Tumor Regression Grading System Research Articles

Pathological response and outcome after neoadjuvant chemotherapy with DOC (docetaxel, oxaliplatin, capecitabine) or EOF (epirubicin, oxaliplatin, 5-fluorouracil) for clinical T3-T4 non-metastatic gastric cancer

PurposeIn this prospective observational study, we sought to compare the efficacy and safety of docetaxel + oxaliplatin + capecitabine (DOC) with epirubicin + oxaliplatin + 5-fluouracil (EOF) as neoadjuvant chemotherapy (NAC) for clinical T3 or T4 non-metastatic gastric cancer (GC) patients. MethodsThe DOC NAC consisted of docetaxel 35 mg/m2 (days 1–8), oxaliplatin 85 mg/m2 (day 1), and capecitabine 750 mg/m2 twice daily (days 1–14), every 3 weeks. The EOF NAC consisted of intravenous (IV) epirubicin 50 mg/m2 combined with IV oxaliplatin 130 mg/m2 on day 1 and continuous infusion 5-fluouracil 750 mg/m2 on days 1–5, every 3 weeks. After 4 cycles of NAC or upon progression during chemotherapy, patients underwent gastrectomy with standard D2 or D3 lymphadenectomy. Pathological complete response rate per Becker tumor regression grading system was the primary endpoint and the secondary endpoints included progression-free survival (2-yr PFS) and 2-year overall survival (2-yr OS) and tolerability. ResultsOverall, we identified 63 patients with T3-4 non-metastatic GC starting either NAC regimen between January 2010 and December 2017 at our Institution: 34 in the DOC group and 29 in EOF group. Thirty patients (88%) in the DOC group and 22 (76%) in the EOF group completed the 4 planned cycles of NAC. Fifty-seven patients received surgery. Results indicated no statistical significant differences between the two groups, and only a trend for some better data in favour of the DOC group. The R0 resection rate was 90.6% and 88.0% for the DOC and EOF cohorts, respectively. The pathological complete response rate was 6.2% in the DOC group and 4.0% in the EOF group. Becker 1–2 pathological response was found in 46.8% of the DOC cohort and 28.0% of the EOF cohort (p = .14). The 2-yr PFS rate was 54.1% for DOC vs. 41.4% for EOF (p = .14) and the 2-yr OS rate was 80.8% for DOC vs. 58.6% for EOF (p = .05). Neutropenia was the most common grade ≥3 toxicity and occurred in 8 (23.5%) patients of the DOC group and 10 (34.4%) patients of the EOF group (p = .33). ConclusionsThese findings seem to confirm the feasibility of NAC for clinically T3 and T4 non-metastatic GC and, despite no statistical significant difference was documented, suggest a trend for better activity and tolerability for the docetaxel-based regimen (DOC) compared to the epirubicin-based combination (EOF).

Pathological Tumor Regression Grade Classifications in Gastrointestinal Cancers: Role on Patients' Prognosis.

Preoperative chemotherapy or combined radiotherapy and chemotherapy (CRT), followed by surgery, represents the standard approach for locally advanced esophageal, gastric, and rectal carcinomas. To adequately evaluate the effects of neoadjuvant CRT in the resection specimens, several histopathologic tumor regression grade (TRG) scoring systems have been introduced into clinical practice. The primary goal of these TRG systems relies on a correct prognostic stratification of patients in the attempt to help clinical decision-making and influence surgical strategies, postoperative adjuvant therapies, and surveillance intensity. However, most TRG systems suffer from poor reproducibility and low interobserver concordance rates. Many efforts have been made in the identification of alternative, robust, simple, and universally accepted TRG scoring systems, which would help in the comparison of different treatment strategies and in the standardization of multimodal therapies. The aim of this review is to analyze the most commonly used TRG systems in gastrointestinal cancers highlighting their pitfalls and usefulness, depending on the tumor type.

A prospective feasibility study evaluating the role of multimodality imaging and liquid biopsy for response assessment in locally advanced rectal carcinoma.

Colorectal cancer is a commonly encountered disease that poses several diagnostic and therapeutic challenges. The inherent heterogeneity of tumor biology and propensity to relapse despite "curative" resection pose significant challenges with regard to response assessment. Although MR imaging already plays a key role in primary staging of patients with rectal carcinoma, its reliability in restaging after neoadjuvant therapy is debatable (Van der broek et al. in Dis Colon Rectum 60(3):274-283, 2017). Therefore, there is significant interest in developing additional methods which may improve diagnostic accuracy. This study aims to evaluate the role of multimodality imaging and liquid biopsy in therapeutic response assessment. Seventeen patients were enrolled into the study over a span of 24months. All underwent hybrid PET-MRI and CT-perfusion (CT-P), prior to and following neoadjuvant therapy for locally advanced rectal carcinoma. Twelve of the 17 patients also underwent liquid biopsy, which consisted of blood sampling and analysis of circulating tumor cells (CTCs) and extracellular vesicles (EVs), includingcell fragments and microparticles (MPs), using the Cell Search System (Menarini Silicon Biosystems). SUV, DWI, and ADC were calculated during PET-MRI, and several parameters were evaluated during CT-perfusion, including average perfusion, blood flow (BF), blood volume (BV), mean transit time (MTT), permeability-surface area product (PS), contrast extraction efficiency (E), and K-trans (K). Changes observed pre- and post-neoadjuvant therapy in each modality were compared to tumor response at histopathology using a modified Ryan tumor regression grading system. Of the 17 patients included in the study, 14 were classified as non-responders, and 3 were classified as responders as determined by the modified Ryan Tumor Regression Grade (TRG) scoring system (Van der broek et al. in Dis Colon Rectum 60(3):274-283, 2017). When combined, blood markers and CT-P parameters (mean transit time (MTT), K-trans, and permeability-surfacearea product (PS)) produced the strongest models (p < 0.01). PET (SUV measurement) combined with CT-P-derived K-trans produced a marginally significant (p = 0.057) model for predicting response. MRI-derived ADC value did not provide a significant model for response prediction. A model of CT-P parameters plus liquid biopsy more accurately predicts tumor response than PET-MRI, CT-P alone, or liquid biopsy alone. These results suggest that in the evaluation of treatment response, liquid biopsy could provide additional information to functional imaging modalities such as CT-P and should therefore be explored further in a trial with larger sample size.

Blast from the past: Perioperative use of the Maruyama computer program for prediction of lymph node involvement in the surgical treatment of gastric cancer following neoadjuvant chemotherapy

BackgroundSurgical quality assurance is a key element of gastric cancer treatment. The Maruyama Computer Program (MCP) allows to predict lymph node involvement in stations no. 1–16. The aim of the current study was to evaluate the accuracy of the MCP predictions in GC patients treated with neoadjuvant chemotherapy (nCTH) followed by gastrectomy with adequate lymphadenectomy. Methods101 patients who underwent preoperative nCTH followed by D2 gastrectomy with curative intent were analysed. The response to nCTH was measured using the tumour regression grade system. ResultsTest sensitivity, specificity, PPV, NPV and accuracy of the MCP were 92%, 33%, 41%, 89%, and 53%, respectively. In patients with response to nCTH, number of false positive (FP) results was significantly higher than in patients who did not respond to nCTH both in the N1 (56.3% vs 28.9%, p < 0.0001) and in the N2 (59% vs 41%, p < 0.0001) trier. The risk for FP results was 6 times higher in N1 (OR = 6.50, 95%CI: 3.91–10.82,; p < 0.0001) and N2 (OR = 5.84, 95%CI: 2.85–11.96; p < 0.0001) triers. In patients with intestinal type GC, the risk for FP results was 4 times higher than in other histologic types of GC in both N1 (OR = 4.23, 95%CI: 2.58–6.95; p < 0.0001) and N2 (OR = 4.23, 95%CI: 2.02–9.62; p = 0.0002) triers. ConclusionsMCP predictions in the GC patients treated with nCTH have low specificity due to significantly high number of FP results. Noticeably low accuracy level of predictions indicate a need for new prediction models, based on Laurén classification, since it may provide some information on expected regression grade.

Pathology of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy and estimated to become the second leading cause of cancer-related deaths by 2030. Although overall 5-year survival rates have constantly remained below 10% for the last decades, several key points important for accurate patient stratification have emerged during recent years. These key points include a highly standardized gross examination of PDAC resection specimens, using an axial slicing technique and inking of the circumferential resection margin (CRM), as well as a meticulous microscopic examination, taking into account the prognostic relevance of factors such as the exact resection status (R0 vs. R1 1-mm vs. R1 resection), histopathological tumor grading and the so-called lymph node ratio (LNR). With increasing use of neoadjuvant therapy in PDAC, tumor regression grading (TRG) for PDAC is currently rising in relevance in order to stratify and manage pre-operatively treated PDAC patients. As all current TRG systems for PDAC are unsatisfactory, new standardized international protocols are urgently needed. Several morphological subtypes of PDAC exist, some of which share the same molecular background with classical PDAC, while others are characterized by a distinct molecular pathogenesis. While some show a prognosis similar to classical PDAC, other subtypes stand out due to a better or even worse prognosis than classical PDAC. Prognostic relevant molecular subtypes of PDAC have been proposed as well, however, limitations of used cohorts and the lacking correlation of molecular subtypes with histomorphological subtypes limit the translation of these findings into valuable clinical applications. Lastly, several macroscopic and microscopic precursor lesions of PDAC have been described in genetically engineered mouse models (GEMM) and humans in recent times, providing further insight into PDAC carcinogenesis. In addition, improved diagnosis of PDAC precursors represents a chance to select patients for resection before invasive PDAC is present.

Comparison of tumor regression grading system in locally advanced esophageal squamous cell carcinoma after preoperative radio-chemotherapy to determine the most accurate system predicting prognosis.

Nowadays, preoperative radio-chemotherapy is a standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). Tumor regression grade (TRG), referring to a classification of cancer response to preoperative treatment, can predict a prognosis of survival. Many TRG systems are proposed for use in esophageal cancer, but none of them has become standard grading system. This research compared five TRG systems, including Mandard system, Chirieac system, Schneider system, Hermann system, and Japan Esophageal Society (JES) system, to find the most accurately predictive system. We recruited 37 participants with locally advanced ESCC from 2006 to 2014. All of them were treated with radio-chemotherapy followed by esophagectomy. The resection specimens were evaluated microscopically for percentage of viable residual tumor comparing with tumor bed, number of positive lymph nodes and, consequently, assigned TRG grade according to each TRG system. Kaplan-Meier (KM) graphs were used to describe the median survival time. Log-rank tests and cox proportional hazard regression models were used in assessing associations between TRG systems and survival. Proportional hazard assumptions were evaluated on the basis of Schoenfeld and log-log plot. Akaike information criterion (AIC) values and pseudo R-squared values assessed model fit. All statistical tests were two-sided. The KM graphs displayed overlapped curves in all TRG systems. The log-rank tests revealed that Schneider, JES and Mandard systems were statistically associated with overall-survival (P<0.05). Only the multivariate cox regression analysis of Schneider system showed the statistically significant hazard ratio (P=0.037). Schneider system also had the best AIC and pseudo R-squared values. Schneider system might be the best predictive system. However, the overlapped KM curve opposed. This study had limitation due to small number of participants. More participants were needed to confirm our findings.

HER2 as a limited predictor of the therapeutic response to neoadjuvant therapy in locally advanced rectal cancer

Human epidermal growth factor 2 (HER2) is a candidate therapeutic and prognostic marker for rectal cancer treated with neoadjuvant chemoradiotherapy. The specific frequency and prognostic role of HER2 protein expression and HER2 gene amplification in those rectal cancers has not been fully investigated. Pretreatment biopsied and surgically resected formalin-fixed paraffin-embedded tissues from 74 patients were retrospectively evaluated for HER2 protein expression and HER2 gene copy number using immunohistochemistry (IHC) and silver in situ hybridization (SISH), respectively. The tumor response to chemoradiation was evaluated with TNM staging and tumor regression grading (TRG) systems. Good response to chemoradiation therapy (TRG3), poor response (22 TRG1 and 19 TRG2), and TNM downstaging achieved in 33 (44.6%), 41 (55.4%), and 42 (56.8%) patients, respectively. The frequency of HER2 positivity is 17.6%, all of which were low-level HER2 gene amplification with 2.2 of median gene copy number ratio, detected in IHC0 (3/39), IHC1+ (2/18), IHC2+ (5/14) and IHC3+ (2/3). There was no association of HER2 positivity with clinicopathological parameters or survival. However, older age (≥61 years) and HER2 positivity were the independent predictive factors for non-down staging, while poorly differentiation and the papillary pattern were predictors for poor response. In multivariate analysis, good response proved as an only independent favorable prognostic factor affecting survivals. In conclusion, HER2 positivity may be predictive for a high-risk therapeutic resistance in rectal cancers. The discrepancy between IHC and gene amplification may result from the low-level amplification, which may explain lack of prognostic impact of HER2 positivity.

Histopathologic tumor regression grading in patients with gastric carcinoma submitted to neoadjuvant treatment: results of a Delphi survey

Studies investigating the histopathologic response of gastric carcinoma to neoadjuvant treatment have used a variety of different tumor regression grading systems. The aim of this Delphi survey was to review the available systems and reach consensus on a potential international standard. An international e-mail-based Delphi survey involving 6 expert pathologists was undertaken between January and October 2017. A questionnaire consisting of 72 items was formed after reviewing the 5 available systems. Rating of the items was done on a symmetric 4-point Likert-type scale, and feedback was provided between rounds. A total of 4 rounds were required to reach consensus on 97% of the items covering the topics: (1) specimen processing, (2) gross examination, (3) cross sectioning/method of sampling, (4) staining, (5) immunohistochemistry, (6) assessment of tumor regression in response to neoadjuvant therapy, (7) tumor regression grading, (8) assessment of regression of nodal metastases, and (9) role of histologic tumor type. Through the outcome of this comprehensive Delphi study, a group of experts is proposing a 4-tiered system for the grading of regression of the primary tumor, combined with a 3-tiered system for lymph node metastases. Grade 1 represents complete response, grade 2 contains less than 10% residual tumor (subtotal regression), grade 3 contains 10% to 50% residual tumor (partial regression), and grade 4 contains greater than 50% residual tumor (minimal/no regression). The addition of "a", "b", or "c" indicates complete, partial, or no response of lymph node metastases. It is recommended to use this grading system irrespective of histologic subtype.

Tu1486 - Development of a Hepatocellular Carcinoma Tumor Regression Grading System to Assess Treatment Response to Transcatheter Arterial Chemoembolization (TACE)

Tu1486 - Development of a Hepatocellular Carcinoma Tumor Regression Grading System to Assess Treatment Response to Transcatheter Arterial Chemoembolization (TACE)

Human Epidermal Growth Factor Receptor 2 Over-Expression in Patients with Esophageal Squamous Cell Carcinoma; Correlation with Response to Neo-Adjuvant Chemoradiation and Survival

Background: Esophageal squamous cell carcinoma (ESCC) is a common malignancy in gastrointestinal tract. Objectives: This study was conducted to investigate the frequency of human epidermal growth factor receptor 2 (HER2), over-expression in patients with ESCC, and its correlation with pathologic response in cases undergoing neo-adjuvant, chemoradiation, and survival. Methods: In this cross sectional study, 68 patients with non-metastatic esophageal SCC, who had undergone neo-adjuvant chemotherapy containing cisplatin and 5FU in conjunction with radiotherapy between 2007 and 2014 were evaluated. HER2 expression assessed by Immunohistochemistry and HER2 score was also calculated for each specimen. Tumor response to neoadjuvant chemoradiotherapy was evaluated in surgical blocks according to tumor regression grading (TRG) system. Patients were followed up every 3 months in first 2 years and every 6 months afterwards. Results: The result of Hercep test was positive in 42.8% of cases, among whom 33.8% were 2+ and 8.8% were 3+. Her2 score was above 100 in 38.3%. Complete pathologic response was observed in 32.3%. There was no significant difference in the rate of complete response between patients with positive and negative HER-2 over-expression (P = 0.71). There was also no significant correlation between Her2 score among groups with favorable and unfavorable response to chemoradiation (P = 0.796 and 0.743). There was no difference in overall survival in Her2 positive and negative groups (3 years survival was 45 and 54 months, P = 0.32). Overall survival significantly reduced in patients with Her2 score above 100 (P = 0.045). Conclusions: Her2 positive in ESCC had no effect on tumors biologic behaviors and its response to chemoradiation. Although no correlation was observed between Her2 expression and survival; Her2 score above 100 was associated with shorter survival.

Histopathological Assessment for Esophageal Adenocarcinoma.

In the World Health Organization (WHO) classification, adenocarcinoma of esophagus comprises preinvasive type (dysplasia), adenocarcinoma, adenoid cystic carcinoma, adenosquamous carcinoma, and mucoepidermoid carcinoma. For adenocarcinoma, it is important to determine the grading of the cancer and histological variants such as signet ring adenocarcinoma. In the current day management of esophageal adenocarcinoma by neoadjuvant therapy, the histology of the cancer and the lymph nodal status may change after the therapy. Tumor regression grading systems could be used to assess the response to the neoadjuvant therapy in esophageal adenocarcinoma.

Mean Corpuscular Volume as a Predictive Factor of Response to Preoperative Chemoradiotherapy in Locally Advanced Rectal Cancer.

Background The aim of this study was to identify if blood routine parameters and serum tumor marker are potential predictive factors for tumor response to preoperative chemoradiotherapy (CRT) in locally advanced rectal cancer. Materials and Methods 55 locally advanced rectal cancer patients were treated with preoperative CRT in this study. The total dose of preoperative radiotherapy was 45 Gy in 25 fractions of 1.8 in 5 weeks. All patients concurrently received 825 mg/m2 capecitabine orally twice daily on days 1 to 14 and 22 to 35. Total mesorectal excision (TME) was performed 6 weeks after the end of preoperative CRT. Blood routine examination and serum tumor marker were checked before preoperative CRT. Tumor response to preoperative CRT was evaluated with the semiquantitative tumor regression grading (TRG) system proposed by Dworak criteria according to histopathological examination of the surgical specimens. Univariable and multivariable logistic regression analyses were used to test the association between blood routine parameters and serum tumor marker and tumor response to preoperative CRT. Results Univariate logistic regression analysis revealed that differentiation, lymphocyte, LMR, MCV, PLR, and CEA have been significantly associated with tumor response to preoperative CRT. Multivariate logistic regression analysis revealed that differentiation, MCV, and CEA were the predictors of tumor response to preoperative CRT. According to the ROC analysis, the AUC of differentiation, MCV, and CEA was 0.794, 0.802, and 0.723, respectively. Optimal cutoff points for MCV and CEA were 87.65 fl and 4.05 ng/ml, respectively. Conclusion MCV is a potential predictive factor for tumor response to preoperative chemoradiation in locally advanced rectal cancer.

Modified 3-Point MRI-Based Tumor Regression Grade Incorporating DWI for Locally Advanced Rectal Cancer.

The purpose of this study was to evaluate the prognostic relevance of a modified 3-point MRI-based tumor regression grading system incorporating DWI for patients with locally advanced rectal cancer after preoperative chemoradiotherapy (CRT). Between March 2012 and September 2013, 118 consecutively registered patients with middle or lower locally advanced rectal cancer who underwent CRT followed by surgery were enrolled in this retrospective study. Two radiologists in consensus assessed MRI tumor regression grade (mrTRG) based on T2-weighted images and high b value DW images (0 and 1000 s/mm2) using the following grades: 0, complete regression (no obvious tumor); 1, intermediate regression (dominant fibrosis, regression > 50%); 2, poor regression (dominant tumor, regression ≤ 50%). Multivariate analysis with a Cox regression model was performed to evaluate the association between modified mrTRG and 3-year disease-free survival (DFS) rate. A Kaplan-Meier method with a log-rank test was used to compare the DFS rate between responder (grades 0 and 1) and nonresponder (grade 2) groups. Both the accuracy (72.9% vs 38.1%; p < 0.001) and the interreader agreement (κ = 0.580 vs 0.338; p < 0.001) of modified 3-point mrTRG were improved over the established 5-point mrTRG. Modified mrTRG (adjusted hazard ratio, 2.505; 95% CI, 1.231-5.100) was independently associated with 3-year DFS rate (p = 0.011). There was also a significant difference in the 3-year DFS rate between responders (73.8%; 95% CI, 64.2-81.3%) and nonresponders (41.7%; 95% CI, 10.9-70.8%) (p = 0.028). In patients with middle or lower locally advanced rectal cancer, the modified 3-point mrTRG incorporating DWI was independently associated with the 3-year DFS rate after CRT followed by surgery. The grading scale may be used as a surrogate for expected prognosis of preoperative CRT. Further prospective trials are warranted.

Tumor regression grading of gastrointestinal cancers after neoadjuvant therapy.

Neoadjuvant therapy has been successfully introduced in the treatment of locally advanced gastrointestinal malignancies, particularly esophageal, gastric, and rectal cancers. The effects of preoperative chemo- or radiochemotherapy can be determined by histopathological investigation of the resection specimen following this treatment. Frequent histological findings after neoadjuvant therapy include various amounts of residual tumor, inflammation, resorptive changes with infiltrates of foamy histiocytes, foreign body reactions, and scarry fibrosis. Several tumor regression grading (TRG) systems, which aim to categorize the amount of regressive changes after cytotoxic treatment in primary tumor sites, have been proposed for gastroesophageal and rectal carcinomas. These systems primarily refer to the amount of therapy-induced fibrosis in relation to the residual tumor (e.g., the Mandard, Dworak, or AJCC systems) or the estimated percentage of residual tumor in relation to the previous tumor site (e.g., the Becker, Rödel, or Rectal Cancer Regression Grading systems). TRGs provide valuable prognostic information, as in most cases, complete or subtotal tumor regression after neoadjuvant treatment is associated with better patient outcomes. This review describes the typical histopathological findings after neoadjuvant treatment, discusses the most commonly used TRG systems for gastroesophageal and rectal carcinomas, addresses the limitations and critical issues of tumor regression grading in these tumors, and describes the clinical impact of TRG.

504P - Comparison between magnetic resonance imaging (MRI) and pathology in the assessment of tumour regression grade (TRG) in rectal cancer (RC)

Background: Based on the ability to distinguish between areas of residual cancer and treatment induced fibrosis after neoadjuvant treatment, a 5-tier MRI-based (mr)TRG system that follows the principles of the pathological (p)TRG system previously proposed by Dworak has been developed for RC. However, limited data exist regarding the correlation between mrTRG and pTRG, and the prognostic value of mrTRG in patients who are assessable for pTRG is unclear. Methods: mrTRG, as assessed by a radiologist according to Patel et al (J Clin Oncol 2011), and pTRG, as assessed by a pathologist according to Dworak et al (Int J Colorect Dis 1997), were compared in MRI-defined, high-risk, locally-advanced RC patients from two phase II trials (EXPERT and EXPERT-C). All patients had received an intensified neoadjuvant treatment with induction chemotherapy followed by chemo-radiotherapy. The agreement between radiologist and pathologist was assessed with the weighted κ test while the Kaplan-Meier method was used to estimate survival outcomes. Results: 191 patients who had undergone neoadjuvant treatment and surgery with a curative intent were included. Median time from completion of neoadjuvant treatment to pre-operative MRI and surgery was 4.1 weeks (interquartile range [IQR]: 3.7-4.7) and 6.6 weeks (IQR: 5.9-7.6), respectively. Fair agreement was found between mrTRG and pTRG when regression was classified according to standard 5-tier systems (κ = 0.24) or modified 3-tier systems (κ = 0.25). After a median follow-up of 65.5 months (95% CI: 65.1-66.2), survival outcomes of patients with intermediate pathological regression (pTRG 2) were numerically better if good/complete regression was also observed on imaging (mrTRG 1-2) compared to poor regression (mrTRG 3-5) (5-year recurrence-free survival 76.9% versus 65.9%, p = 0.18; 5-year overall survival 80.6% versus 68.8%, p = 0.22). Conclusions: Only fair agreement was found between mrTRG and pTRG which suggests that these parameters may represent biologically distinct phenomena. Assessing tumour regression on pre-operative MRI may provide complementary prognostic information to pTRG and help to refine stratification of RC patients after surgery. Legal entity responsible for the study: The Royal Marsden NHS Foundation Trust Funding: National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research. The EXPERT study was supported by a fellowship grant from the Pelican Cancer Foundation and by an education grant from Sanofi-Aventis which also provided the study drug. The EXPERT-C trial was endorsed by Cancer Research UK and was supported by a research grant from Merck & Co. Sanofi-Aventis and Merck & Co. provided the study drugs. Disclosure: D. Cunningham: Research funding from Roche, Amgen, Celgene, Sanofi, Merck Serono, Novartis, AstraZeneca, Bayer, Merrimack and MedImmune. C. Peckitt: Advisory roles with Sanofi. I. Chau: Advisory roles with Merck Serono, Roche, Sanofi Oncology, Bristol Myers Squibb, Eli-Lilly, Novartis, Gilead Science; research funding from Merck-Serono, Novartis, Roche and Sanofi Oncology; honoraria from Roche, Sanofi-Oncology, Eli-Lilly, Taiho. All other authors have declared no conflicts of interest.

Applicability of American Joint Committee on Cancer and College of American Pathologists Regression Grading System in Rectal Cancer.

Different tumor grading systems have been proposed to predict the association between tumor response and clinical outcome after preoperative chemoradiotherapy in patients with rectal cancer. The American Joint Committee on Cancer and College of American Pathologists regression grading system was recommended as the standard tumor regression grading system for rectal adenocarcinoma. This study evaluated the clinical applicability of the American Joint Committee on Cancer and College of American Pathologists regression grading system in neoadjuvant-treated patients with rectal cancer. This is a retrospective cohort study based on clinical data from a prospectively maintained colorectal cancer database. This study was performed at a single tertiary referral center. A total of 144 patients with primary locally advanced mid-to-low rectal adenocarcinoma who underwent preoperative long-course chemoradiotherapy and total mesorectal excision between 2003 and 2012 were included. The primary outcome measures were the 5-year overall survival rate, the relapse-free survival rate, the cancer-specific survival rate, and cumulative recurrence rates. Of the 144 patients, 16 (11%) were diagnosed as American Joint Committee on Cancer and College of American Pathologists regression grade 0, 43 patients (30%) as grade 1, 61 patients (42%) as grade 2, and 25 patients (17%) as grade 3.After a median follow-up time of 83 months (range, 3 to 147 mo), 5-year survival estimates for grades 0, 1, 2, and 3, were 93%, 77%, 81%, and 54% for overall survival (p = 0.006); 93%, 82%, 75%, and 55% for relapse-free survival (p = 0.03); and 100%, 86%, 89%, and 63% for cancer-specific survival (p = 0.006). The multivariate Cox regression analyses confirmed the American Joint Committee on Cancer and College of American Pathologists regression grading system as a prognostic factor for overall (p = 0.04), relapse-free (p = 0.02), and cancer-specific survival (p = 0.04). This was a retrospective study. Our study findings confirm the clinical relevance and applicability of the American Joint Committee on Cancer and College of American Pathologists regression grade system as a predictive factor for patients with rectal cancer. See Video Abstract at http://links.lww.com/DCR/A320.

Association between the expression of microRNAs and the response of patients with locally advanced rectal cancer to preoperative chemoradiotherapy.

Preoperative chemoradiotherapy (CRT) followed by mesorectal excision is the standard treatment for patients with locally advanced rectal cancer (LARC). The balance between treatment efficacy and toxicity is a major issue in the clinical management of these patients. There is a requirement for the identification of predictive molecular biomarkers for the response of patients to CRT. The present study aimed to analyze the association between microRNA (miRNA/miR) expression and treatment efficacy in patients with LARC who were treated with preoperative CRT. From previous clinical trials, 55 patients for the test cohort and 130 patients for the validation cohort met the criteria for the present investigation. Through reverse transcription-quantitative polymerase chain reaction analysis, the expression of miR-21, −31, −125b, −145 and −630 in the diagnostic biopsies was analyzed. The primary endpoint of tumor regression was evaluated according to Mandard's Tumor Regression Grade (TRG) system. In the test cohort, a significant association was identified between low miRNA-145 expression and TRG1+2 (P=0.0003). Similarly, this association was identified in the validation cohort, although it did not reach statistical significance. Furthermore, a significant association between high miRNA-21 expression and TRG1+2 (P=0.035) was observed in the validation cohort. The remaining miRNAs analyzed were not associated with TRG. The results of the present study highlight the clinical importance of miRNAs in LARC and underline the necessity for validation studies in this setting.

Comparison of five tumor regression grading systems for gastric adenocarcinoma after neoadjuvant chemotherapy: a retrospective study of 192 cases from National Cancer Center in China

BackgroundNeoadjuvant chemotherapy has been increasingly practiced on gastric cancer (GC), and histological evaluation to predict outcome is urgent in clinical practice. There are five classic tumor regression grading (TRG) systems, including Mandard-TRG system, the Japanese Gastric Cancer Association (JGCA)-TRG system, College of American Pathologists (CAP)-TRG system, China-TRG system and Becker-TRG system.MethodsTotally, 192 patients of gastric adenocarcinoma (including adenocarcinoma of the esophagogastric junction) treated by neoadjuvant chemotherapy and surgery were evaluated using the above five TRG systems. The clinicopathological characteristics were also assessed. The correlation among TRG systems, clinicopathological characteristics and prognosis were analyzed.ResultsAll the five TRG systems were significantly correlated with differentiation, postsurgical T category, postsurgical N category, American Joint Committee on Cancer (AJCC) stage, lymph-vascular invasion, perineural invasion, as well as tumor size. All the five TRG systems were statistically significant in univariate Cox survival analysis. However, only postsurgical T category, postsurgical N category and R0 resection were independent in multivariate Cox survival analysis. The tight correlation between the TRG systems and other characteristics such as postsurgical stage might affect the independent prognostic role of the TRG systems. As compared with other TRG systems, the hazard ratio of no/slightly response in both Mandard TRG system and JGCA TRG system revealed higher hazard of death and disease progression than that of severe response when using univariate Cox survival analysis. The median survival time of complete response and nearly complete response were much longer than that of partial response, all classified by Mandard-TRG system. This could help clinicians predict prognosis more reasonably than JGCA-TRG which does not have the category of nearly complete response.ConclusionWe recommend Mandard-TRG system for GC after neoadjuvant chemotherapy due to its better prediction of prognosis.

Association of immunologic markers from complete blood counts with the response to preoperative chemoradiotherapy and prognosis in locally advanced rectal cancer.

We investigated retrospectively whether immunologic markers from a complete blood count (CBC) are associated with the responsiveness to preoperative chemoradiotherapy (PCRT) and oncologic outcomes in 984 patients with locally advanced rectal cancer (LARC) who also underwent radical surgery from 2005 to 2013. CBC parameters including the neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR) were recorded. Pathologic responses to PCRT were evaluated in the resected specimens using the tumor regression grade system. The cut-off values of the immunologic markers were calculated to analyze their association with recurrence-free survival (RFS). One hundred ninety-five patients achieved total regression of their primary tumor. By receiver operating characteristic analysis, NLR, PLR, and LMR could not distinguish total regression from residual disease after PCRT. The NLR, LMR and PLR cut-off values were 1.7, 6.8 and 92.88, respectively. By univariate analysis, low NLR (≤1.7), high LMR (>6.8) and high PLR (>92.88) were indicators of a favorable RFS outcome. By multivariate analysis, high PLR was associated with an improved RFS (HR, 0.649; 95% CI, 0.473-0.89; P=0.007). High NLR (>1.7) was an independent negative prognostic factor for RFS in stage II (HR, 1.868; 95% CI, 1.08-3.109; P=0.025) and high PLR was a positive prognostic factor in stage III (HR, 0.675; 95% CI, 0.421-0.957; P=0.03). Immunologic markers derived from CBCs are independently associated with the RFS outcome in LARC patients treated with PCRT followed by radical resection. However, these markers are not predictive of total primary tumor regression after PCRT.

Histopathological regression of gastric adenocarcinoma after neoadjuvant therapy: a critical review.

As the perioperative chemotherapy has been widely implemented on the management of gastric cancer patients, heterogeneity of clinical outcomes has been evidenced in parallel to different histopathological regression pattern of gastric cancer cells. Tumor histological response to preoperative therapy has been graded by various systems in order to categorize the amount of regressive changes induced by chemotherapy in relation to residual tumor. In this context, tumor regression grading (TRG) systems might provide important prognostic information as the variety of tumor response may imply on different clinical outcomes with impact in survival rates. Moreover, gastric cancer behavior varies enormously upon individual factors such as histological classification and tumor anatomic site of involvement that have been shown to affect the TRG interpretation. On the other hand, some studies have assessed the role of molecular markers as a predictor of tumor response to neoadjuvant chemotherapy in terms of TRG. Thus, the aim of this review is to evaluate how TRG has been interpreted in gastric cancer, discuss their clinical and prognostic relevance and also address the molecular markers involved in this process.