Retrospective Study Open Access
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 28, 2025; 31(8): 99036
Published online Feb 28, 2025. doi: 10.3748/wjg.v31.i8.99036
Beyond the tumor region: Peritumoral radiomics enhances prognostic accuracy in locally advanced rectal cancer
Zhi-Ying Liang, Hui Yang, Hao-Jiang Li, Hui Xie, Chun-Yan Cui, Wei-Jing Zhang, Chao Luo, Pei-Qiang Cai, Xiao-Feng Lin, Kun-Feng Liu, Li-Zhi Liu, Bi-Yun Chen, Department of Radiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong Province, China
Mao-Li Yu, Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Mao-Li Yu, West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
Lang Xiong, Department of Medical Imaging, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
ORCID number: Zhi-Ying Liang (0000-0002-8311-5393); Hao-Jiang Li (0000-0001-5854-3989); Li-Zhi Liu (0000-0002-3977-0518); Bi-Yun Chen (0009-0002-6271-7886).
Co-first authors: Zhi-Ying Liang and Mao-Li Yu.
Co-corresponding authors: Li-Zhi Liu and Bi-Yun Chen.
Author contributions: Chen BY, Li HJ and Liang ZY contributed to conceptualization; Li HJ, Xie H contributed to methodology; Yang H, Yu ML, Xie H, Cui CY, Zhang WJ, Luo C, Cai PQ, Lin XF, Liu KF, Xiong L and Chen BY contributed to data curation and investigation; Li HJ, Liang ZY contributed to formal analysis and software; Chen BY, Liang ZY contributed to writing original draft preparation; Liu LZ contributed to resources and supervision; All authors contributed to writing, review, editing, critically reviewed and provided final approval of the manuscript, were responsible for the decision to submit the manuscript for publication.
Institutional review board statement: This investigation was approved by the Institutional Ethics Committee of the Sun Yat-sen University Cancer Center, approval No. B2021-157-Y03.
Informed consent statement: The requirement for informed consent was waived due to the study’s retrospective nature.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Bi-Yun Chen, PhD, Doctor, Department of Radiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Dong Road, Guangzhou 510060, Guangdong Province, China. chenby2@sysucc.org.cn
Received: July 12, 2024
Revised: October 9, 2024
Accepted: November 5, 2024
Published online: February 28, 2025
Processing time: 195 Days and 0.1 Hours

Abstract
BACKGROUND

The peritumoral region possesses attributes that promote cancer growth and progression. However, the potential prognostic biomarkers in this region remain relatively underexplored in radiomics.

AIM

To investigate the prognostic value and importance of peritumoral radiomics in locally advanced rectal cancer (LARC).

METHODS

This retrospective study included 409 patients with biopsy-confirmed LARC treated with neoadjuvant chemoradiotherapy and surgically. Patients were divided into training (n = 273) and validation (n = 136) sets. Based on intratumoral and peritumoral radiomic features extracted from pretreatment axial high-resolution small-field-of-view T2-weighted images, multivariate Cox models for progression-free survival (PFS) prediction were developed with or without clinicoradiological features and evaluated with Harrell’s concordance index (C-index), calibration curve, and decision curve analyses. Risk stratification, Kaplan-Meier analysis, and permutation feature importance analysis were performed.

RESULTS

The comprehensive integrated clinical-radiological-omics model (ModelICRO) integrating seven peritumoral, three intratumoral, and four clinicoradiological features achieved the highest C-indices (0.836 and 0.801 in the training and validation sets, respectively). This model showed robust calibration and better clinical net benefits, effectively distinguished high-risk from low-risk patients (PFS: 97.2% vs 67.6% and 95.4% vs 64.8% in the training and validation sets, respectively; both P < 0.001). Three most influential predictors in the comprehensive ModelICRO were, in order, a peritumoral, an intratumoral, and a clinicoradiological feature. Notably, the peritumoral model outperformed the intratumoral model (C-index: 0.754 vs 0.670; P = 0.015); peritumoral features significantly enhanced the performance of models based on clinicoradiological or intratumoral features or their combinations.

CONCLUSION

Peritumoral radiomics holds greater prognostic value than intratumoral radiomics for predicting PFS in LARC. The comprehensive model may serve as a reliable tool for better stratification and management postoperatively.

Key Words: Rectal cancer; Peritumoral radiomics; Intratumoral radiomics; Prognosis analysis; Variable importance analysis; Tumor microenvironment

Core Tip: This study highlights the superior prognostic value of peritumoral radiomics over intratumoral radiomics in predicting progression-free survival in patients with locally advanced rectal cancer. By integrating peritumoral, intratumoral, and clinicopathological features, our comprehensive model achieved high predictive accuracy, significantly improving risk stratification for disease progression. Notably, peritumoral features emerged as the most influential predictors of progression-free survival among the features analyzed. These findings underscore the importance of focusing on peritumoral radiomic characteristics in prognostic assessments. Additionally, we developed a nomogram incorporating these features to facilitate personalized treatment strategies and clinical decision-making in locally advanced rectal cancer.



INTRODUCTION

Rectal cancer presents a major global health concern, with GLOBOCAN 2020 data indicating approximately 0.7 million new diagnoses and 0.34 million deaths worldwide[1]. Approximately 70% of these new cases are classified as locally advanced rectal cancer (LARC); (T3-T4 Nany or Tany N1-N2)[2]. The primary treatment for LARC involves neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME)[3-5], often supplemented with adjuvant chemotherapy to reduce the risk of distant metastasis[6]. These treatment advancements have reduced local recurrence and distant metastasis to approximately 5%-10%[7-9] and 25%-40%[10,11], respectively; however, achieving long-term disease control remains challenging. Progression-free survival (PFS) is a comprehensive indicator that considers multiple disease events-including recurrence, distant metastasis, and death-to evaluate a patient’s condition after the initial treatment, and accurate PFS prediction is crucial for enabling more personalized and risk-adjusted postoperative treatments to improve prognosis.

Pelvic magnetic resonance imaging (MRI) is routinely used in clinical practice and is the preferred modality for diagnosing and staging rectal cancer[12,13]. However, the pathological tumor node metastasis staging system often faces limitations in patient stratification for postoperative treatment selection owing to the clinical heterogeneity observed in patients with tumors of the same stage, resulting in varied treatment outcomes. This highlights the need for improved patient stratification that considers additional characteristics. In recent years, radiomics has become a significant research area, transforming MRI information into high-dimensional data that enable deeper insights into disease characteristics[14,15].

The peritumoral region, also known as the tumor microenvironment, has distinctive physical and immune attributes that promote cancer growth and progression[16,17]. For example, transforming growth factor beta within the peritumoral region can affect the tumor growth and metastatic potential[18] by modulating the activity and infiltration of immune cells, inflammatory cells, and cancer-associated fibroblasts. In rectal cancer, the peritumoral adipose tissue promotes cancer progression and metastasis[19-21]. In fact, previous studies have demonstrated that mesorectal fat contains important prognostic information[22-24] and radiomic features that can predict local and distant recurrence in patients with LARC[23]. However, the potential prognostic biomarkers in the peritumoral region have remained relatively underexplored in radiomics[25-27], with the focus has traditionally been on the intratumoral region[28-31]. Consequently, the potential value of peritumoral radiomics in predicting PFS has not been thoroughly investigated.

Therefore, the present study aimed to examine the value of peritumoral radiomics from baseline MRI data, both independently and in combination with intratumoral and clinicoradiological features, in predicting PFS in patients with LARC. We also constructed a comprehensive nomogram with risk stratification to facilitate postoperative treatment decisions.

MATERIALS AND METHODS
Patients and clinicoradiological variables

This retrospective study was conducted at a tertiary academic hospital in China. The Institutional Ethics Committee approved this study and waived the requirement for informed consent. To establish the study database, we searched the electronic medical record system for patients with a new biopsy-confirmed diagnosis of LARC who underwent NCRT and TME between January 2015 and July 2018, which yielded 571 patients. Patients were excluded based on the following criteria: Distant metastasis (103 patients); Synchronous primary tumor, rectosigmoid junction cancer, or tumor invading the anal canal (19 patients); And incomplete pretreatment MRI or insufficient image quality (40 patients). The final set included 409 patients who were randomly divided into training and validation sets at a ratio of 2:1. Figure 1 shows the flowchart of patient inclusion and exclusion criteria.

Figure 1
Figure 1 Patient-selection flow diagram. MRI: Magnetic resonance imaging; NCRT: Neoadjuvant chemoradiotherapy; TME: Total mesorectal excision.

Patient characteristics were extracted from the electronic medical records, encompassing age, sex, body mass index (BMI), NCRT regimen, adjuvant chemotherapy, clinical T stage, clinical N stage, clinical overall stage, along with hematological and biochemical parameters [lymphocyte count, lymphocyte percentage, carcinoembryonic antigen (CEA) level, and carbohydrate antigen-199 level]. Pathological evaluations performed by experienced gastrointestinal cancer pathologists were also documented, including immune response in hematoxylin-eosin stained biopsy sections at diagnosis (available for 178 patients) and postoperative pathological T (ypT) stage, pathological N (ypN) stage, and tumor regression grade (TRG)[32] from surgical pathology specimens after NCRT.

Treatments, follow-up, and clinical endpoints

All patients included in this study underwent NCRT followed by TME. Based on the oncologist’s judgement, those with high-risk pathological factors also received postoperative adjuvant chemotherapy. The NCRT regimen is detailed in the Supplementary Information.

Patients were followed up every 3 months in the first 3 years, every 6 months in the subsequent 2 years, and once a year thereafter. Follow-up visits included clinical examination (especially digital rectal examination), hematologic examination with CEA level measurement, abdominal sonography, pelvic MRI, and colonoscopy when necessary.

The endpoint of this study was PFS, which was calculated from the date of treatment initiation to the date of any local recurrence, distant metastasis, or death from any cause.

MRI protocol and image assessment

Patients underwent pelvic MRI within 2 weeks before NCRT with either 1.5-T (Siemens Aera, United States) or 3.0-T MRI scanners (Trio Tim, Siemens Healthcare; Achieva 781-278, Philips Healthcare; Discovery 750/750 W/SIGNA Pioneer, GE Healthcare). Conventional MRI examinations for rectal cancer included axial, coronal, and sagittal T2-weighted imaging (T2WI) sequences followed by diffusion-weighted and contrast-enhanced sequences. The detailed MRI protocols are listed in Supplementary Table 1.

Two radiologists (radiologists 1 and 2) with 15 and 7 years of experience in rectal cancer imaging, respectively-who were blinded to histopathological results retrospectively independently reviewed the MRI data. They mainly evaluated the following: T and N stages (according to the 8th edition of the American Joint Committee on Cancer staging manual)[33], circumferential tumor extent (proportion of the circumferential diameter occupied by the tumor invading the maximal extent of the rectal wall), tumor location (distance from the tumor to the anorectal junction), mesorectal fascia (MRF) status (tumor-MRF distance < 1 mm was defined as positive), and extramural venous invasion (EMVI) according to EMVI scoring system by Smith et al[34]. To evaluate interobserver agreement for radiologist-assessed imaging features, we calculated the intra-class correlation coefficient (ICC) for continuous variables and Cohen’s kappa for categorical variables in 40 randomly selected patients.

Image segmentation

Figure 2 shows our radiomics workflow. Using the open-source software ITK-SNAP (version 3.8.0, http://www.itksnap.org), two radiologists (radiologists 3 and 4) with 4 and 3 years of experience in rectal cancer imaging-manually delineated all regions of interests (ROIs) on axial high-resolution small-field-of-view T2WI slices for three-dimensional segmentation (Figure 3). On each MRI slice, the intratumoral ROI was meticulously delineated to cover the entire rectal tumor, whereas the tube ROI was drawn to encompass both the rectal tube area and tumor. Subsequently, the peritumoral ROI was automatically generated as an overlapping region resulting from a 5-mm dilation of both the intratumoral and tube ROIs. For a subset of 57 randomly selected patients, these ROIs were independently outlined by both radiologists and the dice similarity coefficient was used to assess the accuracy and agreement of their delineations. The remaining 352 patients were randomly divided for individual ROI delineations. Any disagreements in delineation were resolved through consensus-based discussion.

Figure 2
Figure 2 Radiomics workflow. ICC: Intra-class correlation coefficient; LASSO: Least absolute shrinkage and selection operator; MSRS: Maximum selected rank statistic; PCC: Pearson’s correlation coefficient; ROC: Receiver operating characteristic; sFOV: Small-field-of-view; T2WI: T2-weighted imaging.
Figure 3
Figure 3 Example of intratumoral and peritumoral segmentation. The intratumoral region of interest (ROI) (left, red) is manually delineated, while the peritumoral ROI (right, blue) is automatically generated. On axial high-resolution small-field-of-view T2-weighted imaging slices, the intratumoral ROI is meticulously delineated to cover the entire rectal tumor, whereas the tube ROI is drawn to encompass both the rectal tube area and tumor. Subsequently, the peritumoral ROI, representing the area surrounding the tumor, is automatically generated by the overlapping region resulting from a 5-mm dilation of both the intratumoral ROI and tube ROI.
Radiomics feature extraction and selection

Following image segmentation, we implemented image normalization by scaling intensity values between 0 and 100. This step was crucial in minimizing variations in image intensity that could arise from the use of different scanners and scanning parameters. To ensure uniformity across all images, they were resampled to a consistent resolution of 1 mm × 1 mm × 1 mm. Subsequently, a total of 1470 radiomic features for each ROI were automatically extracted using the PyRadiomics package in Python[35], including 14 shape, 18 first-order intensity statistics, 73 texture, 91 gradient, 91 exponential, 91 logarithmic, 91 square, 91 square root, 182 log, and 728 wavelet features.

We employed a multistep process to select radiomic features associated with PFS in LARC. Initially, we randomly selected 59 cases to filter features with good interobserver reproducibility (ICC ≥ 0.80). Next, we removed highly correlated features (Pearson’s correlation coefficient ≥ 0.75) and conducted a univariate Cox analysis and calculated the P value to identify features significantly associated with PFS (P < 0.05) in the training set. Notably, only a few intertumoral and peritumoral features were retained. We converted the remaining continuous features into dichotomous variables using Pearson’s correlation coefficient. This conversion was based on the optimal cutoff values determined using receiver operating characteristic curve and maximum selected rank statistic methods. Subsequently, we re-evaluated these dichotomous features using univariate analysis. Finally, we applied the least absolute shrinkage and selection operator (LASSO) with 10-fold cross-validation followed by bidirectional stepwise analysis to refine the feature selection, using the minimal λ as the optimal penalty in LASSO to automatically determine the final feature set.

Radiomics model building, validation, and application for risk stratification

We built a series of multivariate Cox models for PFS in the training set, each incorporating the following different types of features: Only clinicoradiological, only radiomic (intratumoral or peritumoral), and combined models. Significant clinicoradiological factors affecting PFS were identified using univariate and multivariate analyses.

The model performance was evaluated in terms of discrimination [Harrell’s concordance index (C-index)], calibration, and net clinical benefit. The C-index, which we considered good at approximately 0.7, was used to measure the agreement between the predicted and actual PFS rates. Similarly, calibration curves were plotted to compare the predicted and actual survival, utilizing 1000 times of iterative resampling. Furthermore, decision curve analysis (DCA) evaluated the clinical utility of different models by calculating the net benefits at different threshold probabilities. Additionally, permutation feature importance analysis was used to identify the most influential predictors in the model with the highest C-index. To further investigate the clinical relevance of the identified critical radiomic feature, we evaluated the difference in immune response across groups stratified by this feature within a subset of 178 patients with immune response assessments. Additionally, we analyzed distribution differences in lymphocyte count and percentage both within this subset and across the entire cohort of 409 patients. Finally, patients were assigned risk scores based on prognostic models and stratified into high- or low-risk groups using a cutoff score of zero, with scores above zero indicating high risk and below zero indicating low risk.

Statistical analysis

We analyzed survival differences between the high- and low-risk groups using Kaplan-Meier analysis and log-rank tests. Additionally, the χ2 and Mann-Whitney U tests were used to compare distribution differences between the training and validation sets and between groups of the most important predictor. All statistical analyses were performed using R software (version 3.2.5), with the caret package for Pearson’s correlation analysis, the survival and survminer packages for Kaplan-Meier analysis, and the glmnet package for LASSO. A two-tailed P value < 0.05 indicated statistical significance.

RESULTS
Patient characteristics

The final study sample included a total of 409 patients (276 men and 133 women; median age: 56 years; range: 24-81 years; interquartile range: 49-64 years). The clinicoradiological characteristics of the training (n = 273) and validation (n = 136) sets are summarized in Table 1. The Kappa values for T stage, N stage, circumferential tumor extent, MRF status, and EMVI were 0.778, 0.706, 0.760, 0.714, and 0.783, respectively, while the ICC for tumor location was 0.920. All coefficients indicated good interobserver consistency, and there were no significant differences in clinicoradiological variables between the training and validation sets (all P > 0.05), except for in the ypN stage (P = 0.027). During the follow-up period, 46 (16.8%) and 23 (16.9%) patients in the training and validation sets, respectively, experienced disease progression.

Table 1 Clinicoradiological characteristics of patients, n (%).
Variable
Total (n = 409)
Training (n = 273)
Validation (n = 136)
1P value
Age (years), median (IQR)56 (49-64)58 (49-64)56 (47-64)0.219
Sex> 0.999
Male276 (67.5)184 (67.4)92 (67.6)
Female133 (32.5)89 (32.6)44 (32.4)
BMI0.351
< 18.545 (11.0)31 (11.4)14 (10.3)
18.5-24178 (43.5)112 (41.0)66 (48.5)
> 24186 (45.5)130 (47.6)56 (41.2)
CEA level (ng/mL)0.625
< 5222 (54.3)151 (55.3)71 (52.2)
≥ 5187 (45.7)122 (44.7)65 (47.8)
CA199 level (U/mL)0.695
< 35282 (68.9)186 (68.1)96 (70.6)
≥ 35127 (31.1)87 (31.9)40 (29.4)
NCRT regimen0.952
Capecitabine + RT173 (42.3)114 (41.8)59 (43.4)
CapeOx + RT230 (56.2)155 (56.8)75 (55.1)
Other6 (1.5)4 (1.5)2 (1.5)
Adjuvant chemotherapy> 0.999
No104 (25.4)69 (25.3)35 (25.7)
Yes305 (74.6)204 (74.7)101 (74.3)
Clinical T stage0.914
cT229 (7.1)20 (7.3)9 (6.6)
cT3253 (61.9)167 (61.2)86 (63.2)
cT4127 (31.1)86 (31.5)41 (30.1)
Clinical N stage0.446
cN065 (15.9)45 (16.5)20 (14.7)
cN1192 (46.9)125 (45.8)67 (49.3)
cN299 (24.2)63 (23.1)36 (26.5)
cNx53 (13.0)40 (14.7)13 (9.6)
Overall clinical stage0.643
II65 (15.9)45 (16.5)20 (14.7)
III344 (84.1)228 (83.5)116 (85.3)
Tumor location (cm)0.950
≤ 5166 (40.6)111 (40.7)55 (40.4)
5.1-10221 (54.0)148 (54.2)73 (53.7)
> 1022 (5.4)14 (5.1)8 (5.9)
Circumferential tumor extent0.062
1/4-2/445 (11.0)37 (13.6)8 (5.9)
3/4103 (25.2)68 (24.9)35 (25.7)
4/4261 (63.8)168 (61.5)93 (68.4)
MRF status0.781
Negative187 (45.7)123 (45.1)64 (47.1)
Positive222 (54.3)150 (54.9)72 (52.9)
EMVI0.070
Negative274 (67.0)191 (70.0)83 (61.0)
Positive135 (33.0)82 (30.0)53 (39.0)
ypT stage0.644
ypT 0-2228 (55.7)150 (54.9)78 (57.4)
ypT 3-4181 (44.3)123 (45.1)58 (42.6)
ypN stage0.027a
ypN0331 (80.9)231 (84.6)100 (73.5)
ypN167 (16.4)36 (13.2)31 (22.8)
ypN211 (2.7)6 (2.2)5 (3.7)
TRG0.246
1-2218 (53.3)140 (51.3)78 (57.4)
3-5191 (46.7)133 (48.7)58 (42.6)
Clinicoradiological models

Table 2 summarizes the results of univariate and multivariate analyses. In the training set, BMI, MRF status, ypT stage, ypN stage, and TRG were significantly associated with PFS (all P < 0.05). Additionally, a BMI of 18.5-24 or > 24 was a significant independent predictor of PFS compared with a BMI < 18.5 [both hazard ratio (HR) < 0.50, P < 0.05]. Similarly, compared with ypN stage 0, ypN stage of 1 or 2 was a significant negative independent predictor of PFS (both HR > 2; P < 0.05).

Table 2 Univariate and multivariate analyses of clinicoradiological characteristics in the training set.
VariableTrainingUnivariate analysis
Multivariate analysis
3-year PFS (%)
1P value
HR (95%CI)2
2P value
Age (years)2730.518
Sex0.424
Male18486.23
Female8983.09
BMI0.013a
< 18.53167.591 (Ref.)
18.5-2411286.390.44 (0.20-0.98)0.045a
> 2413088.400.40 (0.18-0.91)0.029a
CEA level (ng/mL)0.312
< 515187.38
≥ 512282.51
CA199 level (U/mL)0.112
< 3518687.54
≥ 358780.19
NCRT regimen
Capecitabine + RT11483.320.667
CapeOx + RT15586.89
Other475.00
Adjuvant chemotherapy0.936
No6985.31
Yes20485.19
Clinical T stage0.698
cT22090.00
cT316783.10
cT48688.24
Clinical N stage0.776
cN04588.72
cN112584.66
cN26384.04
cNx4084.71
Overall clinical stage0.323
II4588.72
III22884.52
Tumor location (cm)0.535
≤ 511185.40
5.1-1014884.36
> 101492.86
Circumferential tumor extent0.810
1/4-2/43786.15
3/46886.74
4/416884.37
MRF status0.011a
Negative12390.121 (Ref.)
Positive15081.191.71 (0.86-3.42)0.129a
EMVI0.667
Negative19185.75
Positive8284.00
ypT stage0.005a
ypT0-215089.881 (Ref.)
ypT3-412379.531.25 (0.59-2.63)0.561
ypN stage< 0.001a
ypN023188.621 (Ref.)
ypN13669.442.45 (1.18-5.07)0.016a
ypN2650.003.88 (1.28-11.79)0.017a
TRG0.006a
1-214089.871 (Ref.)
3-513380.301.71 (0.83–3.53)0.145

We constructed two clinicoradiological models as base models for considering the use of postoperative adjuvant chemotherapy in clinical practice: Model based on the ypT stage and ypN stage (ModelypTN), and model based on BMI, ypN stage, TRG, and MRF status (Modelclin). Notably, Modelclin exhibited higher C-indices than ModelypTN in both the training (0.718 vs 0.670; P = 0.003) and validation sets (0.733 vs 0.670; P = 0.009), indicating better predictive accuracy for PFS (Table 3 and Supplementary Table 2).

Table 3 C-indices of prognostic models for progression free survival prediction in locally advanced rectal cancer.
ModelTraining set
Validation set
C-index (95%CI)
1P value
2P value
C-index (95%CI)
1P value
2P value
Clinicoradiological model
YpTN0.670 (0.593-0.748)Ref.0.0030.670 (0.558-0.781)Ref.0.009
Clin0.718 (0.639-0.797)0.003Ref.0.733 (0.634-0.833)0.009Ref.
Radiomics model
Intra0.670 (0.603-0.736)Ref.0.2970.669 (0.574-0.764)Ref.0.310
Peri0.754 (0.680-0.827)0.0150.1940.703 (0.597-0.809)0.3160.839
Omics0.797 (0.741-0.853)< 0.001< 0.0010.758 (0.670-0.847)< 0.0010.101
Clinicoradiological-omics model
Clin + intra0.764 (0.697-0.832)Ref.< 0.0010.765 (0.677-0.853)Ref.0.030
Clin + peri0.804 (0.740-0.868)0.044< 0.0010.778 (0.685-0.871)0.4320.010
ICRO0.836 (0.787-0.886)< 0.001< 0.0010.801 (0.722-0.879)0.001< 0.001
Radiomics models

We found that dice similarity coefficient values for the tumor and tube ROIs were 0.74 and 0.83, respectively, showing good agreement between the two radiologists regarding their delineations. Figure 2 shows the process of the selection of radiomic features. Of the 2940 radiomic features extracted per patient, 1526 features (757 intratumoral and 769 peritumoral) showed high reproducibility (ICC ≥ 0.80) (Supplementary Figure 1). After removing features with Pearson’s correlation coefficient ≥ 0.75, 64 intratumoral and 65 peritumoral features remained. Following univariate analysis and stepwise LASSO-Cox regression (Supplementary Figure 2), three intratumoral and seven peritumoral features were ultimately selected to construct the radiomics models: Intratumoral (Modelintra), peritumoral (Modelperi), and combined intraperitumoral (Modelomics). Notably, Modelperi outperformed Modelintra in predicting PFS (C-index: 0.754 vs 0.670 in the training set, P = 0.015; and 0.703 vs 0.669 in the validation set, P = 0.316). Furthermore, Modelomics, which combines both intratumoral and peritumoral radiomic features, demonstrated the highest discriminative ability for predicting PFS, significantly outperforming Modelintra (C-index: 0.797 vs 0.670 in the training set, P < 0.001; 0.758 vs 0.669 in the validation set, P < 0.001) (Table 3 and Supplementary Table 2).

Combined clinicoradiological radiomics models

To further validate the added value of peritumoral radiomic features in predicting PFS, we incorporated these features into Modelclin and Modelclin + intra, constructing the new models Modelclin + peri and ModelICRO (integrated clinical-radiological-omics model), respectively. Modelclin + peri significantly improved the C-index, increasing from 0.718 to 0.804 in the training cohort (P < 0.001) and from 0.733 to 0.778 in the validation cohort (P = 0.01). Additionally, ModelICRO demonstrated the highest discriminative capacity, significantly outperforming Modelclin + intra in the training cohort (C-index: 0.836 vs 0.764; P < 0.001) and in the validation cohort (C-index: 0.801 vs 0.765; P = 0.001) (Table 3 and Supplementary Table 2).

Model performance evaluation and permutation feature importance

Table 3 summarizes C-indices for all models predicting PFS, whereas Supplementary Table 2 shows comparisons of C-indices between models, providing a detailed overview of models’ discriminative performances. The variable parameters of all models are detailed in Table 4 and Supplementary Table 3. Notably, the Modelclin, Modelomics, and ModelICRO achieved the highest C-indices within their respective groups.

Table 4 Variable parameters and permutation feature importance of Model based on integrated clinical-radiological-omics.
Variable
β
HR (95%CI)
P value
Relative importance weight 1
Relative importance weight 2
Intratumoral radiomic score10.9362.55 (1.43-4.54)0.0010.3510
Log.sigma50.mm.3D GLDM DependenceVariance1.2670.28 (0.10-0.79)0.0160.6047
Wavelet.HHL_firstorder_RootMeanSquared0.6211.86 (0.95-3.64)0.0690.0388
Wavelet.LHL_GLSZM_LargeAreaLowGrayLevelEmphasis1.0240.36 (0.12-1.04)0.0590.9806
Peritumoral radiomic score10.9482.58 (1.90-3.51)< 0.0011.0000
Wavelet.LLH_GLCM_ClusterShade0.0071.01 (1.00-1.01)0.0080.5858
Wavelet.LLL_GLSZM_LargeAreaLowGrayLevelEmphasis0.0161.02 (1.01-1.03)0.0020.1473
Log.sigma30.mm.3D_firstorder_90Percentile0.6541.92 (0.93-3.99)0.0800.5038
Wavelet.LHL_GLCM_Correlation0.8780.42 (0.22-0.78)0.0070.0226
Wavelet.HLH_firstorder_Kurtosis0.8890.41 (0.22-0.77)0.0050.3817
Wavelet.HHH_NGTDM_Contrast0.7742.17 (1.02-4.62)0.0450.0430
Square_GLDM_DependenceVariance0.8652.37 (1.21-4.65)0.0121.0000
BMI0.09430.5510
< 18.51 (Ref.)
18.5-240.3370.71 (0.32-1.62)0.418
> 240.6730.51 (0.22-1.17)0.111
MRF status-0.0867-0.3670
Negative1 (Ref.)
Positive0.3321.39 (0.69-2.82)0.355
ypN stage-0.0510-0.0208
ypN01 (Ref.)
ypN10.8572.36 (1.14-4.87)0.021
ypN20.9582.61 (0.85-7.97)0.093
TRG0.10190.8614
1-21 (Ref.)
3-50.6912.00 (1.03-3.87)0.040

Furthermore, the calibration curves indicated that the ModelICRO more accurately predicted the 3-year PFS than the clinicoradiological (Modelclin) and intraperitumoral radiomics (Modelomics) models, as evidenced by better agreement with the observed PFS in both the training and validation sets (Figure 4A and B, Supplementary Figure 3).

Figure 4
Figure 4 Calibration and decision curves of the prognostic models. Calibration curves of integrated clinical-radiological-omics model (ModelICRO) showing a robust calibration between the predicted 3-year progression-free survival (X-axis) and the actual 3-year progression-free survival (Y-axis). A: In the training; B: Validation sets; Decision curves of model based on the pathological T stage and pathological N stage (grey line), model based on body mass index, pathological N stage, tumor regression grade, and mesorectal fascia status (Modelclin) (yellow line), Modelclin+peri (orange line), and ModelICRO (blue line) showing the net benefit across a range of threshold probabilities; C: In the training; D: Validation sets. ModelICRO shows the highest net benefit across most threshold probabilities. ICRO: Integrated clinical-radiological-omics; Clin: Clinicoradiological; PFS: Progression-free survival; Intra: Intratumoral; peri: Peritumoral; ypTN: Pathological T and N stages after neoadjuvant chemoradiotherapy.

DCA demonstrated that the inclusion of peritumoral radiomic features improved net benefit for Modelclin + peri, Modelomics, and ModelICRO compared to Modelclin, Modelintra, and Modelclin + intra (Figure 4C and D, Supplementary Figure 4). Both Modelclin + peri and ModelICRO showed greater clinical utility than the conventional pathological staging model (ModelypTN) and the enhanced clinicoradiological model (Modelclin). ModelICRO provided the highest net benefit up to a risk threshold of 0.31 in the training set and 0.20 in the validation set. However, since the majority of patients had risks below these thresholds-even those with high-risk factors, such as positive MRF status, had a progression risk of less than 0.2 (Table 2) ModelICRO remained the optimal predictive model for most clinical scenarios.

We used permutation feature importance analysis within the clinicoradiological-omics model (ModelICRO) to quantify the relative importance weight of each variable in predicting PFS (Table 4). Remarkably, the most influential predictors were a peritumoral feature [square-grey level dependence matrix (GLDM)-dependence variance], followed by intratumoral and clinicoradiological features (Figure 5). When patients were grouped by this critical peritumoral feature, notable distribution differences were noted (Supplementary Table 4). Specifically, immune responses revealed significant inter-group differences (low/high responses; 33.7%/66.3% vs 59.0/41.0%; P = 0.001). Additionally, distribution differences in lymphocyte count and percentage were evident both in the subset of 178 patients with immune response evaluations and the entire cohort of 409 patients.

Figure 5
Figure 5 Relative importance weight of variables in integrated clinical-radiological-omics model. The relative importance weight of a variable was calculated using the permutation feature importance by measuring the change in the model’s C-index after random shuffling of each feature value, with the importance scaled relative to the maximum observed change. BMI: Body mass index; GLCM: Grey level co-occurrence matrix; GLDM: Grey level dependence matrix; GLSZM: Grey level size zone matrix; HHH: High-high-high; HHL: High-high-low; HLH: High-low-high; LHL: Low-high-low; LLH: Low-low-high; LLL: Low-low-low; MRF: Mesorectal fascia; NGTDM: Neighboring grey tone difference matrix; TRG: Tumor regression grade; ypN stage: Pathological N stage after neoadjuvant chemoradiotherapy.
Using models to stratify patients into high- and low-risk groups

Patients were stratified into high- or low-risk groups using different models, with a cutoff risk score of zero. For more convenient use in clinical settings, we plotted a nomogram for the clinicoradiological omics model with the highest performance (ModelICRO) (Figure 6A). In the nomogram, the peritumoral radiomic score exhibits a much larger point range compared to other important prognostic factors, indicating its additional contribution to the predictive accuracy of the ModelICRO for PFS. As shown in Figure 6B and C, most patients with disease progression within 3 years were in the high-risk group. Notably, Kaplan-Meier analysis (Figure 6D and E) showed that the high-risk group had a significantly worse 3-year PFS than the low-risk group in both the training [3-year PFS: 67.6% vs 97.2%; HR = 11.06; 95% confidence interval (CI): 3.88-31.47; P < 0.001] and validation (3-year PFS: 64.8% vs 95.4%; HR = 6.58; 95%CI: 1.92-22.58; P = 0.003) sets.

Figure 6
Figure 6 Nomogram, risk score, and survival analysis using the comprehensive model. A: Nomogram of the integrated clinical-radiological-omics model for predicting 3-year progression-free survival (PFS); The progression status, risk scores, and risk stratification for each patient; B: In the training; C: Validation sets. The Kaplan-Meier survival curves for PFS for patients in the high- and low-risk groups; D: In the training; E: Validation sets. BMI: Body mass index; CI: Confidence interval; PFS: Progression-free survival; HR: Hazard ratio; MRF: Mesorectal fascia; TRG: Tumor regression grade; ypN stage: Pathological N stage after neoadjuvant chemoradiotherapy.

The Modelclin and Modelomics models also effectively stratified patients by risk (Supplementary Figure 5), demonstrating survival outcomes similar to those observed in ModelICRO. Survival analysis (Supplementary Figure 6) corroborated the efficacy of risk-based patient stratification based on these two models. In contrast, the pathological staging model (ModelypTN) was less effective in properly stratifying patients into high- and low-risk groups in both the training and validation sets (both P > 0.05) (Supplementary Figure 7).

DISCUSSION

In this study, we successfully developed and validated a comprehensive model (ModelICRO) to estimate PFS in patients with LARC by incorporating clinicoradiological, intratumoral, and peritumoral radiomic features. This model demonstrated commendable predictive efficacy, with C-indices of 0.836 and 0.801 in the training and validation sets, respectively. It also outperformed models based on single- or bi-type features and effectively identified high-risk patients. Notably, peritumoral radiomic features provided greater prognostic value than intratumoral features. In fact, permutation feature importance analysis showed that the most influential prognostic predictor in the model was the peritumoral radiomic feature or the entire peritumoral radiomic signature.

Accurate prognostic prediction based on available medical data, including clinical, pathological, and imaging data is critical when personalizing medicine for postoperative patients with LARC. Previous research has demonstrated the role of intratumoral radiomics in prognostic prediction[36] and the ability of intratumoral features to reflect biological characteristics within the tumor, such as the degree of differentiation, degree of malignancy, and pathological type. In addition, the peritumoral region also referred to as the tumor microenvironment contains significant prognostic information[16,37,38] and is often undetectable through conventional visual MRI assessments by radiologists. Radiomics can effectively analyze these subtle peritumoral differences, extract a comprehensive set of features for a more thorough evaluation, and reveal important information regarding rectal cancer prognoses. In fact, previous studies have shown that MRI-based peritumoral radiomics is effective in predicting tumor deposits[39], lymphovascular invasion[40], nodal metastasis[41], and treatment response[42] in rectal cancer. However, to the best of our knowledge, the potential value of peritumoral radiomics in predicting PFS has not been comprehensively investigated.

In our study, which included a substantial sample of 409 patients, the peritumoral radiomics model demonstrated superior discriminative performance compared to the intratumoral radiomics model in predicting PFS for patients with LARC. In the training set, the C-indices were 0.754 for the peritumoral model and 0.670 for the intratumoral model (P = 0.015). In the validation set, although the C-index of 0.703 for the peritumoral model did not significantly outperform the intratumoral model’s C-index of 0.669 (P = 0.316), the validation results indicate that the peritumoral model is at least not inferior to the intratumoral model. These results suggest that peritumoral radiomic features hold potentially more significant prognostic value than intratumoral features, reinforcing the importance of incorporating peritumoral radiomic features in prognostic assessments for rectal cancer. This finding aligns with that of other studies in which peritumoral radiomics models surpassed intratumoral models in predicting various prognoses, including recurrence-free survival in a cohort of 346 patients (C-index of peritumoral vs intratumoral radiomics models in the validation set: 0.68 vs 0.64)[26], disease-free survival (DFS) in 209 patients (0.790 vs 0.779)[43], and distance metastasis-free survival in 230 patients (0.703 vs 0.687)[25].

To compare the importance of intratumoral, peritumoral radiomic features, and clinicoradiological features within the model, we conducted a permutation feature importance analysis. The results further emphasized the significance of peritumoral features, which are related to the tumor microenvironment, in predicting PFS in LARC. When ranking the variable importance of peritumoral radiomic score, intratumoral radiomic score, and clinicoradiological features within the ModelICRO, the peritumoral radiomic score emerged as more crucial than the intratumoral score and clinicoradiological features. Notably, further exploration of each variable's importance within this model highlighted that a peritumoral radiomics feature was the most significant predictor, followed by an intratumoral feature, both surpassing the TRG. This underscores the critical importance of integrating peritumoral and intratumoral radiomics characteristics. The top predictor was square GLDM dependence variance, a peritumoral feature that assesses the variation in grey levels and dependency sizes within the peritumoral ROI, with a higher value indicating increased differences in dependencies and a more heterogeneous texture[35]. Clinically, this may suggest greater heterogeneity in the peritumoral region, which could be associated with more aggressive tumor behavior and poorer prognosis, emphasizing the need for careful monitoring for patients exhibiting this characteristic.

Significant distribution differences, as observed simultaneously in biopsy immune response and peripheral lymphocyte count across groups stratified by this critical peritumoral feature, suggest that this feature reflects the immune landscape and therefore it might be used to improve patient stratification for better anticancer treatment decisions. Previous studies[25,43] reported that a slightly smaller peritumoral thickness (4 mm) than that used in our study (5 mm) achieved optimal prognostic prediction performance in patients with LARC. Additionally, they found a poorer prediction performance as the peritumoral thickness increased. Although the optimal peritumoral thickness remains to be investigated, the decrease in predictive accuracy in our study might have resulted from the inclusion of more normal tissues lacking prognosis-related information.

In our study, combining peritumoral with intratumoral radiomic features, rather than using intratumoral features alone, significantly enhanced the predictive performance for PFS in LARC. This improvement can be attributed to the comprehensive reflection of heterogeneity within and around the tumor provided by these combined radiomic features. Our model, which utilized only a single T2WI sequence, achieved a C-index of 0.758 for PFS in the validation set. These findings suggest that even with a single-sequence T2WI-based model, incorporating both peritumoral and intratumoral features can achieve high predictive accuracy. In a related study, Cui et al[44] employed a multiparameter MRI-based intratumoral radiomics approach, including axial T2WI, dynamic contrast-enhanced T1 images, and apparent diffusion coefficient maps, to predict DFS. Their T2WI-based radiomics model achieved a C-index of 0.659, and their overall multiparameter model reached a C-index of 0.752 for predicting 3-year DFS. This indicates that multiparameter MRI can enhance the performance of prognostic models. While our single-sequence high-resolution small-field-of-view T2WI model with combined peritumoral and intratumoral features shows promising results, it raises the question of whether integrating multiparameter MRI radiomics, including both peritumoral and intratumoral features, could further improve predictive performance beyond what is achievable with high-resolution T2WI alone. Further research is needed to explore the potential benefits of such an approach for improving prognostic models in rectal cancer.

This study has few limitations. First, it was a retrospective study conducted at a single center and lacked external validation. Therefore, future studies involving multiple centers are required to enhance the effectiveness and relevance of this model. Second, although a peritumoral thickness of 5 mm was reasonable, we did not compare different peritumoral thickness in this study. Third, the manual delineation of intratumoral ROIs was a laborious process subject to variability among different radiologists, even though peritumoral ROI segmentation was automatically created. Hence, to improve the clinical utility of radiomics, future studies should explore the development of an automated ROI-segmentation tool. Fourth, gene-related biomarkers were not included in this study. Incorporating them in future research and exploring their relationship with radiomic features could enhance the interpretability and clinical utility of the models. Integrating multimodal data with intratumoral and peritumoral radiomics may provide deeper insights into cancer progression and outcomes.

CONCLUSION

This study demonstrated that peritumoral radiomics have greater prognostic value than intratumoral radiomics in predicting PFS in patients with LARC who underwent treatment with NCRT and TME. Therefore, a comprehensive model integrating the radiomic features of peri- and intratumoral regions and clinicoradiological factors may serve as a reliable tool for the better stratification and management of postoperative patients based on their risk of disease progression. Additionally, further research on important peritumoral radiomic features is recommended.

ACKNOWLEDGEMENTS

We would like to express our gratitude to Professor Xie CB of the Department of Cancer Prevention at Sun Yat-sen University Cancer Center for conducting the biostatistics review for our study.

Footnotes

Provenance and peer review: Unsolicited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Gastroenterology and hepatology

Country of origin: China

Peer-review report’s classification

Scientific Quality: Grade B, Grade D

Novelty: Grade B, Grade C

Creativity or Innovation: Grade B, Grade C

Scientific Significance: Grade B, Grade C

P-Reviewer: Yang H; Yang L S-Editor: Fan M L-Editor: A P-Editor: Zhao YQ

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