To Tumor Regression Grade Research Articles

126P From tumor height (TH) to tumor regression grade (TRG) in locally advanced rectal cancers (LARC) during total neadjuvant therapy (TNT): A retrospective analysis

126P From tumor height (TH) to tumor regression grade (TRG) in locally advanced rectal cancers (LARC) during total neadjuvant therapy (TNT): A retrospective analysis

453. THE EFFECTIVITY OF NEOADJUVANT CHEMORADIOTHERAPY IN ESOPHAGEAL ADENOCARCINOMA WITH PRESENCE OF EXTRACELLULAR MUCINE, SIGNET-RING CELLS OR POORLY COHESIVE CELLS

Abstract Five-year overall survival of patients with locally advanced esophageal adenocarcinoma treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgery is 40%. Better understanding of histopathological factors that influence treatment response is necessary to identify patients with expected poor prognosis. Aim of the study was to assess whether pre- and post-treatment presence of excessive (≥1%) extracellular mucus accumulation, signet-ring cells (SRC) and/or poorly cohesive cells were associated with poor response to nCRT, independent of tumor differentiation grade. This was a retrospective cohort study. Patients included were diagnosed with an adenocarcinoma of the esophagus or GEJ, who underwent CROSS and were planned to undergo esophagectomy between 2001–2019 at two university hospitals. Percentages of the factors extracellular mucus, SRC and poorly cohesive cells were scored by experienced pathologists in pre-treatment biopsies and resection specimen slides relative to the primary tumor area. Multivariable logistic regression models and Cox proportional-hazards models were used to evaluate the histopathological factors in relation to tumor regression grade (TRG) 1–2 (<10% tumor) vs TRG 3–4 (>10% tumor), overall survival (OS) and disease-free survival (DFS). Some 325 patients were included (median age 65 years, 280/325 (86%) male). In pre-treatment biopsies, ≥1% extracellular mucus was present in 66/325 (20%); ≥1% SRC 43/325 (13%); ≥1% poorly cohesive cells 126/325 (39%). In patients undergoing esophagectomy, 150/284 (53%) had TRG 3–4. Median OS in all patients was 44 months (95%CI: 36–62). Factors in pre-treatment biopsies were not associated with outcomes independent of differentiation grade. Only patients with ≥1% SRC in the resection specimen had poorer OS (Fig 1): HR for death 1.71, 95%CI: 1.06–2.76, adjusted for age, sex, pre-treatment pathological tumor and nodal stage (pre-pT/pre-pN), ypN and tumor differentiation grade. Extracellular mucus accumulation, SRC and/or poorly cohesive cells in pre-treatment biopsies in patients with esophageal adenocarcinoma treated with nCRT are not associated with response to nCRT, OS or DFS. Their presence should not be a reason to refrain from CROSS nCRT. However, persistence of SRC in the resection specimen after nCRT is an indicator of poor prognosis.

Effect of mistletoe extract on tumor response in neoadjuvant chemoradiotherapy for rectal cancer: a cohort study

BackgroundMistletoe extract, used as a complementary chemotherapeutic agent for cancer patients, has anticancer effects against various malignancies. The aim of the present study was to evaluate the effect of mistletoe extract (Abnoba Viscum Q®) on tumor responses to neoadjuvant chemoradiotherapy (NCRT) for locally advanced rectal cancer.MethodsThis study included patients with rectal cancer who underwent NCRT between January 2018 and July 2020. In the mistletoe group (MG), the patients were administered Abnoba Viscum Q® subcutaneously during chemoradiotherapy—maintained just before surgery. Patient demographics, clinical outcomes, histopathological outcomes, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assay results were compared between the MG and non-mistletoe group (NMG). Two rectal cancer cell lines (SNU-503 and SNU-503R80Gy) were treated with Abnoba Viscum Q® to assess its mechanistic effects in vivo.ResultsOverall, the study included 52 patients (MG: n = 15; NMG: n = 37). Baseline demographics between the two groups were similar, except carbohydrate antigen 19-9 levels and tumor location from the anal verge. There was no difference in the clinical stage between the two groups. A better tumor response in the MG, relative to the NMG, was observed with respect to tumor regression grade (TRG), T stage, and overall tumor–node–metastasis stage. Tumor response was significantly better in the MG than in the NMG in terms of pathologic complete response rate (53.3% vs. 21.6%, P = 0.044), good TRG response (66.7% vs. 32.4%, P = 0.024), T downstaging (86.7% vs. 43.2%, P = 0.004), and overall downstaging (86.7% vs. 56.8%, P = 0.040). The toxicities during NCRT were minimal in both groups. More apoptotic cells were noted in MG samples than in the NMG samples on TUNEL staining. Cleaved caspase-3 level following treatment with Abnoba Viscum Q® was higher in SNU-503R80Gy cells than in SNU-503 cells.ConclusionPatients treated with chemoradiation combined with mistletoe extract showed better outcomes than patients not treated with mistletoe extract in terms of tumor responses. This diversity in treatment may improve the efficacy of NCRT, leading to better oncologic outcomes. Prospective and randomized studies with long-term follow-up are warranted to confirm and extend these results.

Hepatic and Extrahepatic Colorectal Metastases Have Discordant Responses to Systemic Therapy. Pathology Data from Patients Undergoing Simultaneous Resection of Multiple Tumor Sites.

Simple SummaryThe standard treatment of patients with hepatic and extrahepatic metastases from colorectal cancer is systemic chemotherapy. We assume that this therapy has the same effectiveness on all disease foci, independent of the involved organ. The effectiveness of chemotherapy is assessed by the pathological response rate: the higher the response rate, the higher the effectiveness of chemotherapy. In the present manuscript, we analyzed patients undergoing resection of hepatic and extrahepatic metastases from colorectal cancer after preoperative chemotherapy. We observed unexpected heterogeneity of the response to chemotherapy of distant metastases from colorectal cancer according to the involved organ. Peritoneal metastases had the highest pathological response rate, which was much higher than the hepatic metastases, while lung and lymph node metastases had extremely poor response rates. Such inhomogeneous effectiveness of systemic treatment in different organs open new perspectives in the treatment of colorectal cancer with distant metastases and oncological research.Background: Systemic therapy is the standard treatment for patients with hepatic and extrahepatic colorectal metastases. It is assumed to have the same effectiveness on all disease foci, independent of the involved organ. The present study aims to compare the response rates of hepatic and extrahepatic metastases to systemic therapy. Methods: All consecutive patients undergoing simultaneous resection of hepatic and extrahepatic metastases from colorectal cancer after oxaliplatin- and/or irinotecan-based preoperative chemotherapy were analyzed. All specimens were reviewed. Pathological response to chemotherapy was classified according to tumor regression grade (TRG). Results: We analyzed 45 patients undergoing resection of 134 hepatic and 72 extrahepatic metastases. Lung and lymph node metastases had lower response rates to chemotherapy than liver metastases (TRG 4–5 95% and 100% vs. 67%, p = 0.008, and p = 0.006). Peritoneal metastases had a higher pathological response rate than liver metastases (TRG 1–3 66% vs. 33%, p < 0.001) and non-hepatic non-peritoneal metastases (3%, p < 0.001). Metastases site was an independent predictor of pathological response to systemic therapy. Conclusions: Response to chemotherapy of distant metastases from colorectal cancer varies in different organs. Systemic treatment is highly effective for peritoneal metastases, more so than liver metastases, while it has a very poor impact on lung and lymph node metastases.

Hepatic and extrahepatic colorectal metastases: discordant pathologic responses to systemic therapy in patients undergoing simultaneous resection of multiple tumor sites

Purpose: Systemic therapy is the standard treatment for patients with hepatic and extrahepatic colorectal metastases. It is assumed to have the same effectiveness on all disease foci, independent of the involved organ. To compare the response rates of hepatic and extrahepatic metastases to systemic therapy. Methods: All consecutive patients undergoing resection for colorectal metastases were considered. Patients undergoing simultaneous resection of hepatic and extrahepatic metastases after preoperative chemotherapy were analyzed. Specimens of hepatic and extrahepatic metastases were reviewed. Pathological response to chemotherapy was classified according to tumor regression grade (TRG). Results: We analyzed 45 patients undergoing resection of 134 hepatic and 72 extrahepatic metastases. Extrahepatic disease was peritoneal in 21 patients, pulmonary in 15, lymph nodal in 14, and adrenal in one (multiple organs in five patients). All patients had oxaliplatin- and/or irinotecan-based preoperative chemotherapy; 60% had associated targeted therapies. Lung and lymph node metastases had lower response rates to chemotherapy than liver metastases (TRG 4–5 in 95% and 100% vs. 67%, P=0.008 and P=0.006, respectively). Peritoneal metastases had a higher pathological response rate than liver metastases (TRG 1–3 66% vs. 33%, P<0.001) and non-hepatic non-peritoneal metastases (vs. 3%, P<0.001). Multivariate analysis identified metastases site, metastasis size and targeted therapies as predictors of pathological response to systemic therapy. Conclusion: Response to chemotherapy of distant metastases from colorectal cancer varies in different organs. Systemic treatment is highly effective for peritoneal metastases, more so than liver metastases, while it has a very poor impact on lung and lymph node metastases.

Multiparametric MRI and Whole Slide Image-Based Pretreatment Prediction of Pathological Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer: A Multicenter Radiopathomic Study

BackgroundThe aim of this work is to combine radiological and pathological information of tumor to develop a signature for pretreatment prediction of discrepancies of pathological response at several centers and restage patients with locally advanced rectal cancer (LARC) for individualized treatment planning.Patients and MethodsA total of 981 consecutive patients with evaluation of response according to tumor regression grade (TRG) who received nCRT were retrospectively recruited from four hospitals (primary cohort and external validation cohort 1–3); both pretreatment multiparametric MRI (mp-MRI) and whole slide image (WSI) of biopsy specimens were available for each patient. Quantitative image features were extracted from mp-MRI and WSI and used to construct a radiopathomics signature (RPS) powered by an artificial-intelligence model. Models based on mp-MRI or WSI alone were also constructed for comparison.ResultsThe RPS showed overall accuracy of 79.66–87.66% in validation cohorts. The areas under the curve of RPS at specific response grades were 0.98 (TRG0), 0.93 (≤ TRG1), and 0.84 (≤ TRG2). RPS at each grade of pathological response revealed significant improvement compared with both signatures constructed without combining multiscale tumor information (P < 0.01). Moreover, RPS showed relevance to distinct probabilities of overall survival and disease-free survival in patients with LARC who underwent nCRT (P < 0.05).ConclusionsThe results of this study suggest that radiopathomics, combining both radiological information of the whole tumor and pathological information of local lesions from biopsy, could potentially predict discrepancies of pathological response prior to nCRT for better treatment planning.

Evaluation of diffusion kurtosis and diffusivity from baseline staging MRI as predictive biomarkers for response to neoadjuvant chemoradiation in locally advanced rectal cancer.

To evaluate the role of diffusion kurtosis and diffusivity as potential imaging biomarkers to predict response to neoadjuvant chemoradiation therapy (CRT) from baseline staging magnetic resonance imaging (MRI) in locally advanced rectal cancer (LARC). This retrospective study included 45 consecutive patients (31 male/14 female) who underwent baseline MRI with high b-value sequences (up to 1500mm/s2) for LARC followed by neoadjuvant chemoradiation and surgical resection. The mean age was 57.4years (range 34.2-72.9). An abdominal radiologist using open source software manually segmented T2-weighted images. Segmentations were used to derive diffusion kurtosis and diffusivity from diffusion-weighted images as well as volumetric data. These data were analyzed with regard to tumor regression grade (TRG) using the four-tier American Joint Committee on Cancer (AJCC) classification, TRG 0-3. Proportional odds regression was used to analyze the four-level ordinal outcome. A sensitivity analysis was performed using univariable logistic regression for binary TRG groups, TRG 0/1 (> 90% response), or TRG 2/3 (< 90% response). p < 0.05 was considered significant throughout. In the univariable proportional odds regression analysis, higher diffusivity summary (Dsum) values were observed to be significantly associated with higher odds of being in one or more favorable TRG group (TRG 0 or 1). In other words, on average, patients with higher Dsum values were more likely to be in a more favorable TRG group. These results are mostly consistent with the sensitivity analysis, in which higher values for most Dsum values [all but region of interest (ROI)-max D median (p = 0.08)] were observed to be significantly associated with higher odds of being TRG 0 or 1. Tumor volume of interest (VOI) and ROI volume, ROI kurtosis mean and median, and VOI kurtosis mean and median were not significantly associated with TRG. Diffusivity derived from the baseline staging MRI, but not diffusion kurtosis or volumetric data, is associated with TRG and therefore shows promise as a potential imaging biomarker to predict the response to neoadjuvant chemotherapy in LARC. Diffusivity shows promise as a potential imaging biomarker to predict AJCC TRG following neoadjuvant CRT, which has implications for risk stratification. Patients with TRG 0/1 have 5-year disease-free survival (DFS) of 90-98%, as opposed to those who are TRG 2/3 with 5-year DFS of 68-73%.

The High Expression of Inhibitory Lymphoid Receptors after Preoperative Radiation Therapy Predicts Favorable Prognosis of Locally Advanced Rectal Cancer

The combination of immune checkpoint blockade and radiotherapy (RT) is a promising treatment strategy. We analyzed the effect of preoperative RT on the inhibitory lymphoid receptors (PD-1, TIM-3, and LAG-3) and their variation after RT. We also evaluated the prognostic value of those proteins expression. The expression of PD-1, TIM-3, LAG-3, CD8, and CD3 was detected by immunohistochemistry on specimens of 76 rectal cancer patients following neoadjuvant treatment, in which 13 cases of pretreatment specimen were available. The expression of proteins was assessed as the percentage of positive cells. Cutoff Finder application was used to estimate the optimized cutoff point of expression levels. The variation of proteins expression was compared by paired t-test and Mann-Whitney U test analysis. Survival analyses were performed by Kaplan–Meier curves and Cox regression models. Receiving operating characteristic curve analysis was conducted to develop the predictor of disease progression. The levels of PD-1 and immune cells (ICs) LAG-3 in rectal cancer increased after RT (P = 0.043, 0.039). However, TIM-3 in ICs and tumor cells (TCs) were both decreased (P = 0.011, 0.000). Interestingly, the level of ICs TIM-3 was lower for patients with >8 weeks interval after RT (P = 0.045). High level of those inhibitory lymphoid receptors appeared a favorable disease-free survival (DFS). PD-1 and IC TIM-3 were both the independent prognosis factors for DFS. Furthermore, IC TIM-3high and CD8high might improve the predicted sensitive of disease progression by adding to tumor regression grade (TRG) (P = 0.0068). RT had improved the expression of PD-1 and ICs LAG-3, while TIM-3 was inhibited. In addition, high expression of PD-1, TIM-3, and LAG-3 indicated a favorable DFS, and IC TIM-3high CD8high predicted poor outcomes.

Application of intravoxel incoherent motion sequence in evaluating and predicting response to neoadjuvant chemotherapy in esophageal squamous cell carcinoma

Objective To assess intravoxel incoherent motion(IVIM) in evaluating and predicting response to neoadjuvant chemotherapy(NAC) in esophageal squamous cell carcinoma(ESCC). Methods Forty-seven patients with ESCC diagnosed by pathological findings on biopsy from September 2015 to March 2017 were prospectively collected. All patients were examined before and after NAC using routine MRI scan and IVIM. The standard apparent diffusion coefficient (ADCstandard), diffusion coefficient (D), perfusion coefficient (D*) and perfusion score (f) were measured. The patients were divided into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) according to the 1.1 version of the response evaluation criteria in solid tumors (RECIST). Thirty-one patients underwent surgery after NAC, and the patients were divided into TRG 0-3 according to tumor regression grade (TRG). The differences of parameter values before and after NAC between different groups were analyzed using Student's t test (normal distribution) and Wilcoxon rank sum tests (non-normal distribution). The parameters with statistical significance were evaluated by the receiver operating characteristics (ROC) curves. Results The ADCstandard values before and after NAC were (1.97±0.51) ×10-3, (2.42±0.52)×10-3 mm2/s. The D values before and after NAC were (1.30±0.30)×10-3, (1.63±0.35)×10-3 mm2/s. The ADCstandard and D values after NAC were significantly higher than those before NAC, and the differences were statistically significant (t=-6.35, -5.25 respectively, both P 0.05). The patients were divided into PR group (29 cases) and SD group (18 cases) after NAC, without CR and PD patients. The ADCstandard, D and f values of PR group were significantly lower than those of the SD group before NAC (t=-3.11, -2.53 and -2.10 respectively, all P<0.05). The ADCstandard, D, D* and f values after NAC revealed no significant difference between PR and SD groups. Thirty-one patients received operation after NAC, which were divided into TRG 2 group (14 cases) and TRG 3 group (17 cases) according to TRG standard, without TRG 0 and TRG 1 patients. All the parameter values before NAC revealed no significant difference between TRG 2 and TRG 3 groups. The D values after NAC in TRG 2 and TRG 3 groups were (1.81±0.31)×10-3, (1.46±0.39)×10-3 mm2/s respectively, and the significant difference was found between two groups (t=2.76, P<0.05). The efficiency of efficacy evaluation for NAC was the highest at D value of 1.68×10-3 mm2/s, with sensitivity and specificity being 85.7% and 70.6%, respectively. Conclusion IVIM can be used as a new imaging method to evaluate and predict the efficacy of NAC for ESCC, among which the parameter D was the most valuable. Key words: Esophageal neoplasms; Magnetic resonance imaging; Intravoxel incoherent motion; Neoadjuvant chemotherapy

Next-generation expression analysis (NanoString) to develop prognostic and predictive gene signatures for patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.

700 Background: The standard of care for locally advanced rectal cancer (RC) is neoadjuvant chemoradiotherapy (CRT) with 5FU aimed to tumor downstaging prior to radical resection but there is a wide spectrum of responses to it, from none to complete. The aim of this project is to validate top candidate genes previously identified by microarray studies as prognostic and predictive classifiers of locally advanced RC, using the NanoString nCounter Platform. Methods: Two cohorts of RC patients were identified according to tumor regression grade (TRG) of AJCC Staging Manual (7th) system: 1) good prognosis: patients that after neoadjuvant CRT obtained TRG0 (complete response); 2) poor prognosis: patients with TRG1 (moderate response), patients with TRG2 (minimum response rate) and patients with TRG3 (poor response). Pre-treatment biopsies tissues from ten TRG0 patients (ID TRG0bio) and thirteen TRG1-3 patients (ID TRG1-3bio) were macro-dissected from FFPE sections, RNA isolated and used for expression profiling of a 305 genes custom code set consisting of 12 normalizer genes, 101 prognostic genes (markers of stemness, invasiveness, proliferation, drug-resistance), 192 predictive genes (involved in response to 5-FU, to radiation therapy and in the response to CRT). All samples were normalized using the geometric mean of the housekeeper genes. P-values were calculated by student’s t-test and was consider significance if was less than 0.05. Gene-specific RNA expression profiles were compared using Spearman's correlation. The heat map was generated using MeV 4.9.0. Results: When we compared TRG0bio to TRG1-3bio tissues, among the 305 genes assayed, changes in expression levels of 18 genes (SSB, GAPDH, TXNDC9, DUT, PKM, STAT1,SLC28A3, DAG1, TYMS, FERMT1, ARNT,SLC6A6, SMAD3, SCRN1, POU5F1, GNG4, PDRG1, ATP5E) were statistically significant. Conclusions: Results suggest that TRG0 RC is characterized by distinct molecular events compared TRG1-3 disease. Next steps will be: to amplify sample size, to understand signaling pathways of top differentially expressed genes and to validate prospectively our gene signature.

Analysis of short-term efficacy and pathological outcome of paclitaxel plus platinum as neoadjuvant chemotherapy in the treatment of locally advanced cervical cancer.

e17002 Background:The purpose of this study is to observe the short-term efficacy and pathological outcomes of paclitaxel combined with platinum (TP) as neoadjuvant chemotherapy (NACT) regimen in patients with locally advanced cervical cancer (LACC). Methods: This is a prospective study involving 61 women with histologically confirmed LACC referred for NACT at Beijing Obstetrics and Gynecology Hospital between April 2013 and January 2015. Results: The short-term efficacy of NACT was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST). The short-term efficacy of NACT was 91.8% (complete remission and partial remission). The cervical invasion ≤1/2 was 82.4% in the complete remission (CR) group, 46.2% in the partial remission(PR) group and 20% in the stable disease (SD) group. The difference between groups was statistically significant (p=0.012). The slides of all surgical specimens were reviewed and classified according to Tumor Regression Grade (TRG). The good response was defined by good short-term efficacy (RECIST) and the difference between the groups was statistically significant (p=0.042). The short-term efficacy of NACT in artery intervention (AI) group (70-80%) was better than that in intravenous (IV) group (20%-30%) and the difference was statistically significant (p=0.011). The patients with tumor diameter ≤5cm and multiple cycles of chemotherapy have good short-term efficacy of NACT in LACC. All patients were followed up to the last day of 2015 with the median follow-up time of 21.5 months for NACT. For the 61 patients referred for NACT in LACC, two patients had relapsed and 1 patient died from the disease. Conclusions: The study showed that the Paclitaxel plus platinum as NACT for LACC treatment had a significant local effects. It could reduce tumor myometrial invasion and regress tumor. The short-term efficacy of the treatment in the AI group was more effective than in the IV group, two cycles of NACT of AI treatment to LACC patients would obtain an optimal short-term efficacy. Clinical trial information: NCT02471027.

Circulating tumor cells: A promising marker of predicting tumor response in rectal cancer patients receiving neoadjuvant chemo-radiation therapy.

PurposeThe aim of this study was to investigate the role of circulating tumor cells (CTCs) in assessing and predicting tumor response to neoadjuvant chemoradiotherapy (CRT) for patients with locally advanced rectal cancer (LARC).MethodsA total of 115 patients with T3-4 and/or N+ rectal cancer were enrolled. All patients received neoadjuvant CRT followed by radical surgery after 6-8 weeks. The pathological results after surgery were evaluated according to tumor regression grade (TRG) classification.ResultsBased on TRG score, patients were classified as responders (TRG3-4) and non-responders (TRG0-2). The baseline CTC counts of responders were significantly higher than those of non-responders (44.50±11.94 vs. 37.67±15.45, P=0.012). By contrast, the post-CRT CTC counts of responders were significantly lower than those of non-responders (3.61±2.90 vs. 12.08±7.40, P<0.001). According to ROC analysis, Δ%CTC (percentage difference in CTC counts between baseline and post-CRT) was identified as the stronger predictor to discriminate responders from non-responders (AUC: 0.860). The results of multivariate analysis also indicated that post-CRT CTC counts and Δ%CTC were significantly and independently associated with tumor response to CRT.ConclusionsThe detection of CTCs is a powerful and promising tool for evaluating and predicting responses to neoadjuvant CRT in LARC patients.

Neoadjuvant chemotherapy evaluation by MRI volumetry in rectal cancer followed by chemoradiation and total mesorectal excision: Initial experience

To evaluate rectal cancer volumetry in predicting initial neoadjuvant chemotherapy response. Sixteen consecutive patients who underwent neoadjuvant chemotherapy (CX) before chemoradiotherapy (CRT) and surgery were enrolled in this retrospective study. Tumor volume was evaluated at the first magnetic resonance imaging (MRI), after CX and after CRT. Tumor volume regression (TVR) and downstaging were compared with histological results according to Tumor Regression Grade (TRG) to assess CX and CRT response, respectively. The mean tumor volume was 132 cm(3) ± 166 before and 56 cm(3) ± 71 after CX. TVR after CX was significantly different between patients with poor histologic response (TRG1/2) and those with good histologic response (TRG3/4) (P = 0.001). An optimal cutoff of TVR >68% (area under the curve [AUC]: 0.9, 95% confidence interval [CI]: 0.65-0.98, P = 0.0001) to predict good histology response after CX was assessed by receiver operating characteristic curve. According to previous data and this study, we defined 70% as the best cutoff values according to sensitivity (86%), specificity (100%) of TVR for predicting good histology response. In contradistinction, MRI downstaging was associated with TRG only after CRT (P = 0.04). Our pilot study showed that MRI volumetry can predict early histological response after CX and before CRT. MRI volumetry could help the clinician to distinguish early responders in order to aid appropriate individually tailored therapies.

Locally advanced rectal cancer: Value of ADC mapping in prediction of tumor response to radiochemotherapy

PurposeTo evaluate the diagnostic performance of quantitative apparent diffusion coefficient (ADC) measurements, in the assessment of the therapeutic response to chemo-radiation therapy (CRT) in patients with locally advanced rectal cancer, by analyzing post CRT values of ADC, in relation to tumor regression grade (TRG) obtained by histopathologic evaluation of the rectal specimen. MethodsThis prospective study was approved by an Institutional Review Board, and informed consent was obtained from all patients. Thirty-one patients with locally advanced rectal cancer underwent pre and post CRT MR imaging at 1.5T. ADC values were measured in regions of interest (ROIs) drawn independently by two radiologists, blinded to the pathology results, on three slices of the pre and post CRT DW-MR image sets with the corresponding T2 weighted images (T2WI) available for anatomic reference. The two readers’ measurements were compared for differences in ADC values, inter-observer variability (measured as the intraclass correlation coefficient; ICC) and the ADC distributions of responders vs non-responders. The diagnostic performance of ADC in the prediction of the response to CRT was evaluated by calculating the area under the ROC curve (AUC) and the optimal cut-off values. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were assessed. ResultsThe two readers showed an overall strong agreement in measuring ADC values. For both readers, no differences in ADC pre-treatment measurements were observed between responders and non-responders. For reader 1, the post-CRT ADC and the ΔADC presented the higher AUC (0.823 and 0.803, respectively), while Δ%ADC provided the lower AUC value (0.682). The optimal cutoff point was 1.294s/mm2 for post-CRT measures (sensitivity=86.4%, specificity=66.7%, PPV=86.4%, NPV=66.7%), 0.500 for ΔADC (sensitivity=81.8%, specificity=66.7%, PPV=85.7%, NPV=60.0%) and 59.3% for Δ%ADC (sensitivity=63.4%, specificity=66.7, PPV=82.4%, NPV=42.9%). Similar results were observed for reader 2, with better performance obtained with the ADC post-CRT (AUC of 0.833) and an optimal cut off of 1.277×10−3s/mm2. ConclusionPost-CRT ADC measurements are reliable and reproducible and may be used as a non-invasive tool to evaluate response to therapy as post-CRT ADC values and ΔADC presented good diagnostic performance to select responder patients.

Failure patterns correlate with the tumor response after preoperative chemoradiotherapy for locally advanced rectal cancer

To determine whether the patterns of failure are correlated with the degree of response to preoperative chemoradiotherapy (CRT) and to evaluate outcomes after recurrence in rectal cancer patients who underwent CRT followed by resection. Response to CRT was evaluated according to tumor regression grade (TRG), with 581 patients categorized into two groups, a good response (GR, TRG 3/4, n = 224) and a poor response (PR, TRG 1/2, n = 357) group. At a mean follow-up of 61 months, the 5-year overall (88.2% vs. 71.3%, P < 0.001) and disease-free (86.7% vs. 63.6%, P < 0.001) survival rates were higher in the GR group. In patients with recurrence, time to recurrence was shorter (13.5 months vs. 18.7 months, P = 0.01), and the cumulative 2-year recurrence rates (92.9% vs. 73.4%, P = 0.024) was higher in the GR group. Rates of local (1.3% vs. 9.5% P < 0.001) and systemic (11.6% vs. 27.2%, P < 0.001) recurrence were significantly lower in the GR group, as were rates of pulmonary (3.6% vs. 15.1%, P < 0.001) and systemic lymph node (1.3% vs. 5.9%, P = 0.009) recurrences. The 5-year overall survival rates after recurrence were similar (GR: 23.7% vs. PR: 16.0%, P = 0.911). More than one-third of patients with locally advanced rectal cancer showed good response to CRT, with improved local and systemic recurrence rates, especially low rates of pulmonary and systemic lymph node recurrence. Recurrence occurred earlier in the GR than the PR group, and oncologic outcomes after recurrence did not differ between the two groups.

The correlation between tumour regression grade and lymph node status after chemoradiation in rectal cancer

To determine the correlation between tumour response to preoperative RCTX and lymph node status, an established parameter of clinical outcome. After IRB approval, 86 consecutive rectal cancer patients who received preoperative RCTX were identified. Fifty seven were males. Mean age 62 years. Preoperative staging by ultrasound was available in 60 patients. Radiotherapy consisted of (40-60 g) and chemotherapy of 5-FU infusion (1500 mg/m(2) week), assessed using Dworak's system. Tumour response according to Tumor regression grade (TRG) were: TRG 0: 8 (9.3%); TRG 1: 15 (17.4%); TRG 2: 14 (16.2%); TRG 3: 31 (36%); TRG 4: 18 (20%). Eighteen patients had tumour stage 0 (20.9%); while 8 (9.2%), 28 (32.1%), 30 (34.5%) and three had tumours stages 1, 2, 3 and 4 respectively. Evaluation of nodal status revealed no involvement in 65 patients (N0), and positive nodes in 21 (14 N1, 7 N2). Response to RCTX was significantly associated with node stage, hence individuals without node involvement (N0) had 66% of positive tumour response (TRG 4), while individuals with node metastasis had less response to RCTX (TRG 0, 1 and 2) 35% N1 and 14% for N2 (P = 0.007). Node status was independently associated to poor response to preoperative RCTX, even after adjusting for tumour stage, age and gender (OR 0.02, 95% CI 0.0009-0.67). Tumour shrinkage by preoperative RCTX appears to correlate with lymph node metastasis suggesting that neoadjuvant RCTX may have a positive impact in overall patient survival.

A Simplified Tumor Regression Grade Correlates with Survival in Locally Advanced Rectal Carcinoma Treated with Neoadjuvant Chemoradiotherapy

Locally advanced rectal cancer is frequently treated with neoadjuvant chemoradiotherapy to reduce local recurrence and possibly improve survival. The tumor response to chemoradiotherapy is variable and may influence the prognosis after surgery. This study assessed tumor regression and its influence on survival in patients with rectal cancer treated with chemoradiotherapy followed by curative surgery. One hundred twenty-six patients with locally advanced rectal cancer (T3/T4 or N1/N2) were treated with chemoradiotherapy followed by total mesorectal excision. Patients received long-course radiotherapy (50 Gy in 25 fractions) in combination with 5-flourouracil over 5 weeks. By means of a standardized approach, tumor regression was graded in the resection specimen using a 3-point system related to tumor regression grade (TRG): complete or near-complete response (TRG1), partial response (TRG2), or no response (TRG3). The 5-year disease-free survival was 72% (median follow-up 37 months), and 7% of patients had local recurrence. Chemoradiotherapy produced downstaging in 60% of patients; 21% of patients experienced TRG1. TRG1 correlated with a pathological T0/1 or N0 status. Five-year disease-free survival after chemoradiotherapy and surgery was significantly better in TRG1 patients (100%) compared with TRG2 (71%) and TRG3 (66%) (P = .01). Tumor regression grade measured on a 3-point system predicts outcome after chemoradiotherapy and surgery for locally advanced rectal cancer.