Tumor Regression Grade Research Articles

Lymph node volume predicts survival in esophageal squamous cell carcinoma treated with neoadjuvant chemoradiotherapy and surgery.

Large primary tumor volume has been identified as a poor prognostic factor of esophageal squamous cell carcinoma (ESCC) treated with definitive concurrent chemoradiotherapy (CCRT). However, when neoadjuvant CCRT and surgery are adopted, the prognostic impact of primary tumor and lymph node (LN) volume on clinical outcomes in ESCC remains to be elucidated. This study included 107 patients who received neoadjuvant CCRT and surgery for ESCC. The volume of the primary tumor and LN was measured using radiotherapy planning computed tomography scans, and was correlated with overall survival (OS), disease-free survival (DFS), and cancer failure pattern. The median OS was 24.2 months (IQR, 11.1-93.9) after a median follow-up of 18.4 months (IQR, 8.1-40.7). The patients with a baseline LN volume > 7.7 ml had a significantly worse median OS compared to those with smaller LN volume (18.8 vs. 46.9 months, p = 0.049), as did those with tumor regression grade (TRG) 3-5 after CCRT (13.9 vs. 86.7 months, p < 0.001). However, there was no association between OS and esophageal tumor volume (p = 0.363). Multivariate analysis indicated that large LN volume (HR 1.753, 95% CI 1.015-3.029, p = 0.044) and high TRG (HR 3.276, 95% CI 1.556-6.898, p = 0.002) were negative prognostic factors for OS. Furthermore, large LN volume was linked to increased locoregional failure (p = 0.033) and decreased DFS (p = 0.041). In conclusion, this study demonstrated that large LN volume is correlated with poor OS, DFS, and locoregional control in ESCC treated with neoadjuvant CCRT and esophagectomy.

Value of perfusion parameters from golden-angle radial sparse parallel dynamic contrast-enhanced magnetic resonance imaging in predicting pathological complete response after neoadjuvant chemoradiotherapy for locally advanced rectal cancer

Non-invasive methods for predicting pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) can provide distinct leverage in the management of patients with locally advanced rectal cancer (LARC). This study aimed to investigate whether including the golden-angle radial sparse parallel (GRASP) dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion parameter (Ktrans), in addition to tumor regression grading (TRG) and apparent diffusion coefficient (ADC) values, can improve the predictive ability for pCR. Patients with LARC who underwent nCRT and subsequent surgery were included. The imaging parameters were compared between patients with and without pCR. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive ability of these parameters for pCR. A total of 111 patients were included in the study. A pCR was obtained in 32 patients (28.8%). MRI-based TRG (mrTRG) showed a negative correlation with pCR (r = -0.61, P < 0.001), and the average ADC value showed a positive correlation with pCR (r = 0.62, P < 0.001). Before nCRT, Ktrans in the pCR group was significantly higher than in the non-pCR group (1.30 ± 0.24 vs. 0.88 ± 0.34, P < 0.001), but no difference was identified after nCRT. Following ROC curve analysis, the area under the curve (AUC) of mrTRG (level 1-2), average ADC value, and Ktrans value for predicting pCR were 0.738 [95% confidence interval (CI): 0.65-0.82], 0.78 (95% CI: 0.69-0.86), and 0.84 (95% CI: 0.77-0.92), respectively. The model combining the three parameters had significantly higher predictive ability for pCR (AUC: 0.94, 95% CI: 0.88-0.98). The use of a combination of the GRASP DCE-MRI Ktrans with mrTRG and ADC can lead to a better pCR predictive performance.

Abstract 2582: Intra- and peri-tumoral radiomic features are predictive of pathologic response to multiple neoadjuvant therapy regimen in rectal cancers via pre-treatment MRI

Abstract Introduction: Rectal cancers undergo neoadjuvant chemoradiation prior to resection, with increasing evidence that neoadjuvant chemotherapy or immunotherapy can boost clinical or pathologic response rates. However, baseline clinical tumor staging and carcinoembryonic antigen levels are limited for identifying which patients will most benefit from a multimodal neoadjuvant regimen, and which will not. We evaluated whether radiomics (computational features from radiographic images) from pretreatment MRI could identify which rectal cancer patients will achieve clinical or pathologic response to different neoadjuvant treatment regimens. Methods: MRI scans were retrospectively obtained from 3 different institutions for rectal cancer patients who had either undergone neoadjuvant chemoradiation or an experimental immunotherapy + chemoradiation. After pre-processing all MRI scans, tumor was manually delineated with an automated annotation of a 10 mm peritumor region. 916 radiomic features were extracted from two planes of acquisition (axial, coronal) and two ROIs (tumor, peritumor). 5 top-ranked radiomic features were identified from each region and plane via multi-stage mutual information feature selection to train a linear discriminant machine classifier to assign a predicted likelihood of achieving complete response to each patient. Model performance was validated via ROC analysis against response groups defined via (i) tumor regression grade indicating no tumor present on surgical pathology, and (ii) 1-year clinical complete response for patients who underwent non-operative management. Clinical variables (CEA, clinical stage) were statistically compared between response groups. Results: Training cohort comprised 64 patients who underwent chemoradiation alone (2 institutions, median age 61 yrs, M:F:MtF = 36:27:1). Validation cohort included 37 patients who underwent experimental TGFß inhibitor therapy prior to chemotherapy + chemoradiation (1 institution, median age 51 yrs, M:F = 25:12). Area under the ROC curve for multi-plane tumor+peritumor radiomic features (0.765 ± 0.054) was significantly higher for distinguishing complete response vs non/partial response compared to tumor (AUC = 0.635 ± 0.057, p &amp;lt; 0.0001) or peritumor (AUC = 0.612 ± 0.064, p &amp;lt; 0.0001). In holdout validation, performance was maintained with AUCs of 0.742 (tumor) 0.596 (peritumor), and 0.700 (all), respectively. Baseline CEA levels (p=0.3385) and cT stage (p=0.3386) were found to lack statistical significance as a predictor of response. Conclusion: Radiomic features from tumor and peritumor regions on pre-treatment MRI scans in rectal cancer patients may enable robust and accurate identification of pathologic or near-complete response after multiple neoadjuvant treatment regimen, while outperforming baseline clinical variables. Citation Format: Leo Bao, Thomas DeSilvio, Benjamin N. Parker, Mohsen Hariri, Prathyush Chirra, Murad Labbad, Stephen Tang, Gregory M. O'Connor, Emily Steinhagen, Jennifer L. Miller-Ocuin, Amit Gupta, Eric L. Marderstein, Aaron Carroll, Marka Crittenden, Michael J. Gough, Smitha Krishnamurthi, Kristina H. Young, Satish E. Viswanath. Intra- and peri-tumoral radiomic features are predictive of pathologic response to multiple neoadjuvant therapy regimen in rectal cancers via pre-treatment MRI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2582.

Negative prognostic impact of Co-mutations in TGFβ and TP53 pathways in surgically resected rectal tumors following neoadjuvant chemoradiotherapy

BackgroundPreoperative neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) is a common approach for treating patients with locally advanced rectal cancer. Nevertheless, the mutational profile and its prognostic impact in surgically resected tumor specimens after nCRT remains to be clarified. MethodsThe comprehensive analysis of mutational landscape was retrospectively conducted by target regions sequencing approach that covered 150 tumor-related genes. Univariate and multivariate logistic regression and Cox regression was used to examine the association of mutation status in genes and pathways with pathological response and prognosis. Data from Memorial Sloan Kettering Cancer Center (MSK) cohort was used for comparison with our results. ResultsThe top five commonly mutated genes in resected rectal tumor tissue samples following nCRT were TP53 (42%), APC (31%), KRAS (27%), PIK3CA (14%) and FBXW7 (11%). Mutations in the WNT pathway, which was mainly represented by APC mutation, were found to be significantly associated with tumor regression grade (TRG) 3. In our cohort, co-mutations in the receptor tyrosine kinase (RTK)/RAS and WNT pathways were found to be independently associated with reduced risk of recurrent and significantly associated with longer disease-free survival (DFS). In both our cohort and the MSK cohort, co-mutations in the TGF-β and TP53 pathways were significantly associated with worse DFS. ConclusionsResected rectal tumor samples from patients without complete pathological response can be appropriately used to detect mutations. Co-mutations in the TGF-β and TP53 pathways may provide more prognostic information beyond commonly used clinical factors.

Nomograms integrating the collagen signature and systemic immune-inflammation index for predicting prognosis in rectal cancer patients.

This study aimed to develop and validate a model based on the collagen signature and systemic immune-inflammation index to predict prognosis in rectal cancer patients who underwent neoadjuvant treatment. Patients with rectal cancer who had residual disease after neoadjuvant treatment at two Chinese institutions between 2010 and 2018 were selected, one used as a training cohort and the other as a validation cohort. In total, 142 fully quantitative collagen features were extracted using multiphoton imaging, and a collagen signature was generated by least absolute shrinkage and selection operator Cox regression. Nomograms were developed by multivariable Cox regression. The performance of the nomograms was assessed via calibration, discrimination and clinical usefulness. The outcomes of interest were overall survival and disease-free survival calculated at 1, 2 and 3 years. Of 559 eligible patients, 421 were selected (238 for the training cohort and 183 for the validation cohort). The eight-collagen-features collagen signature was built and multivariable Cox analysis demonstrated that it was an independent prognostic factor of prognosis along with the systemic immune-inflammation index, lymph node status after neoadjuvant treatment stage and tumour regression grade. Then, two nomograms that included the four predictors were computed for disease-free survival and overall survival. The nomograms showed satisfactory discrimination and calibration with a C-index of 0.792 for disease-free survival and 0.788 for overall survival in the training cohort and 0.793 for disease-free survival and 0.802 for overall survival in the validation cohort. Decision curve analysis revealed that the nomograms could add more net benefit than the traditional clinical-pathological variables. The study found that the collagen signature, systemic immune-inflammation index and nomograms were significantly associated with prognosis.

Pre-hepatectomy dynamic circulating tumor DNA to predict pathologic response to preoperative chemotherapy and post-hepatectomy recurrence in patients with colorectal liver metastases.

To evaluate the predictive value of pre-hepatectomy dynamic circulating tumor DNA (ctDNA) on pathologic response to preoperative chemotherapy and recurrence after liver resection for colorectal liver metastases (CRLM). Pathologic response is a predictor of clinical outcomes for patients undergoing hepatectomy for CRLM. Postoperative ctDNA has been proven to be sensitive for recurrence detection. However, few studies investigate the impact of pre-hepatectomy ctDNA on pathologic response and recurrence. Patients with potential resectable CRLM underwent preoperative chemotherapy and hepatectomy between 2018 and 2021 was considered for inclusion. Plasma ctDNA was collected before and after preoperative chemotherapy. Pathologic response was analyzed for all patients after liver resection. Recurrence free survival was compared between patients with different ctDNA status and different pathologic response. The relation between ctDNA and pathologic response was also analyzed. A total of 114 patients were included. ctDNA was detectable in 108 of 114 patients (94.7%) before chemotherapy, in 56 of 114 patients (49.1%) after chemotherapy. Patients with ctDNA positive at baseline and negative after chemotherapy had significantly longer RFS (median RFS 17 vs 7months, p = 0.001) and HRFS (median HRFS unreached vs 8months, p < 0.001) than those with ctDNA persistently positive after chemotherapy. Two patients (1.6%) had a pathologic complete response and 56 patients (45.2%) had a pathologic major response. Post-chemotherapy ctDNA- was associated with improved major pathologic response (53.4% vs 32.1%, p = 0.011). In the multivariable analysis, ctDNA- after chemotherapy (HR 0.51, 95% CI 0.28-0.93), major pathologic response (HR 0.34, 95% CI 0.19-0.62) and surgery combined with radiofrequency ablation (HR 2.62, 95% CI 1.38-5.00) were independently associated with RFS (all p < 0.05). Pre-hepatectomy dynamic monitoring of ctDNA could predict pathologic response to preoperative chemotherapy and post-hepatectomy recurrence in CRLM patients. Negative ctDNA after preoperative chemotherapy was associated with better tumor regression grade and recurrence-free survival, which might be used to guide pre-hepatectomy chemotherapy and predict prognosis.

Development of a clinical nomogram for prediction of response to neoadjuvant chemotherapy in patients with advanced gastric cancer.

The efficacy of neoadjuvant chemotherapy (NAC) in advanced gastric cancer (GC) is still a controversial issue. To find factors associated with chemosensitivity to NAC treatment and to provide the optimal therapeutic strategies for GC patients receiving NAC. The clinical information was collected from 230 GC patients who received NAC treatment at the Central South University Xiangya School of Medicine Affiliated Haikou Hospital from January 2016 to December 2020. Least absolute shrinkage and selection operator logistic regression analysis was used to find the possible predictors. A nomogram model was employed to predict the response to NAC. In total 230 patients were finally included in this study, including 154 males (67.0%) and 76 females (33.0%). The mean age was (59.37 ± 10.60) years, ranging from 24 years to 80 years. According to the tumor regression grade standard, there were 95 cases in the obvious response group (grade 0 or grade 1) and 135 cases in the poor response group (grade 2 or grade 3). The obvious response rate was 41.3%. Least absolute shrinkage and selection operator analysis showed that four risk factors significantly related to the efficacy of NAC were tumor location (P < 0.001), histological differentiation (P = 0.001), clinical T stage (P = 0.008), and carbohydrate antigen 724 (P = 0.008). The C-index for the prediction nomogram was 0.806. The calibration curve revealed that the predicted value exhibited good agreement with the actual value. Decision curve analysis showed that the nomogram had a good value in clinical application. A nomogram combining tumor location, histological differentiation, clinical T stage, and carbohydrate antigen 724 showed satisfactory predictive power to the response of NAC and can be used by gastrointestinal surgeons to determine the optimal treatment strategies for advanced GC patients.

Oncological risk of proximal gastrectomy for proximal advanced gastric cancer after neoadjuvant chemotherapy

PurposeThis study assesses the metastasis rate of the key distal lymph nodes (KDLN) that are not routinely dissected in proximal gastrectomy, aiming to explore the oncological safety of proximal gastrectomy for upper gastric cancer who underwent neoadjuvant chemotherapy.MethodsWe analyzed a cohort of 150 patients with proximal locally advanced gastric cancer (cT3/4 before chemotherapy) from two high-volume cancer centers in China who received preoperative neoadjuvant chemotherapy (NAC) and total gastrectomy with lymph node dissection. Metastasis rate of the KDLN (No.5/6/12a) and the risk factors were analyzed.ResultsKey distal lymph node metastasis was detected in 10% (15/150) of patients, with a metastasis rate of 6% (9/150) in No. 5 lymph nodes, 6.7% (10/150) in No. 6 lymph nodes, and 2.7% (2/75) in No. 12a lymph nodes. The therapeutic value index of KDLN as one entity is 5.8. Tumor length showed no correlation with KDLN metastasis, while tumor regression grade (TRG) emerged as an independent risk factor (OR: 1.47; p-value: 0.04). Of those with TRG3 (no response to NAC), 80% (12/15) was found with KDLN metastasis.ConclusionFor cT3/4 proximal locally advanced gastric cancer patients, the risk of KDLN metastasis remains notably high even after NAC. Therefore, proximal gastrectomy is not recommended; instead, total gastrectomy with thorough distal lymphadenectomy is the preferred surgical approach.

Prognostic Value of Inflammatory Burden Index in Advanced Gastric Cancer Patients Undergoing Multimodal Treatment.

Since increasing evidence underlines the prominent role of systemic inflammation in carcinogenesis, the inflammation burden index (IBI) has emerged as a promising biomarker to estimate survival outcomes among cancer patients. The IBI has only been validated in Eastern gastric cancer (GC) patients; therefore, the aim of this study was to evaluate the IBI as a prognostic biomarker in Central European GC patients undergoing multimodal treatment. Ninety-three patients with histologically confirmed GC who underwent multimodal treatment between 2013 and 2021 were included. Patient recruitment started with the standardization of neoadjuvant chemotherapy (NAC). Blood samples were obtained one day prior to surgical treatment. The textbook outcome (TO) served as the measure of surgical quality, and tumor responses to NAC were evaluated according to Becker's system tumor regression grade (TRG). A high IBI was associated with an increased risk of postoperative complications (OR 2.95, 95% CI 1.13-7.72). In multivariate analysis, a high IBI (HR = 2.56, 95% CI 1.28-5.13) and a high neutrophil-to-lymphocyte ratio (NLR, HR = 2.55, 95% CI 1.32-4.94) were associated with an increased risk of death, while NAC administration (HR = 0.40, 95% CI 0.18-0.90) and TO achievement (HR = 0.42, 95% CI 0.22-0.81) were associated with a lower risk of death. The IBI was associated with postoperative complications and mortality among GC patients undergoing multimodal treatment.

Tumour response following preoperative chemotherapy is affected by body mass index in patients with colorectal liver metastases.

Colorectal cancer is the third most prevalent malignancy globally and ranks second in cancer-related mortality, with the liver being the primary organ of metastasis. Preoperative chemotherapy is widely recommended for initially or potentially resectable colorectal liver metastases (CRLMs). Tumour pathological response serves as the most important and intuitive indicator for assessing the efficacy of chemotherapy. However, the postoperative pathological results reveal that a considerable number of patients exhibit a poor response to preoperative chemotherapy. Body mass index (BMI) is one of the factors affecting the tumorigenesis and progression of colorectal cancer as well as prognosis after various antitumour therapies. Several studies have indicated that overweight and obese patients with metastatic colorectal cancer experience worse prognoses than those with normal weight, particularly when receiving first-line chemotherapy regimens in combination with bevacizumab. To explore the predictive value of BMI regarding the pathologic response following preoperative chemotherapy for CRLMs. A retrospective analysis was performed in 126 consecutive patients with CRLM who underwent hepatectomy following preoperative chemotherapy at four different hospitals from October 2019 to July 2023. Univariate and multivariate logistic regression models were applied to analyse potential predictors of tumour pathological response. The Kaplan-Meier method with log rank test was used to compare progression-free survival (PFS) between patients with high and low BMI. BMI < 24.0 kg/m2 was defined as low BMI, and tumour regression grade 1-2 was defined as complete tumour response. Low BMI was observed in 74 (58.7%) patients and complete tumour response was found in 27 (21.4%) patients. The rate of complete tumour response was significantly higher in patients with low BMI (29.7% vs 9.6%, P = 0.007). Multivariate analysis revealed that low BMI [odds ratio (OR) = 4.56, 95% confidence interval (CI): 1.42-14.63, P = 0.011], targeted therapy with bevacizumab (OR = 3.02, 95%CI: 1.10-8.33, P = 0.033), preoperative carcinoembryonic antigen level < 10 ng/mL (OR = 3.84, 95%CI: 1.19-12.44, P = 0.025) and severe sinusoidal dilatation (OR = 0.17, 95%CI: 0.03-0.90, P = 0.037) were independent predictive factors for complete tumour response. The low BMI group exhibited a significantly longer median PFS than the high BMI group (10.7 mo vs 4.7 mo, P = 0.011). In CRLM patients receiving preoperative chemotherapy, a low BMI may be associated with better tumour response and longer PFS.

Predicting pathologic response to neoadjuvant chemotherapy in locally advanced gastric cancer: The establishment of a spectral CT-based nomogram from prospective datasets

BackgroundTo establish a spectral CT-based nomogram for predicting early neoadjuvant chemotherapy (NAC) response for locally advanced gastric cancer (LAGC). MethodsThis study prospectively recruited 222 cases (177 male and 45 female patients, 9.59 ± 9.54 years) receiving NAC and radical gastrectomy. Triple enhanced spectral CT scans were performed before NAC initiation. According to post-operative tumor regression grade (TRG), patients were classified into responders (TRG = 0 + 1) or non-responders (TRG = 2 + 3), and split into a primary (156) and validation (66) dataset at 7:3 ratio chronologically. We compared clinicopathological data, follow-up information, iodine concentration (IC), normalized ICs (nICs) in arterial/venous/delayed phases (AP/VP/DP) between responders and non-responders. Independent risk factors of response were screened by multivariable logistic regression and adopted for model construction. Model was visualized by nomograms and its capability was determined through receiver operating characteristic (ROC) curves. Log-rank survival analysis was conducted to explore associations between TRG, nomogram and patients’ survival. ResultsThis work identified Borrmann classification, ICDP, and nICDP were independent risk factors of response outcomes. A spectral CT-based nomogram was built accordingly and achieved an area under the curve (AUC) of 0.797 (0.692–0.879) and 0.741(0.661–0.811) for the primary and validation dataset, respectively, higher than AUC of individual parameters alone. The nomogram was related to disease-free survival in the validation dataset (Hazard ratio (HR): 5.19 [1.18–12.93], P = 0.02). ConclusionsThe spectral CT-based nomogram provides an efficient tool for predicting the pathologic response outcomes of GC after NAC and disease-free survival risk stratification.

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.

Treatment Response to Neoadjuvant Therapy in Squamous Esophageal Cancer-Correlation Between Metabolic Response and Histopathology.

Esophageal cancer is among the leading causes of cancer-related mortality worldwide. Patients presenting with localized and loco-regionally advanced cancer without distant metastases have reasonable survival with multimodality management. Adequate and comprehensive staging is the backbone for proper selection of patients fit for curative treatment. Positron emission tomography (PET) in combination with contrast-enhanced computed tomography (CECT) is utilized as the standard staging modality. Multimodality treatment has been able to achieve evaluable tumor responses including pathological complete response (pCR). It is, therefore, necessary to understand whether the impact of neoadjuvant therapy can be evaluated on imaging, i.e., standardized uptake value (SUV) on PET scan done for response assessment and if this can be correlated with histopathological response and later, with survival. Squamous cell carcinoma (SCC) is more common globally and in the Indian subcontinent; hence, we chose this subgroup to evaluate our hypothesis. This is a single institution, retrospective study. Out of the 1967 patients who were treated between 2009 and 2019, 1369 (78.54%) patients had SCC. Out of these, 44 received NACTRT, whereas 1325 received NACT followed by curative surgery. The standardized uptake value (SUV) of 18-fluorodeoxyglucose was recorded during pre- and post-neoadjuvant treatment (NAT) using positron emission tomography (PET). The histopathology of the final resection specimen was evaluated using the Mandard tumor regression grade (TRG) criteria with response being graded from 0 to 5 as no residual tumor (NRT), scanty residual tumor (SRT), and residual tumor We attempted to find a cut-off value of the post neoadjuvant SUV of the primary tumor site which correlated with achievement of better histopathological response. Out of 1325 patients of SCC esophagus who underwent surgery, 943 patients had available data of TRG, and it was categorized into the 0-2 category which had 325 patients (34.5%) and 3-5 category, 618 patients (65.5%). The SUV was taken only from the PET scans done at our institution, so as to achieve a more homogenous cohort, and this was available for 186 patients, 151 from the NACT group and 35 from the NACTRT group. The ROC method was used to find the cut-off for SUV (5.05) in the NACT cohort, which depicted significant difference in the outcome. Out of these, 93 patients who underwent NACT had SUV > 5.05 and 58 had SUV < 5.05. It was found that the subjective and objective histopathological scores correlated at a p value of < 0.0001. Specifically, the majority of cases with SRT tended to be in the 3-5 category of TRG, whereas cases with NRT are predominantly in the 0-2 category. In the ≥ 5.05 category of SUV, there were 76 cases with SRT. In the NACT cohort, the < 5.05 category of SUV, there are 26 cases with SRT and 32 cases with NRT. Among cases with SRT, 74.5% had SUV ≥ 5.05, while 25.5% had SUV < 5.05. Among cases with NRT, 34.7% had SUV ≥ 5.05, while 65.3% had SUV < 5.05 (p value 0.007). No significant association was found in the radio-pathological correlation in the NACTRT group. Our study confirms the correlation of post neoadjuvant chemotherapy PET SUV with histopathological response, the cut-off of SUV being 5.05 in our cohort. This confirms the predictive value of FDG PET as demonstrated in other studies. Furthermore, its prognostic value with respect to survival has been verified in multiple other studies. With larger scale randomized studies, we may be able to identify the group of patients who have borderline operability anatomically as well as physiologically, where alternative treatment regimens may be indicated to improve outcomes.

Prognostic value of Mandard score and nodal status for recurrence patterns and survival after multimodal treatment of oesophageal adenocarcinoma.

This study evaluated the association of pathological tumour response (tumour regression grade, TRG) and a novel scoring system, combining both TRG and nodal status (TRG-ypN score; TRG1-ypN0, TRG>1-ypN0, TRG1-ypN+ and TRG>1-ypN+), with recurrence patterns and survival after multimodal treatment of oesophageal adenocarcinoma. This Dutch nationwide cohort study included patients treated with neoadjuvant chemoradiotherapy followed by oesophagectomy for distal oesophageal or gastro-oesophageal junctional adenocarcinoma between 2007 and 2016. The primary endpoint was the association of Mandard score and TRG-ypN score with recurrence patterns (rate, location, and time to recurrence). The secondary endpoint was overall survival. Among 2746 inclusions, recurrence rates increased with higher Mandard scores (TRG1 30.6%, TRG2 44.9%, TRG3 52.9%, TRG4 61.4%, TRG5 58.2%; P < 0.001). Among patients with recurrent disease, the distribution (locoregional versus distant) was the same for the different TRG groups. Patients with TRG1 developed more brain recurrences (17.7 versus 9.8%; P = 0.001) and had a longer mean overall survival (44 versus 35 months; P < 0.001) than those with TRG>1. The TRG>1-ypN+ group had the highest recurrence rate (64.9%) and worst overall survival (mean 27 months). Compared with the TRG>1-ypN0 group, patients with TRG1-ypN+ had a higher risk of recurrence (51.9 versus 39.6%; P < 0.001) and worse mean overall survival (33 versus 41 months; P < 0.001). Improved tumour response to neoadjuvant therapy was associated with lower recurrence rates and higher overall survival rates. Among patients with recurrent disease, TRG1 was associated with a higher incidence of brain recurrence than TRG>1. Residual nodal disease influenced prognosis more negatively than residual disease at the primary tumour site.

Findings in magnetic resonance imaging for restaging locally advanced rectal cancer

PurposeWe aimed to assess the prognostic value of restaging magnetic resonance imaging (MRI) in rectal cancer after neoadjuvant therapy and compare long-course chemoradiotherapy (LC-CRT) to short-course radiotherapy with delayed surgery (SCRT-delay).MethodsThis retrospective study included 267 patients with locally advanced rectal cancer (LARC) operated on between January 2016 and April 2019, all of whom received either LC-CRT or SCRT-delay in the neoadjuvant setting. The primary outcomes were overall survival (OS) and cancer-specific survival (CSS) based on radiological response assessed using the magnetic resonance tumor regression grade (mrTRG).ResultsIn the LC-CRT group, cumulative 1-, 3-, and 5-year OS rates were 94.8%, 86.4%, and 79.0%, while in the SCRT-delay group, they were 83.3%, 68.9%, and 68.9% (P = 0.017). For CSS in the LC-CRT group, cumulative rates were 96.9%, 90.3%, and 85.0%, and in the SCRT-delay group, they were 88.6%, 81.4%, and 81.4% (P = 0.222). There were no significant differences in total histological response rates or local recurrence rates between the treatment groups. The good and moderate response group (mrTRG 1–3) had significantly better cumulative 1-, 3-, and 5-year OS and CSS compared to the poorer response group (mrTRG 4–5) (P = 0.023 for OS and P = 0.048 for CSS).ConclusionUnfavorable MRI response is a sign of poor prognosis in LARC. SCRT-delay is comparable to LC-CRT concerning the oncological outcome.

Evaluating Treatment Response in GEJ Adenocarcinoma: The Role of Pretherapeutic and Posttherapeutic Iodine Mapping.

Neoadjuvant therapy regimens have significantly improved the prognosis of GEJ (gastroesophageal junction) cancer; however, there are a significant percentage of patients who benefit from earlier resection or adapted therapy regimens, and the true response rate can only be determined histopathologically. Methods that allow preoperative assessment of response are lacking. The purpose of this retrospective study is to assess the potential of pretherapeutic and posttherapeutic spectral CT iodine density (IoD) in predicting histopathological response to neoadjuvant chemotherapy in patients diagnosed with adenocarcinoma of the GEJ. In this retrospective cohort study, a total of 62 patients with GEJ carcinoma were studied. Patients received a multiphasic CT scan at diagnosis and preoperatively. Iodine-density maps were generated based on spectral CT data. All tumors were histopathologically analyzed, and the tumor regression grade (TRG) according to Becker et al ( Cancer . 2003;98:1521-1530) was determined. Two experienced radiologists blindly placed 5 defined ROIs in the tumor region of highest density, and the maximum value was used for further analysis. Iodine density was normalized to the aortic iodine uptake. In addition, tumor response was assessed according to standard RECIST measurement. After assessing interrater reliability, the correlation of IoD values with treatment response and with histopathologic TRG was evaluated. The normalized ΔIoD (IoD at diagnosis - IoD after neoadjuvant treatment) and the normalized IoD after neoadjuvant treatment correlated significantly with the TRG. For the detection of responders and nonresponders, the receiver operating characteristic (ROC) curve for normalized ΔIoD yielded the highest area under the curve of 0.95 and achieved a sensitivity and specificity of 92.3% and 92.1%, respectively. Iodine density after neoadjuvant treatment achieved an area under the curve of 0.88 and a sensitivity and specificity of 86.8% and 84.6%, respectively (cutoff, 0.266). Iodine density at diagnosis and RECIST did not provide information to distinguish responders from nonresponders. Using the cutoff value for IoD after neoadjuvant treatment, a reliable classification of responders and nonresponders was achieved for both readers in a test set of 11 patients. Intraclass correlation coefficient revealed excellent interrater reliability (intraclass correlation coefficient, >0.9). Lastly, using the cutoff value for normalized ΔIoD as a definition for treatment response, a significantly longer survival of responders was shown. Changes in IoD after neoadjuvant treatment of GEJ cancer may be a potential surrogate for therapy response.

An update of clinical value of circulating tumor DNA in esophageal cancer: a systematic review and meta-analysis

BackgroundEsophageal cancer (EC) is a deadly disease with limited therapeutic options. Although circulating tumor DNA (ctDNA) could be a promising tool in this regard, the availiable evidence is limited. We performed a systematic review and meta-analysis to summarize the clinical applicability of the next-generation sequencing (NGS) and droplet digital polymerase chain reaction (ddPCR) technology on the ctDNA detection of the EC and listed the current challenges.MethodsWe systematically searched MEDLINE (via PubMed), Embase (via OVID), ISI Web of Science database and Cochrane Library from January, 2000 to April, 2023. Progression-free survival (PFS) and overall survival (OS) were set as primary outcome endpoints. Pathologic response was evaluated by tumor regression grade (TRG), according to the eighth edition of the American Joint Committee on Cancer (AJCC). Major pathologic regression (MPR) was defined as TRG 1 and 2. The MPR was set as secondary endpoint. Hazard rate (HR) and associated 95% CI were used as the effect indicators the association between ctDNA and prognosis of EC. MPR rates were also calculated. Fixed-effect model (Inverse Variance) or random-effect model (Mantel-Haenszel method) was performed depending on the statistically heterogeneity.ResultsTwenty-two studies, containing 1144 patients with EC, were included in this meta-analysis. The results showed that OS (HR = 3.87; 95% CI, 2.86–5.23) and PFS (HR = 4.28; 95% CI, 3.34–5.48) were shorter in ctDNA-positive patients. In the neoadjuvant therapy, the sensitivity analysis showed the clarified HR of ctDNA-positive was 1.13(95% CI, 1.01–1.28). We also found that TP53, NOTCH1, CCND1 and CNKN2A are the most frequent mutation genes.ConclusionsPositive ctDNA is associated with poor prognosis, which demonstrated clinical value of ctDNA. Longitudinal ctDNA monitoring showed potential prognostic value in the neoadjuvant therapy. In an era of precision medicine, ctDNA could be a promising tool to individualize treatment planning and to improve outcomes in EC.PROSPERO registration numberCRD42023412465.

Pembrolizumab, radiotherapy, and chemotherapy in neoadjuvant treatment of malignant esophago-gastric diseases (PROCEED): Assessment of survival and patterns of recurrence in a prospective, phase II single-arm trial.

375 Background: Locally advanced esophagogastric adenocarcinoma (EGA) is commonly treated with neoadjuvant chemoradiation (CRT) prior to surgical resection. Adjuvant immunotherapy has been shown to improve outcomes for these patients. The primary objective of this trial was to investigate whether neoadjuvant pembrolizumab (P) + CRT improves pathologic complete response (pCR) compared to historical control of neoadjuvant CRT alone. Exploratory endpoints included time to local recurrence (TTLR), time to distant recurrence (TTDR), progression-free survival (PFS), and overall survival (OS). Methods: Single-institution, prospective phase II trial (NCT03064490) evaluating neoadjuvant P + CRT followed by adjuvant P in patients with locally advanced operable EGA. CRT (45 Gy in 25 fractions with concurrent, weekly carboplatin [AUC 2] and paclitaxel [50mg/m2 of BSA]) with three cycles of P were administered as neoadjuvant therapy. Patients also received three cycles of adjuvant P. Pathologic response was scored from 0-3 based on tumor regression grading (TRG): 0 indicating a complete response, 1 marked response (&lt;10% residual disease), 2 partial response, and 3 poor or no response. pCR was defined as the absence of viable tumor cells at the primary tumor site and all resected lymph nodes in the surgical specimens (ypT0N0, TRG 0). Major pathologic response (MPR) was defined as TRG 0-1. Treatment-responders (R) are those with MPR, while non-responders (NR) are those with TRG 2-3 TTLR was time from enrollment to local recurrence (LR); distant recurrences (DR) were ignored and deaths were censored. TTDR was defined analogously. PFS was time from enrollment to LR, DR, or death due to any cause. OS was time from enrollment to death due to any cause. The Kaplan-Meier method was used to estimate TTLR, TTDR, PFS, and OS. Two-sided statistical tests were performed with an α of &lt;0.05 considered significant. Results: 35 patients were enrolled from 2017-2022. 30 underwent neoadjuvant P + CRT followed by surgical resection. pCR and MPR rates were previously reported: 35.5% and 50%, respectively. Median follow-up of the whole cohort was 35.5 mo. PFS was significantly improved in R vs NR (p=0.046), and there was a trend towards improved OS (p=0.084), and TTDR (p=0.069). There was no significant difference in TTLR (p=0.128). At three years, in R vs NR, PFS was 72.7% vs 46.2%, OS was 80.0% vs 58.3%, TTLR was 100% vs 81.8%, and TTDR was 81.8% vs 53.8%. Conclusions: Patients undergoing neoadjuvant P + CRT for EGA experienced higher rates of pCR/MPR compared to historical controls treated with CRT alone. MPR correlated with improved PFS, with a trend towards improved OS, indicating the clinical significance of pathologic response. These correlations appear to be driven primarily by decreased risk of developing distant metastases. Clinical trial information: NCT03064490 .

Tumor regression grade after neoadjuvant chemotherapy in patients with locally advanced gastric cancer treated with modern chemotherapy (FLOT): Experience in patients in Guatemala.

287 Background: Perioperative chemotherapy is the standard of care for locally advanced gastric cancers in Western populations. At this moment perioperative chemotherapy with FLOT (Fluorouracil, leucovorin, oxaliplatin and docetaxel) regimen is recommended in patients who are medically fit with benefit in progression-free survival (PFS) and overall survival (OS). However, the impact of response to this treatment is not well established. The objective of this study is to find the pathological response to FLOT chemotherapy measured by the degree of tumor regression (TRG), the benefit on disease-free survival (DFS) and OS, in patients with gastric cancer locally advanced treated with FLOT chemotherapy. Methods: Patients from the Instituto Guatemalteco de Seguridad Social (IGSS) from Guatemala City, who underwent radical gastrectomy for non-metastatic invasive gastric adenocarcinoma after perioperative chemotherapy (T1-4/N0/N+cM0) from 2019 to 2023 were included. Demographic data, clinical staging, histologic phenotype, surgical factors, tumor regression grade after gastrectomy and survival outcomes were included. The association between ORR and OS were evaluated. OS and DFS were estimated using the Kaplan Meier method with adjustment for covariates using Cox regression. Results: Thirty-eight patients with locally advanced cancer gastric were identified. The median age was 58 years (29-79), most of the patients were men (23, 61%), 35 (92%) patients have primary gastric tumor, 26 (68%) has cT3/T4 tumors and 22 (58%) has intestinal gastric cancer, all patients underwent to surgery. Two patients (6%) had TRG of 1 (complete and almost complete), 8 patients (21%) had an TGR of 2, and 28 patients (74%) had an TGR of 3; 13 patients (38%) developed recurrence, median DFS was 5.2 months (95% CI: 1.0–28). The median OS was 15.3 months (95% CI: 3.0-45). Lack of tumor regression (TRG 3) was significantly associated with lower survival HR 1.42 (1.05-2.24) p= 0.008. Clinical T4 tumors and diffuse histology were associated with poor prognostic (cT4 HR 3.04, p = 0.038, diffuse histology HR 2.08 (p = 0.001) (Table). Conclusions: Since cT4 tumors are an independent risk factor associated with poor prognostic HR 3.04, p = 0.038, it is important to make an adequate clinical staging before deciding to use three-drug treatment regimens of chemotherapy. Other factors in addition to clinical ones should be investigated, such as molecular factors that may be related to this poor response and survival in patients with cT4. This study of molecular factors is currently underway at our institution. [Table: see text]

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.