Mandard Tumor Regression Grade Research Articles

Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma.

Simple SummaryEsophageal adenocarcinoma (EAC) is a cancer with very poor survival outcomes. Patients are treated with pre-operative chemotherapy or chemoradiotherapy before surgery. However, four out of every five patients do not respond to pre-operative therapy and these patients (non-responders) have significantly worse outcomes. Identifying non-responders prior to therapy would allow alternative treatment pathways to be offered to these patients. In this study, we analyze whole genome sequences of pre-treatment biopsies from 65 patients and find that non-responders display chromosomal instability and increased gene copy number alterations. We report a distinct profile of copy number alterations in non-responders compared to responders, predominantly in genes involved in cell cycle control and RTK/Ras signaling. Mutations in the tumor suppressor NAV3 are also found exclusively in non-responders. These genetic profiles present potential drug targets for investigation in EAC patients who would not respond to pre-operative chemotherapy.Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20–37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1–2 (n = 27) and non-responders classified as TRG4–5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

Moderately differentiated esophageal squamous cell carcinoma has a poor prognosis after neoadjuvant chemoradiotherapy.

BackgroundNeoadjuvant chemoradiotherapy (NCRT) plus surgery is the standard treatment for esophageal squamous cell carcinoma (ESCC); however, further analysis is needed to detail the histopathological characteristics of ESCC and their clinical significance after NCRT. This study aimed to present the pathological characteristics of ESCC and their association with prognosis after NCRT.MethodsAll patients with ESCC who underwent NCRT followed by surgical resection at Sichuan Cancer Hospital (China) from January 2018 to December 2019 were included. Resection specimens of both the primary disease and lymph nodes were re-evaluated by an experienced pathologist. After NCRT, the pathological characteristics of the residual tumor were evaluated based on the Japanese residual tumor pattern, Mandard tumor regression grade (Mandard-TRG), local inflammatory infiltration classification, and lymph node status.ResultsAmong the 103 patients with ESCC included in this study, the pathological complete response (pCR) rate was 34% (35/103). The pCR rate of patients with poorly differentiated tumors (31/72) was higher (43.1%) than that of patients with well or moderately differentiated tumors (P<0.05). The residual tumor rate was 66% (68/103). A positive correlation was noted between the Japanese residual tumor pattern and Mandard-TRG (Kendall’s tau-b =0.857, P<0.001). Tumor infiltration depth, lymph node positivity, moderate differentiation, and tumor recurrence were associated with poor oncological outcomes (P<0.05).ConclusionsPatients with poorly differentiated tumors can obtain an excellent short-term response; however, they have extremely poor long-term survival. For patients with moderately differentiated tumors, both the short- and long-term outcomes are poor. Lymph node status after NCRT is a prognostic factor for ESCC treated with NCRT.

Body Composition Changes in Gastric Cancer Patients during Preoperative FLOT Therapy: Preliminary Results of an Italian Cohort Study.

Background: The impact of the new chemotherapy, fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) on body composition in gastric cancer (GC) patients remains unknown. We assessed body composition changes of GC patients receiving the FLOT regimen and their impact on treatment outcomes. Methods: Preoperative pre- and post-FLOT computed tomography (CT) scans of advanced GC patients were studied. Lumbar skeletal muscle index (SMI) and adipose indices were calculated before and after FLOT. Results: A total of 26 patients were identified between April 2019 and January 2020. Nineteen patients were sarcopenic at diagnosis. The mean BMI decreased (from 24.4 ± 3.7 to 22.6 ± 3.1; p < 0.0001) as well as the SMI (from 48.74 ± 9.76 to 46.52 ± 9.98; p = 0.009) and visceral adipose index (VAI) (from 49.04 ± 31.06 to 41.99 ± 23.91; p = 0.004) during preoperative FLOT therapy. BMI, SMI, and VAI variations were not associated with toxicity, Response Evaluation Criteria in Solid Tumors (RECIST), response, delay and completion of perioperative FLOT chemotherapy, and the execution of gastrectomy; a decrease of SMI ≥ 5% was associated with a higher Mandard tumor regression grade (p = 0.01). Conclusions: Almost three-quarters (73.1%) of GC patients were sarcopenic at diagnosis. Preoperative FLOT was associated with a further reduction in SMI, BMI, and VAI. These changes were not associated with short-term outcomes.

Addition of HER2 and CD44 to 18F-FDG PET\u2013based clinico-radiomic models enhances prediction of neoadjuvant chemoradiotherapy response in esophageal cancer

ObjectivesTo assess the complementary value of human epidermal growth factor receptor 2 (HER2)-related biological tumor markers to clinico-radiomic models in predicting complete response to neoadjuvant chemoradiotherapy (NCRT) in esophageal cancer patients.MethodsExpression of HER2 was assessed by immunohistochemistry in pre-treatment tumor biopsies of 96 patients with locally advanced esophageal cancer. Five other potentially active HER2-related biological tumor markers in esophageal cancer were examined in a sub-analysis on 43 patients. Patients received at least four of the five cycles of chemotherapy and full radiotherapy regimen followed by esophagectomy. Three reference clinico-radiomic models based on 18F-FDG PET were constructed to predict pathologic response, which was categorized into complete versus incomplete (Mandard tumor regression grade 1 vs. 2–5). The complementary value of the biological tumor markers was evaluated by internal validation through bootstrapping.ResultsPathologic examination revealed 21 (22%) complete and 75 (78%) incomplete responders. HER2 and cluster of differentiation 44 (CD44), analyzed in the sub-analysis, were univariably associated with pathologic response. Incorporation of HER2 and CD44 into the reference models improved the overall performance (R2s of 0.221, 0.270, and 0.225) and discrimination AUCs of 0.759, 0.857, and 0.816. All models exhibited moderate to good calibration. The remaining studied biological tumor markers did not yield model improvement.ConclusionsIncorporation of HER2 and CD44 into clinico-radiomic prediction models improved NCRT response prediction in esophageal cancer. These biological tumor markers are promising in initial response evaluation.Key Points• A multimodality approach, integrating independent genomic and radiomic information, is promising to improve prediction of γpCR in patients with esophageal cancer.• HER2 and CD44 are potential biological tumor markers in the initial work-up of patients with esophageal cancer.• Prediction models combining 18F-FDG PET radiomic features with HER2 and CD44 may be useful in the decision to omit surgery after neoadjuvant chemoradiotherapy in patients with esophageal cancer.

Clinical outcomes in elderly rectal cancer patients treated with neoadjuvant chemoradiotherapy: impact of tumor regression grade : Tumor regression grade after neoadjuvant chemoradiotherapy in elderly rectal cancer patients.

The effect of neoadjuvant chemoradiotherapy (CRT) and the relationship between pathological complete response (pCR) with clinical outcomes has been evaluated in elderly locally advanced rectal cancer (LARC) patients. We retrospectively analyzed 117 LARC patients treated with conformal RT and concomitant fluoropirimidine-based chemotherapy. A dose of 4500cGy, on the pelvis, up to 5500cGy on the tumor was delivered. Multidisciplinary evaluation, including geriatric assessment, was previously performed to identify frail patients unsuitable for combined treatment. The median age was 75 (range 70-88years), and 103 (88%) patients had ECOG Performance Status (PS) = 0. All patients except one completed CRT. Ten (8.5%) patients temporarily suspended CRT for acute severe hematologic complication, diarrhea and/or proctitis and hypokalemia. Of the 103 operated patients (88%), a pCR, according to Mandard tumor regression grade (TRG) score, was obtained in 28 patients (27.2%), with TRG1-2 rate of 43.7%. The 3- and 5-year overall survival (OS) rates were 80.2% ± 4.2% and 68.0% ± 5.2%, 72.4% ± 4.5% and 57.8% ± 5.2% for disease-free survival (DFS), and 92.2% ± 2.8% and 89.5% ± 3.9% for loco-regional control. Patients with TRG1-2 had 3- and 5-year OS rates of 84.1% ± 6.6% and 84.1% ± 6.6% compared with 82.8% ± 5.5% and 67.7% ± 7.2% for patients with TRG3-5 (p = 0.012). The 3- and 5-year DFS rates for patients with TRG1-2 were 77.6% ± 7.0% and 74.2% ± 7.5% compared with 70.9% ± 6.3% and 54.7% ± 7.3% for patients with TRG3-5 (p = 0.009). Our results reported good tolerability and clinical outcomes of neoadjuvant CRT, with a benefit in patients ≥ 70years, confirming the prognostic role of pCR on clinical outcomes.

Adjuvant therapy following oesophagectomy for adenocarcinoma in patients with a positive resection margin.

The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy is contentious. In UK practice, surgical resection margin status is often used to classify patients for receiving adjuvant treatment. The aim of this study was to assess the survival benefit of adjuvant therapy in patients with positive (R1) resection margins. Two prospectively collected UK institutional databases were combined to identify eligible patients. Adjusted Cox regression analyses were used to compare overall and recurrence-free survival according to adjuvant treatment. Recurrence patterns were assessed as a secondary outcome. Propensity score-matched analysis was also performed. Of 616 patients included in the combined database, 242 patients who had an R1 resection were included in the study. Of these, 112 patients (46·3 per cent) received adjuvant chemoradiotherapy, 46 (19·0 per cent) were treated with adjuvant chemotherapy and 84 (34·7 per cent) had no adjuvant treatment. In adjusted analysis, adjuvant chemoradiotherapy improved recurrence-free survival (hazard ratio (HR) 0·59, 95 per cent c.i. 0·38 to 0·94; P =0·026), with a benefit in terms of both local (HR 0·48, 0·24 to 0·99; P =0·047) and systemic (HR 0·56, 0·33 to 0·94; P =0·027) recurrence. In analyses stratified by tumour response to neoadjuvant chemotherapy, non-responders (Mandard tumour regression grade 4-5) treated with adjuvant chemoradiotherapy had an overall survival benefit (HR 0·61, 0·38 to 0·97; P =0·037). In propensity score-matched analysis, an overall survival benefit (HR 0·62, 0·39 to 0·98; P =0·042) and recurrence-free survival benefit (HR 0·51, 0·30 to 0·87; P =0·004) were observed for adjuvant chemoradiotherapy versus no adjuvant treatment. Adjuvant therapy may improve overall survival and recurrence-free survival after margin-positive resection. This pattern seems most pronounced with adjuvant chemoradiotherapy in non-responders to neoadjuvant chemotherapy.

474 GENOMIC ANALYSIS OF RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN ESOPHAGEAL ADENOCARCINOMA

Abstract In the UK, neoadjuvant chemotherapy (NAC) for locally advanced esophageal adenocarcinoma (EAC) is the standard of care. Unfortunately, response to NAC, following surgery is often low (&amp;lt;30%) and survival benefit at 2 years is only 5.1%. The EAC genome is complex and heterogeneous between patients, where specific mutagenic processes and mutations may result in chemotherapy resistance. Here we report preliminary results from whole-genome sequencing (WGS) of 48 patients who were subsequently treated with NAC. Methods We defined response as Mandard Tumor Regression Grade (TRG) 1-2 (n = 15) and non-response as TRG4-5 (n = 33). WGS of 50x coverage and calling of genomic events (Strelka2, SCAT/GISTIC) was performed according to Frankell Nat Genet 2019 with modifications, to differentiate driver from passenger mutations (dNdScv, oncodriveCLUST), determine variant allele frequencies (VAF; copy number-adjusted) and mutation signatures (NMF R-package). Following stringent variant QC (Phred score ≥ 30), filtering (VAF &amp;gt;0.02) and annotation (ANNOVAR, cancer census/helper, the 77 known EAC drivers and false positive genes) and visualisation in maftools, we evaluated the data for associations between genomic events and response to NAC. Results COSMIC mutation signatures 2 (TRG1-2; Cosθ = 0.89) and 6 (TRG4-5; Cosθ = 0.82) were enriched, suggesting defective mismatch repair in non-responders. Using 5,193 high-confidence non-silent mutations (TRG1-2,n = 1969; TRG4-5, n = 3224), we identified 39 mutated driver genes (Figure-1) with a median of 2.9(0-5) (TRG1-2) and 2.7(0-9) (TRG4-5) driver events/patient. Shared dysregulated pathways, included DNA-damage (TP53), cell cycle (CDKN2A), TGF-β (SMAD4) and chromatin regulation (ARID1A). There was no difference in the prognostic of SMAD4 and GATA4 genes. Interestingly, NAV3 mutations were only present in non-responders (21%,7/33); and in responders TP53 incidence was higher (93% vs. 58%) with a concomitant reduction in clonal cell fraction (0.25 vs. 0.39;Wilcoxon, p &amp;lt; 0.0001). Conclusion The data suggest that specific genomic events, such as NAV3 mutation and the intra-tumoral heterogeneity of mutated DNA-damage response genes may offer additional predictive value. Ongoing work includes analysis of the impact of non-coding variation on response. While our analysis is limited by sample size and requires validation in additional cohorts, it demonstrates the potential of genomic sequencing to identify NAC response biomarkers and may guide alternative or novel treatment modalities for chemo-resistant tumours.

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.

Impact of sex and age on chemotherapy efficacy, toxicity and survival in localised oesophagogastric cancer: A pooled analysis of 3265 individual patient data from four large randomised trials (OE02, OE05, MAGIC and ST03)

BackgroundThere is a lack of large-scale randomised data evaluating the impact of sex and age in patients undergoing chemotherapy followed by potentially curative surgery for oesophagogastric cancer. Patients and methodsIndividual patient data from four prospective randomised controlled trials were pooled using a two-stage meta-analysis. For survival analysis, hazard ratios (HRs) were calculated for patients aged <70 and ≥ 70 years, as well as between males and females. Mandard tumour regression grade (TRG) and, ≥grade III toxicities were compared using logistic regression models to calculate odds ratios. All analyses were adjusted for the type of chemotherapy received. Results3265 patients were included for survival analysis (2668 [82%] male, 597 [18%] female; 2627 (80%) <70 years, 638 (20%) ≥70 years). A significant improvement in overall survival (OS) (HR: 0.78; p < 0.001) and disease-specific survival (DSS) (HR: 0.78; p < 0.001) was observed in females compared with males. No significant differences in OS (HR: 1.11; p = 0.045) or DSS (HR: 1.01; p = 0.821) were observed in older patients compared with younger patients.For patients who underwent resection, older patients (15% vs 10%; p = 0.03) and female patients (14% vs 10%, p = 0.10) were more likely to achieve favourable Mandard TRG scores. Females experienced significantly more ≥grade III nausea (10% vs 5%; p≤0.001), vomiting (10% vs 4%; p≤0.001) and diarrhoea (9% vs 4%; p≤0.001) than males. ConclusionsIn this large pooled analysis using prospective randomised trial data, females had significantly improved survival while experiencing more gastrointestinal toxicities. Older patients achieved comparable survival to younger patients and thus, dependent on fitness, should be offered the same treatment paradigm.

Tumor Regression Grade Predicts Survival in Locally Advanced Gastric Adenocarcinoma Patients with Lymph Node Metastasis.

Background Tumor regression grade (TRG) is widely used in gastrointestinal carcinoma to evaluate pathological responses to neoadjuvant chemotherapy (NCT), but whether it is an independent prognostic factor is still controversial. The aim of this study is to investigate the value of TRG in locally advanced gastric adenocarcinoma patients who underwent NCT and curative resection. Methods Pathological regression was reevaluated according to the Mandard TRG. Survival curves were obtained by the Kaplan–Meier method, and differences in overall survival (OS) and disease-free survival (DFS) were compared using the log-rank test. Univariate and multivariate analyses for survival were based on the Cox proportional hazards method. Results In total, 290 patients were identified in our electronic database. In univariable analysis, TRG was associated with OS (HR = 3.822, P ≤ 0.001) and DFS (HR = 3.374, P ≤ 0.001). However, in multivariable analysis, TRG was not an independent factor for OS (P = 0.231) or DFS (P = 0.191). In the stratified analysis, TRG retrieved prognostic significance in patients with the metastasis of lymph node (HR = 2.034, P = 0.035 for OS; HR = 2.220, P = 0.016 for DFS), while not in patients with negative lymph node (P = 0.296 for OS; P = 0.172 for DFS). Conclusions TRG was not an independent predictor for survival, but the system regained its predicting significance in patients with lymph node metastasis.

Does Neutrophil-to-Lymphocyte Ratio (NLR) Predict Pathologic Response to Neoadjuvant Chemoradiotherapy in Patients with Esophageal Squamous Cell Carcinoma?

Neoadjuvant chemoradiotherapy (nCRT), followed by surgery, is the current standard of care for patients with locally advanced esophageal squamous cell carcinoma. However, up to 30% of the patients do not respond to nCRT. Hence, a simple, cost-effective marker to predict response before initiation of nCRT is needed. Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic marker in various cancers. However, its role as a predictive marker in patients with esophageal SCC planned for nCRT has not been prospectively analyzed. All consecutive patients with locally advanced (T1N1 and T2-T4a with or without nodal involvement) SCC planned for nCRT (CROSS protocol) followed by esophagectomy with total two field lymphadenectomy between December 2013 and December 2019 were included in this prospective analytical cohort study. NLR was calculated 1week before starting the nCRT and was correlated with the histopathological response [Mandard tumor regression grade (TRG)]. Of the 216 patients with esophageal cancer evaluated during the study period, 57 patients with SCC who fulfilled the inclusion criteria were included. A good pathologic response (TRG 1 and 2) to nCRT was seen in 28 (49.1%) patients. Using a ROC curve, the optimal cutoff value of pretherapy NLR for predicting good pathologic response was 2.33. With an NLR cutoff value of 2.33, 53.3% of patients had a good pathologic response to nCRT compared with 47.6% patients with NLR ≥ 2.33 (P = 0.77). In patients with locally advanced esophageal SCC, NLR is not a useful marker to predict pathologic response to nCRT.

Modification of preoperative radiochemotherapy for esophageal cancer (CROSS protocol) is safe and efficient with no impact on surgical morbidity

PurposeNeoadjuvant radiochemotherapy (RCTH) is proven to be highly effective in the treatment of esophageal cancer (EC). We investigated oncological outcome and morbidity in patients treated with a modified CROSS protocol followed by esophagectomy at our institution.MethodsPatients with EC receiving neoadjuvant RCTH with paclitaxel and carboplatin and concurrent radiotherapy (46 Gy) followed by esophagectomy were included in this retrospective analysis. Histopathological response, overall survival (OS) and recurrence-free interval (RFI) as well as perioperative morbidity were investigated.ResultsThirty-six patients (86.1% male, mean age 61.3 years, standard deviation 11.52) received neoadjuvant RCTH before surgery. Sixteen patients (44.4%) were treated for squamous cell cancer, whereas 20 patients (55.6%) had adenocarcinoma. The majority (75%) underwent abdominothoracic esophageal resection. Major complications occurred in 7 patients (19.5%) including anastomotic leakage in 4 patients (11.1%). A R0 resection was achieved in 97.2%. A complete pathological remission was seen in 13 patients (36.1%). Major response, classified as Mandard tumor regression grade 1 and 2, was found in 26 patients (72.2%). Median OS and RFI were not reached.ConclusionsNeoadjuvant radiotherapy with 46 Gy and concomitant chemotherapy with paclitaxel and carboplatin for the treatment of locally advanced esophageal carcinoma is safe and effective. The results of this modified radiotherapy protocol are encouraging and should be considered in future patient treatment and study designs.

Propensity score regression analysis of esophageal cancer treatment with surgery alone or neoadjuvant chemotherapy.

405 Background: The aim of this study was to examine the outcomes of oesophageal adenocarcinoma (OC) treatment with either surgery alone (S), or with neoadjuvant chemotherapy (NAC) followed by surgery (NACS), by means of propensity score (PS) regression analysis, in order to examine whether the benefits reported in the MRC OE02 trial were reproducible in UK cancer network clinical practice. Methods: Consecutive patients undergoing potentially curative treatment for OC in a regional cancer network were studied. Multiple regression models, including PS were developed to account for confounding factors and the primary outcome measure was disease-free (DFS) and overall survival (OS). Results: A cohort of 440 patients was included in a regression analysis controlling for confounders (176 S, 264 NACS). NACS was associated with positive margin status (NACS vs. S, 42.4% vs. 26.7%, p&lt;0.05), poor 5-year DFS (32.1% vs. 56.9, p&lt;0.001), and poor 5-year OS (27.5% vs. 47.3%, p&lt;0.001). On regression adjustment based on propensity scores, NACS was not associated with DFS (p=0.220) or OS (p=0.431). Mandard tumour regression grade (TRG) was significantly associated with DFS (hazard ratio (HR) 0.21,95% CI 0.07-0.70) and OS (HR 0.27 (95% CI 0.13-0.59). Five-year DFS and OS related to TRG was 63.6 and 61.5% vs. 8.0 and 8.6% (p&lt;0.001) for good and poor responders respectively. Conclusions: Prescribing NAC to all OC patients risks delay in effective treatment of patients who are relatively chemo-resistant, given the variabilityin pathological response. Identifying OC patients who derive the most NAC benefit should be the focus.

Treatment Intensification for Locally Advanced Rectal Cancer: Impact on Pathological Complete Response and Outcomes.

Pathological complete response (pCR) and clinical outcomes [overall survival (OS), disease-free survival (DFS), locoregional control (LC)] were evaluated in a single-institution experience of different schedules of neoadjuvant chemoradiotherapy (CRT) for patients with locally advanced rectal cancer (LARC). Data for 322 patients with LARC were retrospectively analyzed. pCR was evaluated according to Mandard tumor regression grade (TRG). The Kaplan-Meier method was used to estimate OS, DFS and LC. Three hundred and three (94.1%) patients underwent surgery. pCR was observed in 81 patients (26.7%), with TRG1-2 rate of 41.8%. The 5- and 10-year OS, DFS and LC rates were 82.5%±2.5% and 65.5%±3.8%, 81.2%±2.4% and 79.3%±2.9%, 93.1%±1.7% and 90.5%±2.1%, respectively. Neoadjuvant CRT in LARC patients resulted in favorable long-term oncological outcomes, with a high pCR rate and acceptable toxicity.

Impact of age and sex on chemotherapy (CTx) efficacy, toxicity and survival in early oesophagogastric (OG) cancer: A pooled analysis of 3265 patients from four large randomised trials (OE02, OE05, MAGIC &amp; ST03).

4022 Background: No large scale randomised data exists evaluating the impact of age and sex in patients (pts) undergoing potentially curative surgery and CTx for OG cancer. However, differences in age and sex may be contributing factors to variability in CTx dose-response and toxicity which could also impact survival. Methods: Data from four prospective randomised controlled trials were pooled using a two-stage meta-analysis. For survival data, hazard ratios were calculated for pts &lt;70 and ≥70 years and between males and females. Pts were allocated to receive neoadjuvant platinum and fluoropyrimidine +/- anthracycline and bevacizumab. Mandard tumour regression grade (TRG) and prevalence of ≥G3 toxicities were compared according to the same subgroups using Chi-squared test. Results: 3265 pts were included for survival analysis (2668 (82%) M, 597 (18%) F; 2626 (80%) &lt;70, 639 (20%) ≥70). A significant improvement in disease specific survival (DSS) (HR 0.78; p&lt;0.001) and OS (HR 0.78; p&lt;0.001) was observed in females vs males. Although OS was worse in older vs younger pts (HR 1.15; p=0.01) no significant difference in DSS was observed (HR 1.04; p=0.52). For those pts who underwent resection following neoadjuvant CTx, older patients (19 vs 13%; p=0.01) and female patients (19% vs 13%, p=0.02) were more likely to achieve more favourable Mandard TRG 1&amp;2 scores. Older pts experienced significantly more ≥G3 neutropaenia (30 vs 22%; p=0.004). Females experienced significantly more ≥G3 nausea (12 vs 7%; p=0.006), vomiting (10 vs 5%; p≤0.001) and diarrhoea (9 vs 4%; p=0.001). Conclusions: This study represents the largest pooled analysis of age and sex differences on safety of neoadjuvant CTx and survival in early OG cancer. Females had significantly improved survival while experiencing more GI toxicities. Older pts achieved comparable DSS and thus, dependent on fitness, should be offered the same treatment paradigm as younger pts.

Early response evaluation of neoadjuvant therapy with PET/MRI to predict resectability in patients with adenocarcinoma of the esophagogastric junction.

Positron emission tomography (PET)/magnetic resonance imaging (MRI) is a new modality that has showed promising results for various clinical indications. Currently, evaluation of neoadjuvant therapy (NT) among patients with adenocarcinoma of the esophagogastric junction has primarily been reserved for PET/computed tomography. Our aim was to evaluate if early response evaluation by PET/MRI is a feasible method to predict resectability. Patients with untreated adenocarcinoma of the esophagogastric junction (Siewert types I/II) and fit for NT with no contraindications for PET/MRI were considered eligible. A baseline scan was performed prior to NT induction and an evaluation scan 3weeks later. For histopathological response evaluation, the Mandard tumor regression grade score was applied. Response on PET/MRI was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST 1.1), and change in ADC and SUVmax values. Twenty-eight patients were enrolled, and 22 completed both scans and proceeded to final analyses. Seventeen patients were found resectable versus five who were found unresectable. PET/MRI response evaluation had a sensitivity 94%, specificity 80%, and AUC = 0.95 when predicting resectability in patients with adenocarcinoma of the esophagogastric junction. No association with histopathological response (tumor regression grade) was found nor was RECIST correlated with resectability. Response evaluation using PET/MRI was a feasible method to predict resectability in patients with adenocarcinoma of the esophagogastric junction in this pilot study. However, larger studies are warranted to justify the use of the modality for this indication.

Anaemia and its effects on tumour regression grade and survival following chemotherapy in adenocarcinoma of the oesophagus.

Anaemia reduces the efficacy of chemotherapy in gastric cancer. However, it has not been studied in oesophageal cancer. We investigated whether anaemia impacts on survival and the efficacy of chemotherapy, in adenocarcinoma of the oesophagus for those undergoing neoadjuvant chemotherapy and then surgical resection. This prospective study included 268 patients who received neoadjuvant chemotherapy for oesophageal adenocarcinoma. Patient clinical data as well as Mandard's tumor regression grading (TRG), haemoglobin pre-chemotherapy and during the chemotherapy were compiled. The association between anaemia and TRG was tested using Chi-squared analysis, whilst survival outcomes were investigated by Kaplan-Meier and Cox regression. One hundred participants were anaemic before chemotherapy whilst 224 were anaemic during chemotherapy cycles. Survival analyses found a significant association between lower haemoglobin levels and decreased overall survival (P=0.048). Comparing those without anaemia against those with moderate -severe anaemia (<10.9 g/dL) found a statistically significant association in overall survival (P=0.026). Multivariate cox regression showed those with anaemia were statistically more likely to have decreased overall survival (HR 1.735, 95% CI, 1.050-2.867, P=0.032). No statistical association was seen between those with pre-chemotherapy anaemia and TRG (OR 0.675, 95% CI, 0.420-1.161, P=0.130) or those with anytime anaemia (OR 0.881, 95% CI, 0.406-1.914, P=0.931). These results suggest that anaemia is associated with poorer overall survival time, with lower haemoglobin levels reducing prognosis. However, there does not appear to be an association between anaemia and chemotherapy response in oesophageal adenocarcinoma.

PS02.087: EARLY RESPONSE EVALUATION OF NEOADJUVANT THERAPY WITH PET/MRI TO PREDICT RESECTABILITY IN PATIENTS WITH ADENOCARCINOMA OF THE ESOPHAGOGASTRIC JUNCTION

Abstract Background The primary treatment for locally advanced adenocarcinoma of the esophagogastric junction remains surgery combined with neoadjuvant chemo- or chemoradiotherapy (NT). A prediction of response to NT would be valuable, as insufficient response following NT may reflect therapy resistance leading to disease progression, unnecessary delay of surgery and risk of unresectability. Determining insufficient response to NT could lead to change of therapy and reduce possible chemo(radio)therapy toxicity. Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) is a new modality that has showed promising results for various clinical indications. Currently, evaluation of neoadjuvant therapy (NT) among patients with adenocarcinoma of the esophagogastric junction has primary been reserved for PET/computed tomography (CT). The aim of this study was to investigate if simultaneous PET/MRI is a feasible method to evaluate early tumor response to predict resectability in patients with AEG during NT. We also examined the association between histopathological response and changes on PET/MRI during NT. Methods Patients with untreated adenocarcinoma of the esophagogastric junction (Siewert's I/II) and fit for NT with no contraindications for PET/MRI were considered eligible. A baseline scan was performed prior to NT induction and an evaluation scan 3 weeks later. For histopathological response evaluation the Mandard tumor regression grade score was applied. Response on PET/MRI was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST 1.1), and change in ADC and SUVmax values. Results Twenty-eight patients were enrolled, and 22 completed both scans and proceeded to our final analyses. 17 patients were found resectable vs. five not resectable. PET/MRI response evaluation is a feasible method to predict resectability in patients with adenocarcinoma of the esophagogastric junction with sensitivity 94%, specificity 80%, and AUC = 0.95. However, no association with histopathological response (tumor regression grade) was found nor was RECIST correlated with resectability. Conclusion Our work has identified response evaluation with PET/MRI as a feasible method to predict resectability in patients with adenocarcinoma of the esophagogastric junction, however, larger studies are warranted to justify the use of this modality for this indication. Disclosure All authors have declared no conflicts of interest.

Multicentre cohort study to define and validate pathological assessment of response to neoadjuvant therapy in oesophagogastric adenocarcinoma.

BackgroundThis multicentre cohort study sought to define a robust pathological indicator of clinically meaningful response to neoadjuvant chemotherapy in oesophageal adenocarcinoma.MethodsA questionnaire was distributed to 11 UK upper gastrointestinal cancer centres to determine the use of assessment of response to neoadjuvant chemotherapy. Records of consecutive patients undergoing oesophagogastric resection at seven centres between January 2000 and December 2013 were reviewed. Pathological response to neoadjuvant chemotherapy was assessed using the Mandard Tumour Regression Grade (TRG) and lymph node downstaging.ResultsTRG (8 of 11 centres) was the most widely used system to assess response to neoadjuvant chemotherapy, but there was discordance on how it was used in practice. Of 1392 patients, 1293 had TRG assessment; data were available for clinical and pathological nodal status (cN and pN) in 981 patients, and TRG, cN and pN in 885. There was a significant difference in survival between responders (TRG 1–2; median overall survival (OS) not reached) and non-responders (TRG 3–5; median OS 2·22 (95 per cent c.i. 1·94 to 2·51) years; P < 0·001); the hazard ratio was 2·46 (95 per cent c.i. 1·22 to 4·95; P = 0·012). Among local non-responders, the presence of lymph node downstaging was associated with significantly improved OS compared with that of patients without lymph node downstaging (median OS not reached versus 1·92 (1·68 to 2·16) years; P < 0·001).ConclusionA clinically meaningful local response to neoadjuvant chemotherapy was restricted to the small minority of patients (14·8 per cent) with TRG 1–2. Among local non-responders, a subset of patients (21·3 per cent) derived benefit from neoadjuvant chemotherapy by lymph node downstaging and their survival mirrored that of local responders.

Tumor Regression Grade After Neoadjuvant Chemoradiation and Surgery for Low Rectal Cancer Evaluated by Multiple Correspondence Analysis: Ten Years as Minimum Follow-up

BackgroundThe role of Mandard's tumor regression grade (TRG) classification is still controversial in defining the prognostic role of patients who have undergone neoadjuvant chemoradiation (CRT) and total mesorectal excision. The present study evaluated multiple correspondence analysis (MCA) as a tool to better cluster variables, including TRG, for a homogeneous prognosis. Patients and MethodsA total of 174 patients with a minimum follow-up period of 10 years were stratified into 2 groups: group A (TRG 1-3) and group B (TRG 4-5) using Mandard's classification. Overall survival and disease-free survival were analyzed using univariate and multivariate analysis. Subsequently, MCA was used to analyze TRG plus the other prognostic variables. ResultsThe overall response to CRT was 55.7%, including 13.2% with a pathologic complete response. TRG group A correlated strictly with pN status (P = .0001) and had better overall and disease-free survival than group B (85.1% and 75.6% vs. 71.1% and 67.3%; P = .06 and P = .04, respectively). The TRG 3 subset (about one third of our series) showed prognostically heterogeneous behavior. In addition to multivariate analysis, MCA separated TRG 1 and TRG 2 versus TRG 4 and TRG 5 well and also allocated TRG 3 patients close to the unfavorable prognostic variables. ConclusionTRG classification should be used in all pathologic reports after neoadjuvant CRT and radical surgery to enrich the prognostic profile of patients with an intermediate risk of relapse and to identify patients eligible for more conservative treatment. Thus, MCA could provide added value.