Tumor Regression Grade Groups Research Articles

Prognosis of a Heterogeneous TRG Pathological Response to Neoadjuvant Chemotherapy in Patients who Undergo Resection for Colorectal Liver Metastases.

Optimal management of colorectal liver metastasis (CRLM) is based on a combination of chemotherapy and surgical resection. The tumor regression grade (TRG) score is a histological scoring system to evaluate response to chemotherapy. The prognosis of a heterogeneous response in cases of multiple metastases has not been evaluated according to the TRG score. All patients who underwent liver resection for multiple CRLM after neoadjuvant chemotherapy in two tertiary centers from January 2015 to April 2019 were retrospectively included. Oncological characteristics and outcome between TRG 1-2-3 (good response group), TRG 4-5 (poor response group) and heterogeneous TRG (good and poor TRG among different lesions within the same patient) groups were compared. Among the 327 patients included, 134 (41.0%) had good response (TRG 1-2-3), 120 (36.7%) had poor response (TRG 4-5), and 73 (22.3%) had heterogeneous response. The type and number of cycles of chemotherapy, k-Ras mutational status, and tumor number or size did not differ between the three groups. Use of irinotecan-based and anti-VEGF neoadjuvant therapy was associated with better TRG response [irinotecan-based: hazard ratio (OR) = 1.744; p = 0.045; anti-VEGF neoadjuvant therapy: 2.054; p = 0.005). Overall survival (OS) was higher in the 1-2-3 TRG group than in the heterogeneous TRG group (2-year OS = 81.3% vs. 60.3%, respectively; p = 0.003) and the 4-5 TRG group (2-year OS = 81.3% vs. 55.0%, respectively; p = 0.012) and similar between the heterogeneous and 4-5 TRG groups. The proportion of heterogeneous pathological response according to TRG is 22.3%, and the prognosis is comparable to that of poor pathological response.

Pathological Evaluation of Resected Colorectal Liver Metastases: mFOLFOX6 Plus Bevacizumab versus mFOLFOX6 Plus Cetuximab in the Phase II ATOM Trial.

Simple SummaryWe compared the pre-planned histopathological responses, such as tumor regression grade (TRG), modified TRG, and dangerous halo (DH) of resected liver metastases, in patients who received modified FOLFOX6 plus bevacizumab and modified FOLFOX6 plus cetuximab for liver-limited colorectal metastases from the ATOM trial. We clarified the difference between bevacizumab and cetuximab in terms of histological response. TRG is a useful marker for determining prognosis in both treatments. We also showed, for the first time, that DH is associated with prognosis.We compared the preplanned histopathological responses of resected liver metastases from patients who received modified FOLFOX6 plus bevacizumab or modified FOLFOX6 plus cetuximab for liver-limited colorectal metastases in the ATOM trial. Fibrosis and viable tumor cells in tumor regression grade (TRG), infarct-like necrosis in modified TRG (mTRG), and dangerous halo (DH) were assessed. Fifty-five patients (28 and 27 patients in the bevacizumab and cetuximab arms, respectively) were divided into the low (viable tumor cells ≤ 50%) and high (>50%) TRG or mTRG groups. DH was characterized as absent/rare or focal/diffuse. Compared to the bevacizumab arm, the cetuximab arm was more effective, with respect to low TRG (13 vs. 23 patients) and absent/rare DH (14 vs. 19 patients), respectively. Low mTRG was similarly observed in both arms. Low TRG/mTRG and absent/rare DH showed better relapse-free survival (RFS) than high TRG/mTRG and focal/diffuse DH. In the bevacizumab arm, a significant difference in RFS existed between the low and high TRG groups, while in the cetuximab arm, for TRG, mTRG, and DH, the low and absent/rare groups demonstrated significantly longer RFS than the high and focal/diffuse groups, respectively. TRG could estimate RFS in patients who underwent liver metastasectomy after bevacizumab or cetuximab chemotherapy.

The value of intravoxel incoherent motion diffusion-weighted imaging in predicting the pathologic response to neoadjuvant chemotherapy in locally advanced esophageal squamous cell carcinoma.

To explore the value of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) for the prediction of pathologic response to neoadjuvant chemotherapy (NAC) in locally advanced esophageal squamous cell carcinoma (ESCC). Forty patients with locally advanced ESCC who were treated with NAC followed by radical resection were prospectively enrolled from September 2015 to May 2018. MRI and IVIM were performed within 1week before and 2-3weeks after NAC, prior to surgery. Parameters including apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudodiffusion coefficient (D*), and pseudodiffusion fraction (f) before and after NAC were measured. Pathologic response was evaluated according to the AJCC tumor regression grade (TRG) system. The changes in IVIM values before and after therapy in different TRG groups were assessed. Receiver operating characteristic (ROC) curves analysis was used to determine the best cutoff value for predicting the pathologic response to NAC. Twenty-two patients were identified as TRG 2 (responders), and eighteen as TRG 3 (non-responders) in pathologic evaluation. The ADC, D, and f values increased significantly after NAC. The post-NAC D and ΔD values of responders were significantly higher than those of non-responders. The area under the curve (AUC) was 0.722 for post-NAC D and 0.859 for ΔD in predicting pathologic response. The cutoff values of post-NAC D and ΔD were 1.685 × 10-3mm2/s and 0.350 × 10-3mm2/s, respectively. IVIM-DWI may be used as an effective functional imaging technique to predict pathologic response to NAC in locally advanced ESCC. • The optimal cutoff values of post-NAC D and ΔD for predicting pathologic response to NAC in locally advanced ESCC were 1.685 × 10-3mm2/s and 0.350 × 10-3mm2/s, respectively. • Pathologic response to NAC in locally advanced ESCC was favorable in patients with post-NAC D and ΔD values that were higher than the optimal cutoff values. • IVIM-DWI can potentially be used to preoperatively predict pathologic response to NAC in esophageal carcinoma. Accurate quantification of the D value derived from IVIM-DWI may eventually translate into an effective and non-invasive marker to predict therapeutic efficacy.

The Effect of Obesity on Response to Neoadjuvant Therapy in Locally Advanced Gastric Cancer.

Introduction:The effect of obesity on response to neoadjuvant chemotherapy (NACT) remains unknown. We aimed to investigate the effect of obesity on response to NACT and survival in locally-advanced gastric cancer (GC). Methods:From 2010 to 2019, 142 GC patients with clinical stage III disease who underwent curative surgery after NACT were enrolled. Patients were divided into 3 groups according to body mass index (BMI) as follows; BMI < 25 kg/m2, BMI = 25-30 kg/m2, and BMI > 30 kg/m2. The Mandard tumor regression grading system was used for tumor regression grade (TRG). Results:Of the 142 GC patients, 45(31.7%) were female. The median age was 58 years. BMI was < 25 kg/m2 in 60 (42.3%) patients, 25-30 kg/m2 in 44 (31%) patients, and > 30kg/m2 in 38 (26.8%) patients. The numbers of patients with TRGI-II, TRGIII, and TRGIV-V were 35 (24.6%), 44 (31%), and 63 (44.4%), respectively. There was no statistically significant difference among BMI groups in terms of disease-free survival (DFS) and overall survival (OS) (p = 0.919 and p = 0.398, respectively). According to TRG groups; mDFS was 46 months in TRG I-II, 28 months in TRG III, and 18 months in TRG IV-V (p<0.001). In multivariate analysis, presence of perineural invasion and lymphovascular invasion were the factors affecting TRG. Conclusion:In our study, we found that pre-treatment obesity did not affect the TRG in clinical stage III GC patients. However, a better TRG status was associated with improved survival.

The impact of tumor regression grade on long-term survival in locally advanced rectal cancer treated with preoperative chemoradiotherapy.

The aim of this study is to investigate the prognostic effect of tumor regression grade (TRG) on long-term survival in locally advanced rectal cancer treated with preoperative chemoradiotherapy. Medical records of 182 patients with locally advanced rectal cancer, who were treated with preoperative chemoradiotherapy followed by surgery between 2002 and 2016, were retrospectively reviewed. TRG was classified into five categories based on the pathological response as follows - TRG1: no viable cancer cell, TRG2: single cancer cell or small groups of cancer cells, TRG3: residual tumor outgrown by fibrosis, TRG4: residual tumor outgrowing fibrosis, TRG5: diffuse residual tumor without regression. TRG1, (TRG2+TRG3), and (TRG4+TRG5) were grouped as complete response, intermediate response, and no response, respectively. Of the 182 patients with locally advanced rectal cancer, 112 (61.5%) were male. The mean age was 54.4 (range, 25-87) years. The total number of patients in complete response, intermediate response, and no response group was 24 (13.2%), 105 (57.7%), and 53 (29.1%), respectively. The corresponding five-year relapse-free survival and overall survival rates were 79.8%-92.3%, 74.7%-79.4%, and 55.7%-55.8%, respectively (p < 0.05 for relapse-free survival, p < 0.05 for overall survival). According to ypTNM stage, there was no significant difference in relapse-free survival among TRG groups in ypStage I and II patients (p > 0.05). In ypStage III patients, relapse-free survival was 62 months in no response group vs. not reached in intermediate response group (p < 0.05). According to the ypTNM, there was no significant difference in overall survival among TRG groups in ypStage I, II, and III patients (p > 0.05). In the multivariate analysis, pathological complete response was found to be an independent variable for relapse-free survival and overall survival (hazard ratio (95% confidence interval), 0.34 (0.17-6.77), 0.39 (0.18-0.83), respectively). This study showed that patients with pathological complete response to preoperative chemoradiotherapy had longer relapse-free survival and overall survival rates than those with residual disease.

The value of GRASP on DCE-MRI for assessing response to neoadjuvant chemotherapy in patients with esophageal cancer

BackgroundTo compare the value of two dynamic contrast-enhanced Magnetic Resonance Images (DCE-MRI) reconstruction approaches, namely golden-angle radial sparse parallel (GRASP) and view-sharing with golden-angle radial profile (VS-GR) reconstruction, and evaluate their values in assessing response to neoadjuvant chemotherapy (nCT) in patients with esophageal cancer (EC).MethodsEC patients receiving nCT before surgery were enrolled prospectively. DCE-MRI scanning was performed after nCT and within 1 week before surgery. Tumor Regression Grade (TRG) was used for chemotherapy response evaluation, and patients were stratified into a responsive group (TRG1 + 2) and a non-responsive group (TRG3 + 4 + 5). Wilcoxon test was utilized for comparing GRASP and VS-GR reconstruction, Kruskal-Wallis and Mann-Whitney test was performed for each parameter to assess response, and Spearman test was performed for analyzing correlation between parameters and TRGs, as well as responder and non-responder. The receiver operating characteristic (ROC) was utilized for each significant parameter to assess its accuracy between responders and non-responders.ResultsAmong the 64 patients included in this cohort (52 male, 12 female; average age of 59.1 ± 7.9 years), 4 patients showed TRG1, 4 patients were TRG2, 7 patients were TRG3, 11 patients were TRG4, and 38 patients were TRG5. They were stratified into 8 responders and 56 non-responders.A total of 15 parameters were calculated from each tumor. With VS-GR, 10/15 parameters significantly correlated with TRG and response groups. Of these, only AUCmax showed moderate correlation with TRG, 7 showed low correlation and 2 showed negligible correlation with TRG. 8 showed low correlation and 2 showed negligible correlation with response groups. With GRASP, 13/15 parameters significantly correlated with TRG and response groups. Of these, 10 showed low correlation and 3 showed negligible correlation with TRG. 11 showed low correlation and 2 showed negligible correlation with TRG. Seven parameters (AUC* > 0.70, P < 0.05) showed good performance in response groups.ConclusionsIn patients with esophageal cancer on neoadjuvant chemotherapy, several parameters can differentiate responders from non-responders, using both GRASP and VS-GR techniques. GRASP may be able to better differentiate these two groups compared to VS-GR.Trial registration for this prospective study: ChiCTR, ChiCTR-DOD-14005308. Registered 2 October 2014.

The potential benefit of adjuvant chemotherapy in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy is not predicted by tumor regression grade.

Recommended treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (NACRT) followed by surgery and total mesorectal excision (TME). The role of adjuvant chemotherapy (ACT) in this regimen is still debated. Assessment of Dworak's tumor regression grade (TRG) after NACRT could potentially select patients who might benefit from ACT. Data for patients who underwent NACRT and TME for LARC between 2007 and 2014 were retrieved from the Bordet Institute database. Overall survival (OS) and disease-free survival (DFS) were calculated for the whole population, according to whether or not they received ACT, and according to TRG. We included 74 patients (38 males) with a median age of 62.7years (33-84years). AJCC stage cIIIb disease was the most frequent (73%). Pathologic complete response (pCR) was achieved in 13 patients (17.6%). ACT was administered to 42 patients (56.8%). Five-year OS and DFS of patients who received ACT or not were 92 and 84.5% (p = ns), and 79.9 and 84.8% (p = ns), respectively. OS was related to TRG (cut-off value of 3) (p = 0.001). ACT administration was not correlated with improved outcomes in any TRG groups. TRG is a prognostic factor for both OS and DFS but does not appear to have a significant benefit for the selection of patients with LARC treated with NACRT who might benefit from the administration of ACT. Prospective randomized trials with larger populations are needed to identify factors that predict which patients may benefit from the administration of ACT.

Correlation Between Standardized Uptake Value in Preneoadjuvant and Postneoadjuvant Chemoradiotherapy and Tumor Regression Grade in Patients With Locally Advanced Esophageal Cancer.

To investigate whether positron emission tomography/computed tomography (PET/CT) initial and restaging imaging predicts for pathologic response measured by tumor regression grade (TRG) after preoperative chemoradiotherapy (CRT) in patients with locally advanced esophageal cancer. A retrospective review of 220 patients with stage II-III esophageal cancer treated with neoadjuvant CRT followed by surgery was performed. In total, 187 patients were eligible for statistical analysis. Pretreatment and posttreatment PET/CT scans were reviewed. Maximum standard uptake value (SUV) at the site of the primary tumor was recorded before and 6 weeks after neoadjuvant therapy. Upon completion of surgery, TRG was determined by a specialized site-specific gastrointestinal pathologist. Spearman correlation was used to compare pre, post, and change in maximum SUV, TRG, and overall survival. The median follow-up was 24 months. Although no significant correlation was found between pretreatment SUV and TRG (r=0.073, P=0.32), post-CRT SUV, however, showed a significant positive correlation with TRG (r=0.374, P<0.01). There was no significant correlation between the absolute change in fluorodeoxyglucose uptake after CRT and TRG (r=0.057, P=0.44); however, the rate of SUV change showed a significant correlation with TRG (r=0.178, P=0.017). Similar to previous studies, our study showed a significant difference in overall survival between TRG groups (log-rank test, P=0.019). Patients with TRG 3 showed prominently worse survival with median survival of 27.4 months. Patients with favorable pathologic responses were those whose scans demonstrated a metabolic response defined as a decrease in SUV≥70%. Changes in SUV uptake on PET/CT scans after CRT have prognostic value in predicting pathologic response of esophageal cancer after neoadjuvant therapy. Further studies are needed to validate the integration of PET/CT as a decision-making tool.

Predictors and survival for pathologic tumor response grade in borderline resectable and locally advanced pancreatic cancer treated with induction chemotherapy and neoadjuvant stereotactic body radiotherapy

Background: Neoadjuvant therapy response correlates with survival in multiple gastrointestinal malignancies. To potentially augment neoadjuvant response for pancreas adenocarcinoma, we intensified treatment with stereotactic body radiotherapy (SBRT) following multi-agent chemotherapy. Using this regimen, we analyzed whether the College of American Pathology (CAP) tumor regression grade (TRG) at pancreatectomy correlated with established response biomarkers and survival.Materials and methods: We identified borderline resectable (BRPC) and locally advanced (LAPC) pancreatic cancer patients treated according to our institutional clinical pathway who underwent surgical resection with reported TRG (n = 81, median follow-up after surgery 24.2 months). Patients had baseline CA19-9, computed tomography (CT), endoscopic ultrasound, and FDG positron emission tomography (PET)/CT then underwent multi-agent chemotherapy (79% with three cycles of gemcitabine, docetaxel and capecitabine) followed by 5-fraction SBRT. They then underwent restaging CT, PET/CT and CA19-9. Overall (OS) and progression-free (PFS) survival were estimated and compared by Kaplan–Meier and log-rank methods. Univariate ordinal logistic regression correlated TRG with baseline, restaging and change in CA19-9 and the PET maximum standardized uptake value (SUVmax).Results: Restaging level and decrease in CA19-9 correlated with improved TRG (p = .02 for both) as did restaging SUVmax (p < .01), yet there was no TRG correlation with decrease in SUVmax (p = .10) or CT response (p = .30). The TRG groups had similar OS and PFS except the TRG 0 (complete response) group. Compared to partial response levels (TRG 1-3, median OS 33.9 months, median PFS 13.0 months), the six (7%) patients with TRG 0 had no deaths (p = .05) and only one progression (p = .03). A group of 10 (12%) TRG 1 patients with only residual isolated tumor cells had similar outcomes to the other TRG 1-3 patients.Conclusion: Pre-operative PET-CT and CA19-9 response correlate with histopathologic tumor regression. Patients with complete pathologic response have superior outcomes, suggesting a rationale for intensification and personalization of neoadjuvant therapy in BRPC and LAPC.

481P - The correlation between tumor regression grade and retrieved lymph nodes status in locally advanced rectal cancer after neoadjuvant treatment: results from a prospective study

A paucity of lymph nodes harvested is common in rectal cancer after neoadjuvant treatment and the significance is still uncertain. We aimed to evaluate the correlation between tumor regression grade (TRG) and retrieved lymph nodes status in patients who underwent neoadjuvant treatment followed by total mesorectal excision (TME) for locally advanced rectal cancer. From Jan 2011 to Feb 2015, complete data was available for 447 patients with rectal cancer who received neoadjuvant treatment followed by TME enrolled in FOWARC study. According to the post-operative pathologic TRG of primary lesion, patients were categorized into 4 groups, TRG 0, 1, 2 and 3.The number of harvested lymph nodes, lymph node metastasis, and extranodal tumor deposits in each group were analyzed. Of the 447 patients, 77 (17.2%) patients were TRG 0, and 143 (32.0%) patients were TRG 1. Another 156 (34.9%) and 71 (15.9%) patients were TRG 2 and TRG 3, respectively. The median retrieved lymph node counts among the 4 groups were 8, 10, 11 and 13, respectively. The harvested lymph node in better TRG groups was less than that of poor TRG group (p = 0.001). The lymph node metastasis rates of the 4 groups were 7.8%, 14.7%, 21.8% and 38.0%, respectively. The differences were statistically significant (p < 0.001). And the extranodal tumor deposits rates of the 4 groups were 3.9%, 7.7%, 16.0% and 21.1%, respectively (p = 0.002).Tabled 1ItemsTRG 0 (N = 77)TRG 1 (N = 143)TRG 2 (N = 156)TRG 3 (N = 71)PHarvested lymph nodes (median)81011130.001LN metastasis (n,%)6(7.8)21(14.7)34(21.8)27(38.3)<0.001Extranodal TD (n,%)3(3.9)11(7.7)25(16.0)15(21.1)0.002 Open table in a new tab Lymph node metastasis and extranodal tumor deposits were correlated with TRG. The paucity of lymph nodes retrieved did not infer poor oncologic outcomes in rectal cancer after neoadjuvant treatment. The number of retrieved lymph nodes should be redefined according to the pathologic response to neoadjuvant treatment. Further analysis of optimal lymph node counts in different TRG group will be performed with survival data.

Correlation between tumor regression grade and rectal volume in neoadjuvant concurrent chemoradiotherapy for rectal cancer.

PurposeTo determine whether large rectal volume on planning computed tomography (CT) results in lower tumor regression grade (TRG) after neoadjuvant concurrent chemoradiotherapy (CCRT) in rectal cancer patients.Materials and MethodsWe reviewed medical records of 113 patients treated with surgery following neoadjuvant CCRT for rectal cancer between January and December 2012. Rectal volume was contoured on axial images in which gross tumor volume was included. Average axial rectal area (ARA) was defined as rectal volume divided by longitudinal tumor length. The impact of rectal volume and ARA on TRG was assessed.ResultsAverage rectal volume and ARA were 11.3 mL and 2.9 cm². After completion of neoadjuvant CCRT in 113 patients, pathologic results revealed total regression (TRG 4) in 28 patients (25%), good regression (TRG 3) in 25 patients (22%), moderate regression (TRG 2) in 34 patients (30%), minor regression (TRG 1) in 24 patients (21%), and no regression (TRG0) in 2 patients (2%). No difference of rectal volume and ARA was found between each TRG groups. Linear correlation existed between rectal volume and TRG (p = 0.036) but not between ARA and TRG (p = 0.058).ConclusionRectal volume on planning CT has no significance on TRG in patients receiving neoadjuvant CCRT for rectal cancer. These results indicate that maintaining minimal rectal volume before each treatment may not be necessary.

Oncologic Result as According to Tumor Regression Grade after Neoadjuvant Chemoradiation Therapy in Locally Advanced Rectal Cancer

Purpose: The effects of neoadjuvant chemoradiation therapy (NCRT) in cases of locally advanced rectal cancer include tumor downstaging with respect to a curative resection and a decreasing incidence of local recurrence. The aim of this study is to evaluate the oncologic results according to the tumor regression grade (TRG) after NCRT and radical surgical resection in cases of locally advanced rectal cancer. Methods: From 1999 to 2003, 140 consecutive patients, who suffered from locally advanced rectal cancer (T3 or T4, or lymph node positive) were enrolled in this study. They all received neoadjuvant chemoradiation therapy and a radical resection. Chemotherapy was based on 5-fluorouracil (5-FU), and the total radiation dose was 5,040 cGy over 6 weeks. A radical surgical resection, including a total mesorectal excision, was done 6 to 8 weeks after the completion of NCRT. We classified patients into subgroups by using the TRG; then, we investigated the overall and the disease-free survival rates and the local recurrence and the distant metastasis rates. Results: One hundred twenty-six (126, 90%) patients responded to radiation therapy. According to the TRG, the numbers of nonresponders (Grade I, NR), partial responders (Grade II, PR), and patients who went into complete remission (Grade III, CR) were 14 (10%), 98 (70%), and 28 (20%), respectively. The overall survival (OS) and the disease-free survival (DFS) rates for 3 years (n=140) were 91.43% and 74.29%, and the rates for 5 years (n=117) were 81.20% and 67.52%, respectively. While there was no significant difference in the 3-year OS or DFS between the three groups stratified by TRG (P=0.1136, P=0.1215), the 5-year OS and DFS showed a statistical difference (P=0.0485, P=0.0458). Furthermore, the 3-year OS and DFS rates (P=0.0451, P=0.0458), as well as the 5-year OS and DFS rates (P=0.0139, P=0.0131) were significantly better for patients in the CR group than for the other patients. Still, no statistical significance differences existed between the CR group and the non-CR groups or between the TRG groups in terms of the local recurrence and the distant metastasis rates (P=0.447, P=0.271). Conclusions: Any tumor response group that shows complete Rremission after NCRT and radical surgical resection has an oncologic benefit in overall survival and disease- free survival in our study.

Histomorphological tumor regression grading of esophageal carcinoma after neoadjuvant radiochemotherapy: which score to use?

Histopathological tumor regression grade (TRG) has been shown to be a prognostic factor in patients with esophageal cancer after neoadjuvant radiochemotherapy (RCT). The system introduced by Mandard to group TRG (Cancer 1994;73:2680-2686) has been used to analyse and discuss its prognostic significance on survival in a single institution retrospective analysis: TRG 1 (complete regression) - TRG 5 (absence of regressive changes). Sixty patients with locally advanced (T3/4 or N1) adenocarcinoma or squamous cell carcinoma received cisplatin-based RCT. Three to four weeks later operation for curative intent was performed. Median follow-up was 17.7 months. Histopathological tumor stages were stage 0 in 17%, stage I in 10%, stage II in 60%, stage III in 12% and stage IVA in 1%. The 5-year overall survival (OS) rate was 35%. In univariate analysis, ypN-status and TRG correlated significantly with OS (P = 0.004, P = 0.0008, respectively). While OS of TRG 1 differed significantly from all other groups, no differences in OS between the other TRG groups were seen. Patients with complete tumor regression after neoadjuvant RCT showed a much better survival than patients with tumors that responded less to induction therapy. Further qualitative subdivision of tumor regression could not identify patient groups with significant differences in prognosis. After comparing our data with the literature, it is reasonable to consider classifying all patients into 'Complete tumor regression' and 'Incomplete tumor regression'.