Cancer Lymph Node Research Articles

Mapping sentinel lymph nodes in early-stage ovarian cancer (MELISA) trial: A further step towards lymphadenectomy replacement?

Mapping sentinel lymph nodes in early-stage ovarian cancer (MELISA) trial: A further step towards lymphadenectomy replacement?

Incidence of isolated tumor cells in sentinel lymph node in early cervical cancer

Incidence of isolated tumor cells in sentinel lymph node in early cervical cancer

Utilizing the Postvascular Phase of Contrast-Enhanced Ultrasound to Predict Breast Cancer Lymph Node Metastasis

Background and Objectives: To evaluate the value of the postvascular phase of contrast-enhanced ultrasound (CEUS) in differentiating between benign and metastatic lymph nodes (LNs) in patients with breast cancer (BC). Materials and Methods: This study retrospectively analyzed 96 suspicious LNs in the lymphatic drainage area of the breast from 90 patients with BC. All LNs were assessed by conventional ultrasound (US) and CEUS following intravenous Sonazoid injection. All LNs underwent puncture biopsy, and pathological results were obtained. The correlations between US and CEUS indicators of LNs and LN metastasis (LNM) were analyzed. Results: Of the 96 LNs, 66 were metastatic. Overall, 80.00% (24/30) of the benign LNs exhibited relative hyper-enhancement in the postvascular phase, whereas 96.97% (64/66) of the metastatic LNs exhibited relative hypo-enhancement (p < 0.001). This CEUS finding was highly predictive of metastasis, with a sensitivity of 96.97%, specificity of 80.00%, positive predictive value of 91.43%, negative predictive value of 92.31%, and accuracy of 91.67%. The mean postvascular phase intensity (MPI) was significantly lower for malignant (median MPI, 12 dB) than for benign (median MPI, 75 dB) LNs. The postvascular phase was more sensitive, specific, and accurate than conventional US or the vascular phase of CEUS for the diagnosis of LNM, with an area under the curve of 0.95 (95% confidence interval: 0.89–0.99). Conclusions: Qualitative and quantitative indicators of the postvascular phase of CEUS provide a reliable diagnostic approach to differentiate benign and metastatic LNs in patients with BC.

Fisher discriminant analysis of multimodal ultrasound in diagnosis of cervical metastatic lymph nodes in papillary thyroid cancer.

The purpose of this study was to develop a diagnostic model utilizing multimodal ultrasound parameters to aid in the detection of cervical lymph node metastasis in papillary thyroid cancer (PTC) patients. The study included 84 suspicious lymph nodes from 69 PTC patients, all of whom underwent fine needle aspiration with pathological results. Data from conventional grayscale ultrasound, shear wave elastography (SWE), and superb microvascular imaging were analyzed. Key ultrasound features were compared between benign and metastatic groups to create a diagnostic model using Fisher's stepwise discriminant analysis. The model's effectiveness was assessed with self-testing, cross-validation, and receiver operating characteristic curve analysis. Four features, namely lymphatic hilum (X1), cortical hyperechogenicity (X2), vascular pattern (X4), and SWEmean (X7), were integral to the discriminant analysis, resulting in the equation: Y1 = -3.461 + 2.423X1 + 0.321X2 + 1.620X4 + 0.109X7, Y2 = -8.053 + 0.414X1 + 2.600X2 + 2.504X4 + 0.192X7. If Y1 < Y2, the LN would be diagnosed as metastatic lymph nodes. The model demonstrated an area under the curve of 0.833, with a sensitivity of 83.33% and specificity of 83.33%. The multimodal ultrasound diagnostic model, established through Fisher's stepwise discriminant analysis, proved effective in identifying metastatic lymph nodes in PTC patients.

Artificial Intelligence-Based Sentinel Lymph Node Metastasis Detection in Cervical Cancer

Background/objectives: Pathological ultrastaging, an essential part of sentinel lymph node (SLN) mapping, involves serial sectioning and immunohistochemical (IHC) staining in order to reliably detect clinically relevant metastases. However, ultrastaging is labor-intensive, time-consuming, and costly. Deep learning algorithms offer a potential solution by assisting pathologists in efficiently assessing serial sections for metastases, reducing workload and costs while enhancing accuracy. This proof-of-principle study evaluated the effectiveness of a deep learning algorithm for SLN metastasis detection in early-stage cervical cancer. Methods: We retrospectively analyzed whole slide images (WSIs) of hematoxylin and eosin (H&amp;E)-stained SLNs from early-stage cervical cancer patients diagnosed with an SLN metastasis with either H&amp;E or IHC. A CE-IVD certified commercially available deep learning algorithm, initially developed for detection of breast and colon cancer lymph node metastases, was employed off-label to assess its sensitivity in cervical cancer. Results: This study included 21 patients with early-stage cervical cancer, comprising 15 with squamous cell carcinoma, five with adenocarcinoma, and one with clear cell carcinoma. Among these patients, 10 had macrometastases and 11 had micrometastases in at least one SLN. The algorithm was applied to evaluate H&amp;E WSIs of 47 SLN specimens, including 22 that were negative for metastasis, 13 with macrometastases, and 12 with micrometastases in the H&amp;E slides. The algorithm detected all H&amp;E macro- and micrometastases with 100% sensitivity. Conclusions: This proof-of-principle study demonstrated high sensitivity of a deep learning algorithm for detection of clinically relevant SLN metastasis in early-stage cervical cancer, despite being originally developed for adenocarcinomas of the breast and colon. Our findings highlight the potential of leveraging an existing algorithm for use in cervical cancer, warranting further prospective validation in a larger population.

Prognostic value of isolated tumor cells and micrometastasis of lymph nodes in invasive urinary bladder cancer.

The prognostic significance of nodal micrometastasis and isolated tumor cells (ITC) in urinary bladder cancer (UBC) is unknown. We aimed to evaluate the prevalence, clinical impact, and clinicopathological characteristics of nodal micrometastasis and ITC in UBC. A total of 124 patients with UBC undergoing surgery were investigated. Detection of micrometastasis and ITC was performed using pancytokeratin immunohistochemistry (IHC). Histopathologic and clinical findings were correlated with patients' outcome. IHC detected nodal micrometastasis and ITC (pNmi group) in 12.9% (13/101) of originally node-negative patients and in 26.1% (6/23) of originally node-positive patients (pN+ group). The remaining 88 were truly node-negative patients (pN0 group). After IHC, all 13 patients in the pNmi group were upstaged from pN0 to pN1-2 and one patient in the pN+ group was changed from pN1 to pN2. Nodal micrometastasis and ITC were significantly associated with mixed urothelial carcinoma (UC) (p = 0.002), UC with discohesive pattern (p = 0.006), glandular differentiation (p = 0.043), lymphovascular invasion (p = 0.009), and budding-like tumor cell clusters (p = 0.002). The pNmi group had significantly worse cancer-specific survival than the pN0 group in univariate (p = 0.004) and multivariate (p = 0.040) analysis. IHC frequently identified nodal micrometastasis and ITC in originally node-negative UBC patients on routine pathological examination. Nodal micrometastasis and ITC were independently associated with cancer-related mortality in UBC. IHC might be selectively used to detect micrometastasis and ITC in UBC having specific pathological features.

Prognostic Impact of Skip Metastasis to the Lateral Lymph Nodes in Lower Rectal Cancer.

Some patients with lower rectal cancer develop "skip metastasis," in which lymph node metastasis occurs in the lateral but not the mesenteric lymph nodes. However, the prognostic impact of skip metastasis is unclear. This study aimed to determine the long-term prognosis of skip metastasis in lower rectal cancer. This retrospective study included patients with stage I-III lower rectal cancer who underwent total mesorectal excision and lateral lymph node dissection at our institution between 2000 and 2019. We investigated the association of lymph node metastasis with relapse-free and overall survival. Multivariate analyses were performed using Cox proportional hazards regression models. Of a total of 371 patients, 183 (49%) were negative for lymph node metastasis, 115 (31%) were positive for mesenteric lymph nodes only, 18 (5%) were positive for lateral lymph nodes only (skip metastasis), and 55 (15%) were positive for both mesenteric and lateral lymph nodes; the 5-year relapse-free survival rates were respectively 79.9%, 60.0%, 68.3%, and 32.7%, and 5-year overall survival rates were 96.6%, 90.0%, 85.6%, and 57.3%. Multivariable analysis revealed significant differences in relapse-free and overall survival between those positive for both mesenteric and lateral lymph nodes and those positive for lateral lymph nodes only (relapse-free survival, hazard ratio 2.30, p=0.048; overall survival, hazard ratio 3.50, p=0.030). In patients with lower rectal cancer who underwent total mesorectal excision and lateral lymph node dissection, those with skip metastasis had better relapse-free and overall survival than those with both mesenteric and lateral lymph node metastases.

A case of successful conversion surgery for unresectable gallbladder cancer treated with durvalumab in combination with gemcitabine plus cisplatin.

We report a rare case of a patient with initially unresectable gallbladder cancer who underwent conversion surgery with durvalumab in combination with gemcitabine plus cisplatin and achieved an R0 resection. A 68year-old woman was found to have gallbladder cancer and multiple enlarged lymph nodes around the suprapancreatic rim and hepatic hilum invading the proper hepatic artery on computed tomography. The diagnosis was cT3cN2cM0, cStage IVB. After eight cycles of durvalumab in combination with gemcitabine plus cisplatin, all tumor markers became negative, and lymph node invasion of the hepatic artery disappeared. The patient underwent conversion surgery with gallbladder bed resection and regional lymph node dissection. There was no need for hepatic artery reconstruction. Pathology revealed ypT2aypN0ycM0, ypStage IIA, and radical resection was considered. Immunostaining of tissue collected at the time of endoscopic ultrasound-guided tissue acquisition revealed less than 1% programmed death ligand-1 expression. The patient continued adjuvant chemotherapy with single-agent durvalumab every 4weeks and maintained a relapse-free survival of 8months postoperatively. The utility of durvalumab in combination with gemcitabine plus cisplatin in unresectable gallbladder cancer independent of programmed death ligand-1 expression has been confirmed and may be an important option in future multimodal treatment, including conversion surgery.

Optimised treatment of patients with enlarged lateral lymph nodes in rectal cancer: protocol of an international, multicentre, prospective registration study after extensive multidisciplinary training (LaNoReC)

IntroductionInadequate treatment of enlarged lateral lymph nodes (LLNs) in rectal cancer patients is associated with an increased lateral local recurrence (LLR) risk, despite neoadjuvant treatment and total mesorectal excision (TME)...

Assessing para-aortic nodal status in high-grade endometrial cancer patients with negative pelvic sentinel lymph node biopsy.

To determine the accuracy of pelvic sentinel lymph node biopsy (SLN) in detecting positive para-aortic (PA) lymph nodes in high-grade uterine cancer, and to determine the recurrence rate in patients with high-grade uterine cancers who did not receive adjuvant chemotherapy based on negative pelvic SLNs. This was a retrospective cohort study of patients with newly diagnosed, high-grade endometrial cancer who underwent surgery, including pelvic SLNs with or without PA node dissection, at a tertiary care institution between 2015 and 2020. Baseline demographics, surgical management, pathology data, and outcomes were analyzed using descriptive statistics, and survival analysis. Postoperative histology of the 110 patients meeting inclusion criteria was 45.5% grade 3 endometrioid, 36.4% serous, 10.9% clear cell, and 7.3% carcinosarcoma. On final pathology, 63.7% were stage 1, and 23.6% were stage 3C with positive nodes. A total of 63 patients (57.3%) had a PA lymph node dissection (56 bilateral, 7 unilateral) in addition to the pelvic SLN. Among this group, 5.8% (95% confidence interval 1.2%-16.0%) had a positive PA node despite a negative pelvic SLN. Among those with a negative pelvic SLN and no adjuvant chemotherapy (n = 75), the rate of distant recurrence was 14.7%, and 3-year recurrence-free survival was 71.9%. The rate of isolated PA node metastasis in high-grade endometrial cancers despite a negative pelvic SLN may be significantly higher than the accepted rate of isolated PA node metastasis in low-grade endometrial cancer. This supports adjuvant treatment decisions continuing to incorporate primary tumor pathology and molecular classification.

Node Reporting and Data System Combined With Computed Tomography Radiomics Can Improve the Prediction of Nonenlarged Lymph Node Metastasis in Gastric Cancer.

To investigate the diagnostic performance of Node Reporting and Data System (Node-RADS) combined with computed tomography (CT) radiomics for assessing nonenlargement regional lymph nodes in gastric cancer (GC). Preoperative CT images were retrospectively collected from 376 pathologically confirmed of gastric adenocarcinoma from January 2019 to December 2023, with 605 lymph nodes included for analysis. They were divided into training (n = 362) and validation (n = 243) sets. Radiomics features were extracted from venous-phase, and the radiomics score was obtained. Clinical information, CT parameters, and Node-RADS classification were collected. A combined model was built using machine-learning approach and tested in validation set using receiver operating characteristic curve analysis. Further validation was conducted in different subgroups of lymph node short-axis diameter (SD) range. Node-RADS score, SD, maximum diameter of thickness of tumor, and radiomics were identified as the most predictive factors. The results demonstrated that the integrated model combining SD, maximum diameter of thickness of tumor, Node-RADS, and radiomics outperformed the model excluding radiomics, yielding an area under the receiver operating characteristic curve of 0.82 compared with 0.79, with a statistically significant difference (P < 0.001). Subgroup analysis based on different SDs of lymph nodes also revealed enhanced diagnostic accuracy when incorporating the radiomics score for the 4- to 7.9-mm subgroups, all P < 0.05. However, for the 8- to 9.9-mm subgroup, the combination of the radiomics did not significantly improve the prediction, with an area under the receiver operating characteristic curve of 0.85 versus 0.85, P = 0.877. The integration of radiomics scores with Node-RADS assessments significantly enhances the accuracy of lymph node metastasis evaluation for GC. This combined model is particularly effective for lymph nodes with smaller standard deviations, yielding a marked improvement in diagnostic precision. The findings of this study indicate that a composite model, which incorporates Node-RADS, radiomics features, and conventional parameters, may serve as an effective method for the assessment of nonenlarged lymph nodes in GC.

Size and SUVmax define the contribution of nodal metastases to PSA in oligorecurrent prostate cancer.

To evaluate how prostate-specific antigen (PSA) levels decrease after removal of isolated prostate cancer (PCa) nodal metastases in relation to their diameter/volume ("PSA-density of PCa-metastases") and maximum standardized uptake value (SUVmax). A total of 83 consecutive patients with solitary nodal recurrence after radical prostatectomy who underwent prostate-specific membrane antigen-radioguided salvage surgery were retrospectively analyzed. Using multivariable linear regression models, the PSA-decrease after removal of each PCa-metastases (=PSA-contribution of each PCa-metastases) was correlated with the long axis diameter/estimated volume and the SUVmax of each removed metastasis. Sizes were measured by imaging and histopathologic examination. A total of 83 patients were included with a median (interquartile range [IQR]) PSA-decrease of 0.56 [0.22, 1.31] ng/mL after salvage surgery. The median [IQR] long axis diameters in imaging and histopathological examination were 8.0 [6.0, 11.0] mm and 8.4 [5.5, 11.1] mm, respectively. The median [IQR] estimated volumes were 0.13 [0.05, 0.32] cc (imaging) and 0.05 [0.02, 0.17] cc (pathology). In multivariable linear regression analyses, the estimated PSA-contribution ([95% confidence interval [CI]) of each millimeter of long axis diameter was 0.09 [0.03, 0.14] ng/mL (imaging) or 0.08 [0.03, 0.12] ng/mL (histology). The minimum diameter for biochemical recurrence (PSA ≥ 0.2 ng/mL) was >2.2 mm (imaging) or >2.5 mm (histology). The estimated PSA-contribution [95% CI] of each cc cancer volume was 1.23 [0.51, 1.94] ng/mL (imaging) or 1.46 [0.40, 2.52] ng/mL (histology). SUVmax as surrogate parameter for tissue composition was associated with increased PSA-contribution of PCa-metastases (+0.03-0.05 ng/mL per unit increase). The diameter/volume and SUVmax of metastatic tissue correlate with its contribution to PSA levels. Therefore, very small metastases may produce too little PSA for biochemical recurrence.

Sentinel node mapping decreases the risk of failed detection of isolated positive para-aortic lymph node in endometrial cancer

BackgroundIsolated positive para-aortic lymph node metastasis in endometrial cancer is an uncommon event, ranging from 1% to 3%.ObjectiveOur aim was to evaluate the impact of sentinel lymph node (SLN) mapping...

Are metastatic central lymph nodes (D3 volume) in right-sided colon cancer “REALLY” a sign of systemic disease?—a sub-group analysis of an ongoing multicenter trial

Are metastatic central lymph nodes (D3 volume) in right-sided colon cancer “REALLY” a sign of systemic disease?—a sub-group analysis of an ongoing multicenter trial

Pathological responses of primary tumor and lymph nodes in non-small cell lung cancer after neoadjuvant chemoimmunotherapy: a retrospective real-world study

Pathological responses of primary tumor and lymph nodes in non-small cell lung cancer after neoadjuvant chemoimmunotherapy: a retrospective real-world study

Risk factor analysis and establishment of a predictive model for complications of elderly advanced gastric cancer with Clavien-Dindo classification ≥ II grade

BackgroundThe occurrence of complications following radical gastrectomy for gastric cancer significantly impacts patients’ quality of life. Elderly patients are susceptible to postoperative complications. This study seeks to investigate the risk factors associated with Clavien-Dindo ≥IIgrade complications following radical gastrectomy for advanced gastric cancer in elderly patients, develop a nomogram risk prediction model, and validate its accuracy.MethodsRetrospective collection of clinical and pathological data was conducted on 442 elderly patients with advanced gastric cancer who underwent radical gastrectomy at Shaanxi Provincial People’s Hospital from January 2015 to December 2020. They were randomly divided into a training set (n = 310) and a validation set (n = 132) in a 7:3 ratio. The severity of postoperative complications was graded using the Clavien-Dindo classification system, resulting in two complication groups: Clavien-Dindo <II group (n = 229) and Clavien-Dindo ≥II group (n = 81). Univariate and multivariate logistic regression analyses were performed to identify independent risk factors affecting the occurrence of Clavien-Dindo ≥II grade complications, and a predictive model was established based on the results. The model was then validated using the validation set.ResultsAmong the 442 patients included in the study, 121 cases (27.38%) experienced postoperative complications, with 111 cases (25.11%) classified as Clavien-Dindo ≥II grade complications. Multivariable logistic analysis revealed that the Prognostic Nutritional Index (PNI), surgical duration, age, and history of Diabetes mellitus were independent risk factors for the occurrence of Clavien-Dindo ≥IIgrade complications in elderly patients with advanced gastric cancer after surgery (P < 0.05). The nomogram model constructed based on these factors demonstrated good discriminative ability, as indicated by the area under the Receiver Operating Characteristic (ROC) curve. Calibration plots showed that the predicted probability of gastric cancer lymph node metastasis using the nomogram model was well aligned with actual outcomes. Decision curve analysis indicated the clinical utility of the nomogram model across a wide range of thresholds, demonstrating its practicality and potential for clinical benefit.ConclusionThis study identified Prognostic Nutritional Index (PNI), surgical duration, age, and history of Diabetes mellitus as risk factors for the occurrence of Clavien-Dindo ≥ II grade complications in elderly patients with advanced gastric cancer after surgery. Based on these four risk factors, a nomogram risk prediction model was constructed. This model can be used to personalize the prediction of the risk of Clavien-Dindo ≥ II grade complications occurring after surgery in elderly patients with advanced gastric cancer.

Research progress on the distribution patterns and surgical dissection of central lymph nodes in left-sided colon cancer

Lymphatic metastasis is one of the main pathways of colorectal cancer spread and also a crucial factor in patient long-term prognosis. Lymph node dissection in the possible tumor drainage area, particularly the central group of lymph nodes at the root of the tumor-associated supplying artery, is a key and challenging aspect of surgical techniques. Currently, the patterns of lymphatic drainage and the distribution of central lymph nodes in left-sided colon cancer are not well illustrated, and there is no consensus on the necessity and extent of central lymph node dissection. This has led to significant variability in the extent of lymph node dissection among different surgeons in clinical practice, a lack of quality control standards for surgical procedures, and impacts on postoperative treatment strategy and long-term outcomes. Moreover, current research on lymphatic drainage and metastasis is primarily based on traditional anatomy, whereas individualized, precise approaches to lymph node dissection have not been realized. The application of preoperative and intraoperative lymph node imaging techniques based on functional anatomy in colorectal cancer patients is still under exploration.

Clinical significance of intensity-modulated radiotherapy (IMRT) to the distant metastatic lymph nodes for metastatic cervical cancer

ObjectiveTo retrospectively explore the clinical significance of radiotherapy to the distant metastatic lymph nodes (cervical/ clavicular/ mediastinal et al.) in metastatic cervical cancer. Hereinto, these cervicothoracic lymph nodes were metastasized from IB1-IVA (initial stage at first treatment), and IVB initially had metastatic disease in these areas at diagnosis.MethodsMetastatic cervical cancer only with the distant cervicothoracic metastatic lymph nodes (cervical/ clavicular/ mediastinal et al.), without distant parenchymal organs metastasis such as lung, liver, bone, and peritoneum, were enrolled in the analysis. These patients were classified into IB1-IVA and IVB based on their initial stage of first treatment. All patients received IMRT for the distant metastatic lymph nodes. The progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan–Meier method.ResultsOverall, the median PFS was 9 months, and the median OS was 27 months. The subgroup analysis showed that for IB1-IVA, the median PFS was 11 months, and the median OS was 30.5 months. For IVB, the median PFS was 8 months, and the median OS was 16 months.ConclusionRadiotherapy is beneficial to the distant metastatic lymph nodes (cervical/ clavicular/ mediastinal et al.), and could effectively bring the longer PFS and OS for metastatic cervical cancer.

Integrin profle of circulating tumour cells in breast cancer patients

Background. Integrins, as adhesion molecules, play a key role in the interaction of cells with the basal membrane and intercellular matrix. Numerous studies demonstrate evidence of increased expression of integrins on tumor cells in different types of cancer. Thus, β3 and αV integrins are associated with stem-like features of tumor cells, and β4 integrin as α6β4 heterodimer provides anchorage-independent survival of malignant mammary epithelial cells. However, all the described functions of integrins have been investigated exclusively on primary tumor cells. The functional significance and expression pattern of integrins on circulating tumor cells (CTCs) remains unclear. The aim of the study was to evaluate the β3, β4 and αvβ5 integrin expression on CTCs and its association with molecular subtype, stage and lymph node metastasis in breast cancer patients Material and Methods. The study included 22 patients with T1–4N0–3M0 invasive ductal breast carcinoma. Venous blood was taken from patients without neoadjuvant chemotherapy (group 1) and after neoadjuvant chemotherapy (group 2) in the volume of 12 ml into vacuum tubes with EDTA. The expression of CTC integrins including stemness features CD44/CD24, CD133 and ALDH1, and epithelial-mesenchymal transition (EMT) (N-cadherin) was evaluated by flow cytometry. Results. CTCs with β3+β4-αvβ5- and β3-β4+αvβ5+ phenotypes and stemness properties were associated with larger tumor size (T4) in breast cancer patients. The β3 integrin expression was associated with more aggressive molecular subtypes of breast cancer. Administration of neoadjuvant chemotherapy did not affect the expression pattern of β3, β4 and αvβ5 integrins in CTCs. Conclusion. In breast cancer, most CTCs expressed β3, β4 and αvβ5 integrins despite the lack of attachment to the basal membrane and intercellular matrix. The expression of the above integrins on CTCs was associated with breast cancer molecular subtype, stage and lymph node metastasis, and therefore its evaluation can be considered as one of the objectives of liquid biopsy study.

Persistent Lymph Node Metastases After Neoadjuvant Chemoradiotherapy for Rectal Cancer

Patients with locally advanced rectal cancer and persistent lymph node metastases (PLNM) after neoadjuvant treatment are at high risk of developing locoregional and distant metastasis, yet optimal postsurgical treatment of these patients is limited. To analyze the association of PLNM with pretreatment clinical parameters, intensity of neoadjuvant treatment, and long-term oncological outcomes. This cohort study is a post-hoc analysis of 3 randomized clinical trials (Surgical Oncology Working Group of Germany [CAO], Radiological Oncology Working Group of Germany [ARO], and Working Group for Internal Oncology in the German Cancer Society [AIO]) conducted in Germany in 1994, 2004, and 2012 that included 1948 patients with locally advanced rectal cancer recruited between February 1995 and January 2018. Statistical analysis was conducted between September 2023 and February 2024. Receiving preoperative fluorouracil-based chemoradiotherapy (CRT, comprising the preoperative group of CAO/ARO/AIO-94 and the control group of CAO/ARO/AIO-04), fluorouracil-based CRT plus oxaliplatin (experimental group of CAO/ARO/AIO-04), or total neoadjuvant treatment (TNT) with fluorouracil-based CRT plus oxaliplatin with induction or consolidation leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin chemotherapy within the CAO/ARO/AIO-12 trial. The associations of PLNM with clinical parameters, intensity of neoadjuvant treatment, and cumulative incidences of LR, DM, and overall survival were assessed. A total of 1888 patients (1333 male participants [70.6%]; median [range] age, 62 [19-84] years) with locally advanced rectal adenocarcinoma (clinical tumor stage 3 to 4 and/or clinically node-positive) treated within 3 consecutive clinical trials were analyzed. A total of 522 (29%) experienced PLNM; 378 had lymph node stage (ypN) 1 (20%) after neoadjuvant treatment (ypN) 1 (20%), and 174 had ypN2 (9%). Age, clinical T-stage, N-stage, grading, carcinoembryonic antigen levels, and time interval from completion of CRT to surgery were significantly associated with PLNM, whereas sex and tumor location were not. The percentage of patients with ypN2 stage was almost halved after TNT (18 of 293 patients [6%]) compared with patients treated with fluorouracil-based CRT (114 of 1009 patients [11.3%]; χ26 = 16.693; P = .01). After a median (IQR) follow-up of 54 (37-62) months, 5-year overall survival was 86.1% (95% CI, 83.9%-88.4%) for ypN0, 74.0% (95% CI, 83.9%-88.4%) for ypN1, and 43% for ypN2 (95% CI, 35.4%-52.2%) (P < .001). The 5-year cumulative incidences of locoregional and distant metastases were, respectively, 3% (95% CI, 2.1%-4.2%) and 20% (95% CI, 18%-23%) for ypN0, 6% (95% CI, 3.4%-8.8%) and 40% (95% CI, 34%-46%) for ypN1, and 19% (95% CI, 13%-26%) and 72% (95% CI, 63%-79%) for ypN2 (both P < .001). In this cohort study, PLNM unmasked an unfavorable phenotype of rectal cancer at high risk for treatment failure. More aggressive adjuvant treatment might be considered; however, risk-adapted surveillance strategies and early recurrence-directed surgery, if feasible, are important strategies in this group of patients with CRT- and/or chemotherapy-resistant disease.