Pathological Tumor Regression Grade Research Articles

Longitudinal circulating tumor DNA monitoring in predicting response to short-course neoadjuvant radiotherapy in locally advanced rectal cancer: Data from a phase III clinical trial (UNION).

LBA3606 Background: The data presented here is from a multicenter, randomized, open-label, controlled Phase III clinical study evaluating the feasibility of short-course radiotherapy (shortRT) sequentially combined with camrelizumab and chemotherapy as neoadjuvant therapy (NAT) for locally advanced rectal cancer (LARC)(UNION). Our aim is to explore the value of circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) in assessing the comparative efficacy of short-course and long-course chemoradiotherapy (CRT). Methods: A total of 244 plasma samples from 79 LARC patients, who underwent NAT prior to curative surgery, were collected at baseline (C1), on-NAT (C2), post-NAT (C3), and post-surgery (C4). Deep targeted panel sequencing of 556 cancer-related genes was performed. The changes in genomic features and ctDNA-MRD status during treatment were monitored, and the relationship between these changes and treatment response were explored. Results: During NAT, the ctDNA-MRD positivity rate showed significant declining trends. Patients with high baseline TMB tend to show a significant inclination towards major pathological response and tumor regression grade 0/1 after NAT, while there is no significant correlation observed between baseline ctDNA-MRD status and treatment response. Interestingly, compared to long-course radiotherapy, microsatellite instability is more pronounced after shortRT ( P=0.042), and ctDNA negativity is significantly associated with pathological complete response (pCR) ( P=0.022). Furthermore, both ctDNA clearance ( P=0.049) and MRD clearance ( P=0.015) after shortRT are significantly correlated with pCR. A risk scoring predictive model based on ctDNA-MRD was established, with achieving the highest C-index at the C2 time point. This model, combining MRD clearance and CEA, outperforms models using only MRD clearance (AUC=0.917, 95% CI=0.753 to 1.000) or only CEA (AUC=0.733, 95% CI=0.449 to 1.000), demonstrating superior performance in predicting pCR/non-pCR (AUC=0.983, 95% CI=0.937 to 1.000). Conclusions: These findings offers valuable insights into the dynamic landscape of NAT for LARC management and emphasize the potential of ctDNA-based MRD assessment as a valuable tool for tailoring treatment strategies. The differences observed between shortCRT and longCRT regimens underscore the need for personalized treatment approaches. Overall, our study contributes valuable insights into optimizing treatment decision-making and predicting treatment response in LARC patients, ultimately advancing the field of rectal cancer management.

Circulating tumor DNA as a predictor of treatment response to neoadjuvant chemotherapy in stage 2/3 rectal cancer without high risks: Subset analysis from the COPEC trial.

e15623 Background: Circulating tumor DNA (ctDNA) serves as a valuable tool for minimal residual disease (MRD) assessment. It has been reported as a promising noninvasive biomarker for the dynamic monitoring of treatment response of metastatic colorectal cancers to chemotherapy and locally advanced rectal cancers (LARC) to neoadjuvant chemoradiotherapy. However, the potential role of ctDNA in neoadjuvant chemotherapy (NCT) in LARC remains unexplored. The present study aims to investigate the value of ctDNA in NCT based on a prospective, multicentered, non-inferior, randomized, controlled trial (ClinicalTrials.gov ID, NCT04922853). The COPEC trial enrolls stage 2/3 LARC with low or intermediate and is designed to determine the optimal time (after 2 or 4 cycles of CAPOX) to evaluate treatment response based on pathological regression grades. Methods: Colonoscopy biopsy was taken before neoadjuvant therapy. Peripheral blood samples were collected before neoadjuvant (baseline, BL), one cycle (C1) and two cycles (4-cycle group, C2) after NCT, before surgery (BS), and within one month after surgery (postoperative, OP). All tissue biopsy and plasma specimens were analyzed by NGS assays using the MinerVA platform (Genecast Biotechnology Co., Ltd). MRI tumor regression grade (mrTRG) was assessed after 2 and 4 cycles (4-cycle group) of NCT. The primary outcome was the accuracy of ctDNA in the prediction of pathological tumor regression grade (pTRG). Results: A total of 151 LARC patients were enrolled, including 82 in the 2-cycle group and 69 in the 4-cycle group. The ctDNA was detectable in 87.4% (132/151), 39.6% (55/139), 29.0% (18/62), 38.4% (58/151), and 4.4% (6/138) at BL, C1, C2, BS and OP, respectively. The ctDNApositivity rates were significantly lower in good responders determined by mrTRG (mrTRG 1-3) compared to mrTRG 4-5 group at C1 (29% vs. 63.89%, p < 0.001), C2 (20% vs.56.25%, p = 0.011), and BS time points (23.85% vs. 74.36%, p < 0.001). Furthermore, the ctDNA-positivity rates at C1 in the good response group determined by TRG (pTRG 0-1) were 6.25%, significantly lower than that in the pTRG 2-3 group (49.53%). At neither C2 nor BS time point, patients in the pTRG 0-1 subgroup were detected as ctDNA positive while the ctDNA positivity rates for patients in pTRG 2-3 subgroup were 39.13% and 50%, respectively. Additionally, the mean of hGE/ml was 0.045 in pTRG 0-1 group at C1, significantly lower comparing to 1.337 in pTRG 2-3 group (p < 0.001). Conclusions: We find that dynamic monitoring of ctDNA status was a useful tool in early predicting the effect of (treatment response to) NCT in LARC patients with low/intermediate risks. The monitoring of ctDNA status can supplement MRI in determining the NCT response and could potentially help identify poor responders to discontinue the treatment with inadequate efficacy. Clinical trial information: NCT04922853 .

Role of pathological tumor regression grade of lymph node metastasis following neoadjuvant chemotherapy in locally advanced gastric cancer

AimsTo confirm whether the pathological response of lymph node metastasis (LNM) to neoadjuvant chemotherapy (NCT) can predict the prognosis of patients with gastric cancer (GC). MethodsA total of 979 patients with locally advanced GC were included. χ2 test was used to analyze the relationship between LNM TRG and clinicopathological factors. Cox proportional hazards model was used to analyze the relationship between LNM TRG, clinicopathological factors, and overall survival (OS). ResultsA total of 21,162 lymph nodes were evaluated, with 237 patients (35.4%) in the response group and 433 patients (64.6%) in the non-response group. The non-responsive group was strongly associated with higher ypT, ypN, ypTNM, primary tumor (PT) TRG (all p < 0.001), positive cancer nodules (p = 0.001), and more distant LNM location (p < 0.001). Patients with the same PT TRG but different LNM TRG had different prognosis. There was no difference in OS between the responding and non-responding groups of LNM at location 2, 3, and M. YpN, tumor location, and LNM location were independent prognostic factors. ConclusionsThe combination of LNM TRG and PT TRG could better predict patient prognosis. Lymph node dissection should be routinely performed after NCT to provide the reference of radical resection.

Machine learning–based response assessment in patients with rectal cancer after neoadjuvant chemoradiotherapy: radiomics analysis for assessing tumor regression grade using T2-weighted magnetic resonance images

PurposeThis study aimed to assess tumor regression grade (TRG) in patients with rectal cancer after neoadjuvant chemoradiotherapy (NCRT) through a machine learning–based radiomics analysis using baseline T2-weighted magnetic resonance (MR) images.Materials and methodsIn total, 148 patients with locally advanced rectal cancer(T2-4 or N+) who underwent MR imaging at baseline and after chemoradiotherapy between January 2010 and May 2021 were included. A region of interest for each tumor mass was drawn by a radiologist on oblique axial T2-weighted images, and main features were selected using principal component analysis after dimension reduction among 116 radiomics and three clinical features. Among eight learning models that were used for prediction model development, the model showing best performance was selected. Treatment responses were classified as either good or poor based on the MR-assessed TRG (mrTRG) and pathologic TRG (pTRG). The model performance was assessed using the area under the receiver operating curve (AUROC) to classify the response group.ResultsApproximately 49% of the patients were in the good response (GR) group based on mrTRG (73/148) and 26.9% based on pTRG (28/104). The AUCs of clinical data, radiomics models, and combined radiomics with clinical data model for predicting mrTRG were 0.80 (95% confidence interval [CI] 0.73, 0.87), 0.74 (95% CI 0.66, 0.81), and 0.75(95% CI 0.68, 0.82), and those for predicting pTRG was 0.62 (95% CI 0.52, 0.71), 0.74 (95% CI 0.65, 0.82), and 0.79 (95% CI 0.71, 0.87).ConclusionRadiomics combined with clinical data model using baseline T2-weighted MR images demonstrated feasible diagnostic performance in predicting both MR-assessed and pathologic treatment response in patients with rectal cancer after NCRT.

Evaluation of the prognostic impact of pathologic tumor regression grade on patients with colorectal cancer after preoperative chemoradiotherapy.

The prognostic value of the pathological response to preoperative chemoradiotherapy (CRT) in rectal cancer (RC) remains unknown. We aimed to assess the predictive value of the response to CRT that was derived from an evaluation of the histological findings (whole-section vs. representative-section sampling) and attempted to determine an objective cut-off value for the tumor regression grade (TRG). We examined the association of the TRG with the outcomes (recurrence-free survival [RFS] and overall survival [OS]) of 78 patients with RC. Patients with RC treated with preoperative CRT were divided into development (30 cases) and validation (48 cases) cohorts. The TRG was classified as grades I (Ia, Ib), II, and III. The cut-off value was determined by receiver operating characteristic (ROC) curve analysis. The TRG determined from whole-section sampling versus representative-section sampling was more strongly correlated with patient survival. We found that in both cohorts, patients with a cut-off value of <73% had a poor prognosis. Finally, the cut-off value was found to be an independent predictive factor in both univariate and multivariate analysis. The TRG that was used to evaluate patients with RC who underwent preoperative CRT was an independent prognostic factor for outcome.

Spectral CT vs. diffusion-weighted imaging for the quantitative prediction of pathologic response to neoadjuvant chemotherapy in locally advanced gastric cancer.

To compare the performance of spectral CT and diffusion-weighted imaging (DWI) for predicting pathologic response after neoadjuvant chemotherapy (NAC) in locally advanced gastric cancer (LAGC). This was a retrospective analysis drawn from a prospective dataset. Sixty-five patients who underwent baseline concurrent triple-phase enhanced spectral CT and DWI-MRI and standard NAC plus radical gastrectomy were enrolled, and those with poor images were excluded. The tumor regression grade (TRG) was the reference standard, and patients were classified as responders (TRG 0 + 1) or non-responders (TRG 2 + 3). Quantitative iodine concentration (IC), normalized IC (nIC), and apparent diffusion coefficient (ADC) were measured by placing a freehand region of interest manually on the maximal two-dimensional plane. Their differences between responders and non-responders were compared. The performances of significant parameters were evaluated by the receiver operating characteristic analysis. The correlations between parameters and TRG status were explored through Spearman correlation coefficient test. Kaplan-Meier survival analysis was adopted to analyze their relationship with patient survival. nICDP and ADC were associated with the TRG and yielded comparable performances for predicting TRG categories, with area under the curve (AUC) of 0.674 and 0.673, respectively. Their combination achieved a significantly increased AUC of 0.770 (p ; 0.05) and was associated with patient disease-free survival, with hazard ratio of 2.508 (1.043-6.029). Spectral CT and DWI were equally useful imaging techniques for predicting pathologic response to NAC in LAGC. The combination of nICDP and ADC gained significant incremental benefits and was related to patient disease-free survival. Spectral CT and DWI-based quantitative measurements are effective markers for predicting the pathologic regression outcomes of locally advanced gastric cancer patients after neoadjuvant chemotherapy. • The pathologic tumor regression grade, the standard criteria for treatment response after neoadjuvant chemotherapy in gastric cancer patients, is difficult to predict early. • The quantitative parameters of normalized iodine concentration at delay phase and apparent diffusion coefficients were correlated with pathologic response; their combination demonstrated incremental benefits and was associated with patient disease-free survival. • Spectral CT and DWI are equally useful imaging modalities for predicting tumor regression grade after neoadjuvant chemotherapy in patients with locally advanced gastric cancer.

Association of pathologic nodal status with minimal residual disease after neoadjuvant treatment and resection of locally advanced rectal cancer.

205 Background: Studies have shown that minimal residual disease (MRD) identified by detection of circulating tumor DNA (ctDNA) is associated with recurrence after surgical resection of colorectal cancer. Though multiple trials are evaluating the use of ctDNA to guide adjuvant therapy, data on the utility of ctDNA after neoadjuvant therapy is limited. In this study, we evaluated the associations between ctDNA and recurrence after neoadjuvant treatment and resection of rectal cancer (LARC). Methods: Consecutive patients with primary rectal cancer treated with neoadjuvant systemic therapy and/or chemoradiotherapy followed by resection between 12/2020-4/2023 were identified. Patients were tested for ctDNA via the MD Anderson INTERCEPT platform using a high-sensitivity patient informed assay. Patients with metastases or a first ctDNA test more than 3 months after resection were excluded. MRI-determined stage, extramural vascular invasion (mrEMVI), pelvic sidewall adenopathy (PSW), pathologic lymphovascular invasion (LVI), perineural invasion (PNI) and tumor regression grade (TRG) were collected. Associations between these factors and ctDNA status were analyzed with Fischer’s exact test. Recurrence free survival (RFS) was analyzed with the log-rank test. Results: Sixty-seven patients (3 treated with chemoradiotherapy alone, 15 with systemic therapy alone and 49 with total neoadjuvant therapy) were identified. Positive ctDNA was identified in 6 (8.9%) within 3 months after resection, all of whom received total neoadjuvant therapy, and 3/6 recurred within 12 months. Clinical T status (p=0.146), N status (p=0.842), mrEMVI (p=0.475) and PSW (p=0.318) were not associated with MRD. TRG was not associated with MRD (TRG0-1: 4% vs TRG2-3: 11.3%, p=0.547). Pathologic N status was associated with MRD (ypN0: 4.4% vs ypN+: 18%, p=0.049). MRD was associated with a median RFS of 3.2 months (HR 39, 95% CI: 4.1-380, p=0.0015). 1-year RFS was 98% for patients without MRD. Conclusions: Minimal residual disease after multi-modality treatment of LARC is associated with early metastatic recurrence. The patient informed MRD assay appears both sensitive and specific for detection of relapse. Advanced clinical stage and high-risk radiologic features were not associated with MRD, while post-treatment pathologic N status was. Given the high relapse rate for MRD+ patients, MRD detection after resection warrants additional investigation for metastases and/or enrollment on MRD treatment clinical trial. Methods to predict MRD prior to resection are urgently needed.

Texture analysis of apparent diffusion coefficient maps: can it identify nonresponse to neoadjuvant chemotherapy for additional radiation therapy in rectal cancer patients?

Neoadjuvant chemotherapy (NCT) alone can achieve comparable treatment outcomes to chemoradiotherapy in locally advanced rectal cancer (LARC) patients. This study aimed to investigate the value of texture analysis (TA) in apparent diffusion coefficient (ADC) maps for identifying non-responders to NCT. This retrospective study included patients with LARC after NCT, and they were categorized into nonresponse group (pTRG 3) and response group (pTRG 0-2) based on pathological tumor regression grade (pTRG). Predictive texture features were extracted from pre- and post-treatment ADC maps to construct a TA model using RandomForest. The ADC model was developed by manually measuring pre- and post-treatment ADC values and calculating their changes. Simultaneously, subjective evaluations based on magnetic resonance imaging assessment of TRG were performed by two experienced radiologists. Model performance was compared using the area under the curve (AUC) and DeLong test. A total of 299 patients from two centers were divided into three cohorts: the primary cohort (center A; n = 194, with 36 non-responders and 158 responders), the internal validation cohort (center A; n = 49, with 9 non-responders) and external validation cohort (center B; n = 56, with 33 non-responders). The TA model was constructed by post_mean, mean_change, post_skewness, post_entropy, and entropy_change, which outperformed both the ADC model and subjective evaluations with an impressive AUC of 0.997 (95% confidence interval [CI], 0.975-1.000) in the primary cohort. Robust performances were observed in internal and external validation cohorts, with AUCs of 0.919 (95% CI, 0.805-0.978) and 0.938 (95% CI, 0.840-0.985), respectively. The TA model has the potential to serve as an imaging biomarker for identifying nonresponse to NCT in LARC patients, providing a valuable reference for these patients considering additional radiation therapy.

Prospective evaluation of MR-TRG (Tumor Regression Grade) in esophageal cancer after neo-adjuvant therapy: Preliminary results

PurposeTo develop MRI-based criteria to assess tumor response to neoadjuvant therapies (NAT) of esophageal cancers (EC) and to evaluate its diagnostic performance in predicting the pathological Tumor Regression Grade (pTRG). MethodFrom 2018 to 2022, patients with newly diagnosed locally advanced EC underwent MRI examinations for initial staging and restaging after NAT. Magnetic Resonance TRG (MR-TRG), equivalent to the Mandard and Becker classifications, were developed and independently assessed by two radiologists, blinded to pTRG, using T2W and DW-MR Images. All patients underwent surgery and benefited from a blinded pTRG evaluation by two pathologists. The agreement between readers and between MR-TRG and pTRG were assessed with Cohen’s Kappa. The correlation of MR-TRG and pTRG was determined using Spearman’s correlation. Results28 patients were included. Interrater agreement was substantial between radiologists, improved when grouping grade 1 and 2 (κ = 0.78 rose to 0,84 for Mandard and 0.68 to 0,78 for Becker score). Agreement between pTRG and MR-TRG was moderate with a percentaged agreement (p) = 87.5 %, kappa (κ) = 0.54 and p = 83.3 %, κ = 0.49 for Mandard and Becker, respectively. Agreement was improved to substantial when grouping grades 1–2 for Mandard and 1a-1b for Becker with p = 89.3 %, κ = 0.65 and p = 85.2 %, κ = 0.65 respectively. Sensitivity and specificity of MR-TRG in predicting pTRG were 88.2 % and 72.7 % for Mandard system (scores 1–2 versus 3–5), and 83.3 % and 80 % for Becker system (scores 1a-1b versus 2–3). ConclusionA substantial agreement between MR-TRG and pTRG was achieved when grouping grade 1–2. Hence, MR-TRG could be used as a surrogate of complete and near-complete pTRG.

MRI Tumor Regression Grade Combined with T2-Weighted Volumetry May Predict Histopathological Response in Locally Advanced Rectal Cancer following Neoadjuvant Chemoradiotherapy-A New Scoring System Proposal.

Modern studies focus on the discovery of innovative methods to improve the value of post-treatment magnetic resonance imaging (MRI) in the prediction of pathological responses to preoperative neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). The aim of this study was to assess the potential benefits of combining magnetic resonance tumor regression grade (mrTRG) with T2-weighted volumetry in the prediction of pathological responses to nCRT in LARC. This was a cohort study conducted on patients with histopathologically confirmed LARC in a period from 2020 to 2022. After histopathological verification, all patients underwent initial MRI studies, while the follow-up MRI was performed after nCRT. Tumor characteristics, MRI estimated tumor regression grade (mrTRG) and tumor volumetry were evaluated both initially and at follow-up. All patients were classified into responders and non-responders according to pathological tumor regression grade (pTRG) and mrTRG. A total of 71 patients, mostly male (66.2%) were included in the study. The median tumor volume reduction rate was significantly higher in nCRT-responders compared to non-responders (79.9% vs. 63.3%) (p = 0.003). Based on ROC analysis, optimal cut-off value for tumor volume reduction rate was determined with an area under the curve (AUC) value of 0.724 (p = 0.003). Using the tumor volume reduction rate ≥75% with the addition of response to nCRT according to mrTRG, a new scoring system for prediction of pTRG to preoperative nCRT in LARC was developed. Diagnostic performance of prediction score was tested and the sensitivity, PPV, specificity, and NPV were 81.8%, 56.3%, 71.4%, and 89.7%, respectively. The combination of mrTRG and T2-weighted volumetry increases the MRI-based prediction of pTRG to preoperative nCRT in LARC. The proposed scoring system could aid in distinguishing responders to nCRT, as these patients could benefit from organ-preserving treatment and a "watch and wait" strategy.

Value of spectral CT parameters in predicting the efficacy of neoadjuvant chemotherapy for gastric cancer

To investigate the value of pre-chemotherapy spectral computed tomography (CT) parameters in predicting neoadjuvant chemotherapy (NAC) response in gastric cancer (GC). Sixty patients with GC who received NAC and underwent spectral CT examination before chemotherapy were enrolled retrospectively and divided into a responsive group and a non-responsive group according to the postoperative pathological tumour regression grade. Clinical characteristics were collected. The iodine concentration (IC), water concentration (WC), and effective atomic number (Eff-Z) of the portal venous phases were measured before chemotherapy, and IC was normalised to that of the aorta to provide the normalised IC (NIC). An independent samples t-test, Mann-Whitney U-test, or chi-square test was used to analyse the differences between the two groups, and the receiver operating curve (ROC) was used to evaluate the predictive performance of different variables. The neutrophil-to-lymphocyte ratio (NLR) was lower in the responsive group than in the non-responsive group (p<0.05). IC, NIC, and Eff-Z values were significantly higher in the responsive group than in the non-responsive group (p<0.01). The areas under the ROC curves for the NLR, IC, NIC, and Eff-Z were 0.694, 0.688, 0.799, and 0.690, respectively. The combination of NIC, Eff-Z, and NLR values showed good diagnostic performance in predicting response to NAC in GC, with an area under the ROC curve of 0.857, 76.92% sensitivity, 80% accuracy, and 85.71% specificity. Spectral CT parameters may serve as non-invasive tools for predicting the response to NAC in patients with GC.

Evaluation of an Objective MRI-Based Tumor Regression Grade (mrTRG) Score and a Subjective Likert Score for Assessing Treatment Response in Locally Advanced Rectal Cancers-A Retrospective Study.

Purpose: Magnetic resonance imaging (MRI) with the help of MRI-based tumor regression grade (mrTRG) score has been used as a tool to predict pathological tumor regression grade (pTRG) in patients of rectal cancer post-neoadjuvant chemoradiation. Our study aims to evaluate the ability of MRI in assessing treatment response comparing an objective mrTRG score and a subjective Likert score, with a focus on the ability to predict pathologic complete response (pCR). Methods: Post-treatment MRI studies were retrospectively reviewed for 170 consecutive cases of histopathologically proven rectal cancer after receiving neoadjuvant chemoradiation and prior to surgery by two oncoradiologists blinded to the eventual postoperative histopathology findings. An objective (mrTRG) and a subjective Likert score were assigned to all the cases. Receiver operating characteristic curves were constructed to determine the ability of Likert scale and mrTRG to predict pCR, with postoperative histopathology being the gold standard. The optimal cutoff points on the scale of 1 to 5 were obtained for mrTRG and Likert scale with the greatest sum of sensitivity and specificity using the Youden Index. Results: The most accurate cutoff point for the mrTRG to predict complete response was 2.5 (using Youden index), with a sensitivity of 69.2%, specificity of 69.6%, positive predictive value (PPV) of 85.6%, negative predictive value (NPV) of 46.4%, and accuracy of 69.3%. The most accurate cutoff for the Likert scale to predict complete response was 3.5, with a sensitivity of 47.5%, specificity of 89.1%, PPV of 91.9%, NPV of 39.4%, and accuracy of 59%. mrTRG had a lower cutoff and was more accurate in predicting pCR compared to Likert score. Conclusion: An objective mrTRG was more accurate than a subjective Likert scale to predict complete response in our study.

Imaging lymph node regression can predict the pathological tumor regression grade in gastric cancer after neoadjuvant treatment

BackgroundNeoadjuvant chemotherapy has become the standard treatment for locally advanced gastric cancer. The tumor regression grade system is an effective and widely used tool for the evaluation of treatment response to neoadjuvant chemotherapy. However, whether tumor regression grade could be predicted using clinical characteristics is uncertain. MethodsA total of 287 locally advanced gastric cancer patients from 2014 to 2021 were retrospectively included. According to the College of American Pathologists' tumor regression grade system, patients were classified into response group (tumor regression grade 0–1) and non-response group (tumor regression grade 2–3). Associations between clinical characteristics and neoadjuvant chemotherapy response were performed by the logistic regression model. The Kaplan–Meier method was used to estimate the survival. A prediction scoring system was constructed based on the β coefficients of multivariate analysis. The receiver operating characteristic curve and decision curve analysis were used to evaluate the performance of the predictive scoring system. ResultsSurvival analysis showed that patients with tumor regression grades 0 to 1 had significantly better disease-free survival and overall survival than the tumor regression grades 2 to 3. Tumor differentiation, ycT stage, immunotherapy, and lymph node regression were independent predictors of pathological response to neoadjuvant chemotherapy. We further developed a scoring system to predict the tumor regression grade. The receiver operating characteristic and decision curve analysis showed good predictive performance of the scoring system. ConclusionLymph node regression could be used as a predictor for pathological response. We developed a scoring system to predict the treatment response of patients with gastric cancer receiving neoadjuvant chemotherapy. The scoring system based on the predictors could provide guidance for making clinical decisions.

Sense and nonsense of yT-staging on MRI after chemoradiotherapy in rectal cancer.

The aim of this work was to investigate the value of rectal cancer T-staging on MRI after chemoradiotherapy (ymrT-staging) in relation to the degree of fibrotic transformation of the tumour bed as assessed using the pathological tumour regression grade (pTRG) of Mandard as a standard of reference. Twenty two radiologists, including five rectal MRI experts and 17 'nonexperts' (general/abdominal radiologists), evaluated the ymrT stage on the restaging MRIs of 90 rectal cancer patients after chemoradiotherapy. The ymrT stage was compared with the final ypT stage at histopathology; the percentages of correct staging (ymrT = ypT), understaging (ymrT < ypT) and overstaging (ymrT > ypT) were calculated and compared between patients with predominant tumour at histopathology (pTRG4-5) and patients with predominant fibrosis (pTRG1-3). Interobserver agreement (IOA) was computed using Krippendorff's alpha. Average ymrT/ypT stage concordance was 48% for the experts and 43% for the nonexperts; ymrT/ypT stage concordance was significantly higher in the pTRG4-5 subgroup (58% vs. 41% for the pTRG1-3 group; p = 0.01), with the best results for the MRI experts. Overstaging was the main source of error, especially in the pTRG1-3 subgroup (average overstaging rate 38%-44% vs. 13%-55% in the pTRG4-5 subgroup). IOA was higher for the expert versus nonexpert readers (α = 0.67 vs. α = 0.39). ymrT-staging is moderately accurate; accuracy is higher in poorly responding patients with predominant tumour but low in good responders with predominant fibrosis, resulting in significant overstaging. Radiologists should shift their focus from ymrT-staging to detecting gross residual (and progressive) disease, and identifying potential candidates for organ preservation who would benefit from further clinical and endoscopic evaluation to guide final treatment planning.

Prognosis of Concurrent Versus Sequential Chemo-Radiotherapy Induction Followed by Surgical Resection in Patients with Advanced Thymic Epithelial Tumors: A Retrospective Study.

This study aimed to evaluate the prognosis of concurrent chemo-radiotherapy (CCRT) versus sequential chemo-radiotherapy (SCRT) induction followed by surgical resection in patients with advanced thymic epithelial tumors (TETs). This retrospective study included patients with advanced TETs who underwent CCRT or SCRT induction followed by surgical resection at the Second General Hospital of Guangdong Province between January 2008 and December 2019. The primary outcomes were induction response rate and surgical complete resection rate. The secondary outcomes were surgery combined resection, post-induction T staging, postoperative TNM staging, postoperative pathological tumor regression grade, progression-free survival (PFS) and overall survival (OS), and adverse events (AEs). A total of 31 patients were included, 15 of whom received CCRT and the other 16 SCRT. The induction response rates were 80.0 and 62.5%, respectively, the post-induction step-down rates were 46.7 and 31.3%, respectively, and the post-induction R0 resection rates were 80.0 and 68.8%, respectively, without significant differences between CCRT and SCRT groups (all P > 0.05). The 5-year OS rate was 64.2 and 51.6%, respectively, and PFS was 42.3 and 21.4%, respectively, without significant differences between CCRT and SCRT groups (both P > 0.05). AEs in the hematologic system were significantly higher with CCRT compared with SCRT (P = 0.009). Patients with advanced TETs might have a good prognosis with both CCRT and SCRT induction therapy, while SCRT induction may result in a lower probability of AEs in the hematologic system.

Serum Interleukin 6 Level is Associated With Overall Survival and Treatment Response in Gastric and Gastroesophageal Junction Cancer.

To identify novel prognostic and predictive biomarkers for gastric and gastroesophageal junction (G+GEJ) adenocarcinoma. There are few biomarkers to guide treatment for G+GEJ. The systemic inflammatory response of G+GEJ patients is associated with survival. In this study, we evaluated the relationship of circulating serum cytokine levels with overall survival (OS) and pathologic tumor regression grade (TRG) in G+GEJ patients. We queried the UT Southwestern gastric cancer biobank to identify consecutive patients diagnosed with G+GEJ from 2016 to 2022; these patients had pretreatment serum collected at diagnosis. For patients who received neoadjuvant therapy, an additional serum sample was collected immediately before surgical resection. An unbiased screen of 17 cytokines was measured in a discovery cohort. A multivariable Cox proportional hazards model was used to assess the association of cytokine concentration with OS. Findings were validated in additional patients. In patients who received neoadjuvant therapy, we assessed whether the change in interleukin 6 (IL-6) after therapy was associated with TRG. Sixty-seven patients were included in the discovery cohort, and IL-6 was the only pretreatment cytokine associated with OS; this was validated in 134 other patients (hazard ratio: 1.012 per 1pg/mL increase, 95% CI: 1.006-1.019, P = 0.0002). Patients in the top tercile of IL-6 level had worse median OS (10.6 months) compared with patients in the intermediate (17.4 months) and bottom tercile (35.8 months, P < 0.0001). Among patients who underwent neoadjuvant therapy (n = 50), an unchanged or decrease in IL-6 level from pretreatment to posttreatment, had a sensitivity and specificity of 80% for predicting complete or near-complete pathologic tumor regression (TRG 0-1). Pretreatment serum level of IL-6 is a promising prognostic biomarker for G+GEJ patients. Comparing pre and post-neoadjuvant IL-6 levels may predict pathologic response to neoadjuvant therapy.

Nuclear Factor Erythroid 2-Related Factor 2/Kelch-Like ECH-Associated Protein 1 as a Predictor of Prognosis and Radiotherapy Resistance in Patients With Locally Advanced Rectal Cancer: A Prospective Analysis.

The nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) signaling pathway is involved in the regulation of cellular responses to oxidative stress. Nrf2 acts as a cell protector from inflammation, cellular damage, and tumorigenesis, whereas Keap1 is a negative regulator of Nrf2. Dysregulation of the Nrf2/Keap1 pathway results in tumorigenesis and the active metabolism of tumor cells, leading to high resistance to radiotherapy. This study aimed to evaluate the predictive role of Nrf2 and Keap1 in the radiosensitivity and prognosis of locally advanced rectal cancer (LARC). In total, 90 patients with LARC underwent surgery after preoperative chemoradiotherapy (CRT). Endoscopic biopsies from the tumors were obtained before radiation, and the Nrf2 and Keap1 expressions were assessed by immunohistochemistry. The response to therapy was evaluated after surgery following CRT according to the pathologic tumor regression grade. The disease-free survival (DFS) and overall survival rates were also documented. The association between the Nrf2 and Keap1 immunoreactivity and the clinicopathological parameters was analyzed. The overexpression of the nuclear Nrf2 before CRT showed a significant correlation with better DFS. The cytoplasmic Nrf2 expression was associated with more residual tumors after radiotherapy and a more unfavorable DFS, indicating lower radiosensitivity. CRT is an important issue in LARC and is a major aspect of treatment. Thus, the Nrf2/Keap1 expression may be a potential predictor of preoperative therapeutic resistance. The Nrf2-Keap1 modulators that interact with each other may also be effectively applicable to CRT effect in LARC.

Comparison of the pathological response to 2 or 4 cycles of neoadjuvant CAPOX in II/III rectal cancer patients with low/intermediate risks: study protocol for a prospective, non-inferior, randomized control trial (COPEC trial)

BackgroundFor patients with low- and intermediate-risk stage II/III rectal cancer, current studies have reached a consensus that preoperative radiotherapy may be dispensed with, and neoadjuvant chemotherapy (NCT) alone might achieve an accepted local control. Our previous phase II study has evidenced that the morphological response of NCT could be better judged at a relatively early stage. Low- and intermediate-risk stage II/III rectal cancer patients could achieve a high rate of tumor shrinkage and downgrade after only 4 cycles of NCT and obvious tumor morphological changes could be observed after 2 cycles of NCT. However, there is still a lack of more detailed stratification and evidence for pathological criteria. The aim of the present study (comparison of the pathological response to 2 or 4 cycles of neoadjuvant CAPOX in II/III rectal cancer patients with low/intermediate risks, COPEC trial) is to determine the pathological tumor regression grade (pTRG) rate of 2 or 4 cycles of NCT in low- and intermediate-risk stage II/III rectal cancer and verify the feasibility of early identification of chemotherapy-insensitive population.Methods/designThis is a multicenter, prospective, non-inferior, randomized controlled trial (RCT) initiated by West China Hospital of Sichuan University and designed to be conducted in fourteen hospitals around China. Eligible patients will be centrally randomized into 2 or 4 cycles of CAPOX in a 1:1 ratio using the central automated randomization system offered by the O-trial online system (https://plus.o-trial.com/) and accept total mesorectal excision after 2 or 4 cycles of CAPOX (oxaliplatin 130 mg/m2, once daily on day 1, every 21 days and capecitabine 1000 mg/m2, twice daily on days 1 to 14, every 21 days). The primary endpoint is the proportion of patients with pathological no-tumor regression (pTRG 3), which is determined postoperatively by each sub-center and verified by the primary center.DiscussionCOPEC trial is designed to verify that the preoperative CAPOX chemotherapy for low- and intermediate-risk stage II/III rectal cancer could achieve a good response judgment after 2 cycles and obtain the tumor pathological response rate after 2 cycles of CAPOX. We hope the COPEC trial could help in establishing a consensus standard of low- and intermediate-risk rectal cancer and the early identification of stage II/III rectal patients with low- and intermediate-risk who are poorly responding to NCT.Trial registrationClinicaltrial.gov NCT04922853. Registered on June 4, 2021.

The role of MRI after neochemoradiotherapy in predicting pathological tumor regression grade and clinical outcome in patients with locally advanced rectal adenocarcinoma.

To evaluate the predictive value of tumor regression grade assessed by MRI (mr-TRG) after neoadjuvant chemoradiotherapy (neo-CRT) for postoperative pathological TRG (pTRG) and prognosis in patients with locally advanced rectal adenocarcinoma (LARC). This was a retrospective study from a single center experience. The patients who were diagnosed with LARC and received neo-CRT in our department between January 2016 and July 2021 were enrolled. The agreement between mrTRG and pTRG was assessed with the weighted κ test. Overall survival (OS), progress-free survival (PFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were calculated by Kaplan-Meier analysis and log-rank test. From January 2016 to July 2021, 121 LARC patients received neo-CRT in our department. Among them, 54 patients had complete clinical data, including MRI of pre- and post-neo-CRT, postoperative tumor samples, and follow-up. The median follow-up time was 34.6 months (range: 4.4-70.6 months). The estimated 3-year OS, PFS, LRFS and DMFS were 78.5%, 70.7%, 89.0%, and 75.2%, respectively. The median time from the completion of neo-CRT to preoperative MRI and surgery was 7.1 weeks and 9.7 weeks, respectively. Out of 54 patients, 5 patients achieved mrTRG1 (9.3%), 37 achieved mrTRG2 (68.5%), 8 achieved mrTRG3 (14.8%), 4 achieved mrTRG4 (7.4%), and no patient achieved mrTRG5 after neo-CRT. Regarding pTRG, 12 patients achieved pTRG0 (22.2%), 10 achieved pTRG1 (18.5%), 26 achieved pTRG2 (48.1%), and 6 achieved pTRG3 (11.1%). The agreement between three-tier mrTRG (mrTRG1 vs. mrTRG2-3 vs. mrTRG4-5) and pTRG (pTRG0 vs. pTRG1-2 vs. pTRG3) was fair (weighted kappa=0.287). In a dichotomous classification, the agreement between mrTRG(mrTRG1 vs. mrTRG2-5)and pTRG(pTRG0 vs. pTRG1-3) also resulted in fair agreement (weighted kappa=0.391). The sensitivity, specificity, positive, and negative predictive values of favorable mrTRG (mrTRG 1-2) for pathological complete response (PCR) were 75.0%, 21.4%, 21.4%, and 75.0%, respectively. In univariate analysis, favorable mrTRG (mrTRG1-2) and downstaging N were significantly associated with better OS, while favorable mrTRG (mrTRG1-2), downstaging T, and downstaging N were significantly associated with superior PFS (p<0.05). In multivariate analysis, downstaging N was an independent prognostic factor for OS. Meanwhile, downstaging T and downstaging N remained independent prognostic factors for PFS. Although the consistency between mrTRG and pTRG is only fair, favorable mrTRG after neo-CRT may be used as a potential prognostic factor for LARC patients.

Perioperative immunochemotherapy (mDCF + avelumab) in locally advanced gastro-esophageal adenocarcinoma: A phase II trial.

4055 Background: Perioperative chemotherapy improves cure rate in locally advanced gastro-esophageal adenocarcinoma (GEA). Immune checkpoint inhibitors have activity in GEA. This trial is testing the hypothesis that the addition of avelumab, an anti-PD-L1 antibody, to perioperative mDCF chemotherapy, will increase the pathologic complete response (pCR) rate, a potential surrogate for overall survival, in comparison with a historical pCR rate of 7%. Methods: Single-arm phase II study (NCT03288350) of avelumab + chemotherapy (modified docetaxel/cisplatin/5-FU or mDCF) given every 2 weeks x 4 cycles before and after surgery. Planned sample size of 50 operated patients. The hypothesis cannot be refuted if ≥6 patients show pCR, the primary endpoint. Inclusion criteria: histologically proven GEA, locally advanced disease (cT3-4 and/or N+), adequate organ function, WHO performance status 0-1. Exclusion criteria: other histology, metastatic stage, use of immunosuppressants, serious autoimmune disease, intake &gt;10 mg prednisone/d. Adverse effects prospectively recorded per NCI CTCAE guidelines. Pathological response and tumor regression grade (TRG) determined by CAP criteria: 0=complete;1=near complete; 2=moderate; 3 = poor/no response. Data presented as median (range), KM determined survival. Results: Study accrual completed August 2022: 51 patients enrolled, 45 M/6 F, age 64 (18-79), ECOG 0 (35) and 1 (16). One patient withdrew consent after 2 treatment cycles and is excluded from efficacy analysis. Tumor anatomic site: Esophagus =19(38%)/gastroesophageal junction 21(42%)/subcardia stomach 10(20%). Staging: cT3 (88%), cT4 (6%), N+ (62%). Histology: all adenocarcinoma; dMMR 9/50 in 18%; CPS&lt;1, 1-5, 6-10, &gt;10 in 0%/33%/27%/40% of tumors tested. All 4 pre-operative cycles administered to 48/50 (96%); 36/50 received ≥2 adjuvant treatment cycles and 23/50 (46%) received all 8 cycles. Grade 3-4 toxicity events from neoadjuvant therapy affected: GI tract (diarrhea 4%); respiratory system (pneumonia 4%); endocrine system (adrenal insufficiency 2%). Other common side effects (grades 1-2, incidence &gt; 15%) were: fatigue, diarrhea, skin rash/pruritus. Post-operative mortality at 30 and 90 days was 0/50 (0%) and 1/50 (2%). R0 resection was achieved in 48/50 (96%); a median of 36 (13-78) lymph nodes were resected. Pathological response was TRG 0/1/2/3 in 7/2/16/25 with pCR seen in 7 (14%), meeting the primary endpoint. Major pathologic response (TRG 0 and 1) was seen in 9 (18%), but without correlation with CPS or dMMR biomarker status. At 37.5 (9-71) months follow up, overall survival at 1, 2, and 3 years is 93.6%, 75.7%, and 69.2%. MPR showed a trend to improved survival ( p = 0.06). Conclusions: The neoadjuvant combination of avelumab with chemotherapy (mDCF) shows promising safety and efficacy in gastroesophageal adenocarcinoma, without obvious correlation to known biomarkers. Clinical trial information: NCT03288350 .