associated with increased rates of distant metastases and poor treatment sensitivity. A meta-analysis including 2237 patients from 11 studies indicated that baseline EMVI positivity was associated with worse OS (P < .001).²⁴ Zhang et al.²⁵ analyzing 517 LARC patients undergoing NCRT, similarly identified EMVI as a predictor of metastasis-free survival (P < .010) and OS (P = .010). Our study demonstrated that even in patients with pCR, the 5-year DFS and OS of EMVI-positive patients were significantly lower than those of EMVI-negative.

In our study, MRF status, tumor length and thickness also demonstrated correlations with long-term prognosis in pCR patients in the univariate analysis. Previous studies had similar findings. The MERCURY study revealed that the 5-year OS was 62.2% in patients with MRF-positive compared with 42.2% in patients with MRI-negative (P < .01), and the 5-year DFS was 67.2% vs 47.3% (P < .05) in LARC patients.²⁶ As for tumor length, a sub-analysis of the TRIGGER feasibility study indicated a median tumor length of 43 mm in patients with a good response to NCRT, compared to 50 mm in those with poor response (P < .001).²⁷ Tumor thickness was a predictor for pCR in LARC patients after NCRT in a study.²⁸ Although the relationship between these three factors and prognosis was not significant in the multivariate analysis of our study, this is likely due to the limited sample size and number of events. The predictive values of MRF status, tumor length, and thickness in pCR patients warrant further research.

The mechanisms underlying the relationship between NLR and outcomes in LARC patients remain unclear. Tumor progression may be associated with an imbalance between protumor (inflammatory) and antitumor (immune) forces.^12,29 Neutrophils are known to release inflammatory cytokines that promote angiogenesis and accelerate tumor progression,³⁰ and neutrophilia were linked to poor outcomes in LARC patients, as evidenced in the CAO/ARO/AIO-04 trial.³¹ Conversely, lymphocytes are crucial for immunity and tumor control, with tumor-infiltrating lymphocytes playing a significant role in the antitumor immune response.³² A high NLR may indicate an immune microenvironment that promotes tumor progression. A meta-analysis of thirty-one studies reported that pretreatment high-NLR was associated with worse OS and DFS in patients undergoing curative rectal cancer resection.³³ Similarly, a study including 199 LARC patients identified that a cut-off value of NLR ≥ 2.8 was an independent predictor for OS after NCRT.³⁴ Our results are consistent with previous studies, confirming that NLR level is correlated with long-term prognosis in patients with pCR.

As a retrospective study, this research inevitably has some limitations. First, due to the limitations of the screening criteria, the study population exhibited relative heterogeneity. Additionally, both the sample size of a single-center, and the number of events in the multivariate analysis were limited. Multicenter, prospective, and large-scale trials are needed to further confirm our findings.

Conclusion

In conclusion, pretreatment high NLR (> 2.8) and EMVI-positive status were independent prognostic factors of poor OS and DFS among LARC patients with pCR. The 5-year DFS and OS for pCR patients in the low-risk group (EMVI-negative and/or NLR ≤ 2.8) were better than those in the high-risk group (EMVI-positive and NLR > 2.8). A closer clinical follow-up strategy is recommended for pCR patients, especially routine chest CT examination. High-risk patients with pCR may warrant intensive adjuvant therapy.

Footnotes

Acknowledgments

The authors would like to thank all patients who participated in this study.

ORCID iD

Weihu Wang

Statements and Declarations

Author Contributions

Yujun Cui: Writing – original draft, Writing – review & editing, Methodology.

Shuai Li: Writing – original draft, Writing – review & editing, Methodology.

Jian Tie: Writing – original draft, Writing – review & editing, Methodology.

Maxiaowei Song: Writing – review & editing, Funding acquisition.

Yangzi Zhang: Writing – review & editing.

Hongzhi Wang: Writing – review & editing.

Jianhao Geng: Writing – review & editing.

Zhiyan Liu: Writing – review & editing.

Huajing Teng: Software, Formal analysis.

Xin Sui: Software, Formal analysis.

Xianggao Zhu: Data curation.

Yong Cai: Data curation.

Yongheng Li: Conceptualization, Funding acquisition, Resources, Supervision.

Weihu Wang: Conceptualization, Funding acquisition, Resources, Supervision.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Beijing Hospitals Authority Clinical medicine Development of special funding support (No. ZLRK202327), Beijing Municipal Science &Technology Commission (No. Z181100001718192), Beijing Hospitals Authority’s Ascent Plan (No. DFL20220902), National Natural Science Foundation (No. 82073333), Capital’s Funds for Health Improvement and Research (No. 2020-2-1027), Science Foundation of Peking University Cancer Hospital (No. BJCH2024CZ09), Peking University Medicine Sailing Program for Young Scholars’ Scientific & Technological Innovation (No. BMU2023YFJHPY022), Clinical Research Fund For Distinguished Youth Scholars of Peking University Cancer Hospital (No.QNJJ202419), and Science Foundation of Peking University Cancer Hospital (No. ZY202506).

Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The datasets analyzed during the current study are available from the corresponding author upon reasonable request.

Appendix

References

Bray

Laversanne

Sung

, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca Cancer J Clin. 2024;74:229-263. doi:10.3322/caac.21834

van Gijn

Marijnen

Nagtegaal

, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12:575-582. doi:10.1016/S1470-2045(11)70097-3

Maas

Nelemans

Valentini

, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010;11:835-844. doi:10.1016/S1470-2045(10)70172-8

Park

You

Agarwal

, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol. 2012;30:1770-1776. doi:10.1200/JCO.2011.39.7901

Fokas

Glynne-Jones

Appelt

, et al. Outcome measures in multimodal rectal cancer trials. Lancet Oncol. 2020;21:e252-e264. doi:10.1016/S1470-2045(20)30024-3

Dossa

Acuna

Rickles

, et al. Association between adjuvant chemotherapy and overall survival in patients with rectal cancer and pathological complete response after neoadjuvant chemotherapy and resection. JAMA Oncol. 2018;4:930-937. doi:10.1001/jamaoncol.2017.5597

Glynne-Jones

Wyrwicz

Tiret

, et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv263. doi:10.1093/annonc/mdy161

Al-Sukhni

Milot

Fruitman

, et al. Diagnostic accuracy of MRI for assessment of T category, lymph node metastases, and circumferential resection margin involvement in patients with rectal cancer: a systematic review and meta-analysis. Ann Surg Oncol. 2012;19:2212-2223. doi:10.1245/s10434-011-2210-5

Bahadoer

Dijkstra

van Etten

, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22:29-42. doi:10.1016/S1470-2045(20)30555-6

10.

Fokas

Allgauer

Polat

, et al. Randomized phase II trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO/ARO/AIO-12. J Clin Oncol. 2019;37:3212-3222. doi:10.1200/JCO.19.00308

11.

Choi

Kim

Chie

Gim

Kang

. A meta-analysis of the impact of neutrophil-to-lymphocyte ratio on treatment outcomes after radiotherapy for solid tumors. Medicine (Baltim). 2019;98:e15369. doi:10.1097/MD.0000000000015369

12.

Portale

Bartolotta

Azzolina

Gregori

Fiscon

. Prognostic role of platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte, and lymphocyte-to-monocyte ratio in operated rectal cancer patients: systematic review and meta-analysis. Langenbecks Arch Surg. 2023;408:85. doi:10.1007/s00423-023-02786-8

13.

Lee

Kim

Park

. Meta-analysis on the neutrophil-lymphocyte ratio in rectal cancer treated with preoperative chemoradiotherapy: prognostic value of pre- and post-chemoradiotherapy neutrophil-lymphocyte ratio. Front Oncol. 2022;12:778607. doi:10.3389/fonc.2022.778607

14.

von Elm

Altman

Egger

, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147:573-577. doi:10.7326/0003-4819-147-8-200710160-00010

15.

Beets-Tan

Lambregts

Maas

, et al. Magnetic resonance imaging for clinical management of rectal cancer: updated recommendations from the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur Radiol. 2018;28:1465-1475. doi:10.1007/s00330-017-5026-2

16.

Zhang

Song

Geng

, et al. Patterns of failure and implications for clinical target volume definition of locally advanced T4b rectal cancer identified with magnetic resonance imaging and treated using neoadjuvant chemoradiotherapy and surgery. Radiother Oncol. 2021;161:132-139. doi:10.1016/j.radonc.2021.06.017

17.

Parfitt

Driman

. The total mesorectal excision specimen for rectal cancer: a review of its pathological assessment. J Clin Pathol. 2007;60:849-855. doi:10.1007/10.1136/jcp.2006.043802

18.

Camp

Dolled-Filhart

Rimm

. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004;10:7252-7259. doi:10.1158/1078-0432.CCR-04-0713

19.

Jiang

Liu

, et al. Nomogram to predict distant metastasis probability for pathological complete response rectal cancer patients after neoadjuvant chemoradiotherapy. Cancer Manag Res. 2021;13:4751-4761. doi:10.2147/CMAR.S313113

20.

Fan

Xiao

, et al. Patterns of recurrence in patients achieving pathologic complete response after neoadjuvant chemoradiotherapy for rectal cancer. J Cancer Res Clin Oncol. 2017;143:1461-1467. doi:10.1007/s00432-017-2383-9

21.

Polanco

Mokdad

Zhu

Choti

Huerta

. Association of adjuvant chemotherapy with overall survival in patients with rectal cancer and pathologic complete response following neoadjuvant chemotherapy and resection. JAMA Oncol. 2018;4:938-943. doi:10.1001/jamaoncol.2018.0231

22.

Ding

, et al. Association between adjuvant chemotherapy and survival in patients with rectal cancer and pathological complete response after neoadjuvant chemoradiotherapy and resection. Br J Cancer. 2020;123:1244-1252. doi:10.1038/s41416-020-0989-1

23.

Zhang

Cai

Peng

. Adjuvant chemotherapy for rectal cancer with complete pathological response (pCR) may not be necessary: a pooled analysis of 5491 patients. Cancer Cell Int. 2019;19:127. doi:10.1186/s12935-019-0851-9

24.

Chen

Tang

, et al. The prognostic value of MRI-detected extramural vascular invasion (mrEMVI) for rectal cancer patients treated with neoadjuvant therapy: a meta-analysis. Eur Radiol. 2021;31:8827-8837. doi:10.1007/s00330-021-07981-z

25.

Zhang

Wang

, et al. MRI of extramural venous invasion in locally advanced rectal cancer: relationship to tumor recurrence and overall survival. Radiology. 2018;289:677-685. doi:10.1148/radiol.2018172889

26.

Taylor

Quirke

Heald

, et al. Preoperative magnetic resonance imaging assessment of circumferential resection margin predicts disease-free survival and local recurrence: 5-year follow-up results of the MERCURY study. J Clin Oncol. 2014;32:34-43. doi:10.1200/JCO.2012.45.3258

27.

Hodges

Battersby

Rao

Brown

TRIGGER Study Group . Relationship between baseline rectal tumor length and magnetic resonance tumor regression grade response to chemoradiotherapy: a subanalysis of the TRIGGER feasibility study. Ann Surg Oncol. 2023;30:4729-4735. doi:10.1245/s10434-022-11914-5

28.

Chen

Guo

, et al. Pretreatment tumor thickness as a predictor of pathologic complete response to neoadjuvant chemoradiation therapy for stage II/III rectal adenocarcinoma. Am J Clin Oncol. 2018;41:601-606. doi:10.1097/COC.0000000000000333

29.

Grivennikov

Greten

Karin

. Immunity, inflammation, and cancer. Cell. 2010;140:883-899. doi:10.1016/j.cell.2010.01.025

30.

Powell

Huttenlocher

. Neutrophils in the tumor microenvironment. Trends Immunol. 2016;37:41-52. doi:10.1016/j.it.2015.11.008

31.

Diefenhardt

Hofheinz

Martin

, et al. Leukocytosis and neutrophilia as independent prognostic immunological biomarkers for clinical outcome in the CAO/ARO/AIO-04 randomized phase 3 rectal cancer trial. Int J Cancer. 2019;145:2282-2291. doi:10.1002/ijc.32274

32.

Bai

Zhou

Xiong

Lan

Wang

. Tumor-infiltrating lymphocytes in colorectal cancer: the fundamental indication and application on immunotherapy. Front Immunol. 2021;12:808964. doi:10.3389/fimmu.2021.808964

33.

Hamid

Davis

Trejo-Avila

Igwe

Garcia-Marín

. Prognostic and predictive value of neutrophil-to-lymphocyte ratio after curative rectal cancer resection: a systematic review and meta-analysis. Surg Oncol. 2021;37:101556. doi:10.1016/j.suronc.2021.101556

34.

Shen

Zhang

Liang

, et al. Baseline neutrophil-lymphocyte ratio (>/=2.8) as a prognostic factor for patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation. Radiat Oncol. 2014;9:295. doi:10.1186/s13014-014-0295-2

Pretreatment MRI Parameters and Neutrophil-to-Lymphocyte Ratio Could Predict the Long-Term Prognosis of Locally Advanced Rectal Cancer Patients With Pathological Complete Response after Neoadjuvant Chemoradiotherapy

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Materials and Methods

Patients Selection

MRI Assessment

Neoadjuvant Treatment

Surgical and Postoperative Treatment

Follow-up

Statistical Analysis

Results

Patient Characteristics

Outcomes in Patients with pCR

Association Between MRI Parameter and Survival Outcomes

Association Between NLR Level with Survival Outcomes

Univariate and Multivariate Analysis for Survival Outcomes

Risk Stratification in Patients with pCR

Discussion

Conclusion

Footnotes

Acknowledgments

ORCID iD

Statements and Declarations

Author Contributions

Funding

Conflicting Interests

Data Availability Statement

Appendix

References