Mandard Tumor Regression Grade Research Articles

Correlations between Apparent Diffusion Coefficient (ADC) and Prognosis in Patients with Locally Advanced Rectal Cancer.

the aim of this study is to assess the performance of diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) values in predicting the response to neoadjuvant chemoradiation therapy (CRT) and outcome in patients with locally advanced rectal cancer (LARC). ninety-four patients with magnetic resonance imaging (MRI) pre- and post-neoadjuvant treatment were retrospectively enrolled. Three regions of interest (ROIs) were manually drawn on three different slices of the tumor for every DWI sequence. ROIs were positioned to include only high signal areas and avoid artifacts or necrotic areas. ROIs were automatically copied onto the corresponding ADC maps and the system derived three different ADC values, distinguishing between mean, maximum, and minimum values, and the standard deviation (SD). Only mean ADC values were considered. After surgical intervention, pTNM and the Mandard tumor regression grade (TRG) were obtained. Patients with a TRG of 1-2 were classified as responders, while patients with a TRG from 3 to 5 were classified as non-responders. no correlation was found between pre-ADC values and TRG classes, while post-ADC and ΔADC values showed a significant correlation with TRG classes (r = -0.285, p = 0.002 and r = -0.290, p = 0.019, respectively). Post-ADC values were statistically different between responders and non-responders (p = 0.019). When considering the relation between overall survival (OS) and ADC values, pre-ADC showed a negative correlation with OS (r = -0.381, p = 0.001), while a positive correlation was found between ΔADC values and OS (r = 0.323, p = 0.013). According to ΔADC values, the mean OS time between responders and non-responders showed a significant difference (p = 0.030). A statistical difference was found between TRG classes and OS (p = 0.038) and by dividing patients in responders and non-responders (p = 0.019). the pre-ADC and ΔADC values could be used as useful predictors for patient prognosis, thus helping the treatment planning. On the other hand, the post-ADC values, thanks to their relationship with the TRG classes, could be the ideal tool to predict the histopathological response and plan a conservative approach to the treatment of rectal cancer.

523. FIVE YEARS OF FLOT THERAPY. RANDOMIZED CONTROLLED TRIAL EVIDENCE IN PRACTICE

Abstract Introduction The combination of 5-flurouracil, oxaliplatin, leucovorin and docetaxel (FLOT) is an effective chemotherapy regime in locally advanced, resectable gastro-oesophageal adenocarcinoma. Since the FLOT4-AIO randomised controlled trial demonstrated superiority over ECF/ECX it has been standard of care at many centres and European Society of Medical Oncology’s recommended perioperative regimen. After over five years of offering this treatment to patients we assessed how this evidence had translated into practice; identifying factors that predict dose reduction or incomplete therapy and overall survival. Method Patients who had the combination of neoadjuvant FLOT chemotherapy and oesophagectomy for adenocarcinoma of the oesophagus or gastro-oesophageal junction between February 2018 and September 2023 were identified from a prospectively collected database. Data on completion of chemotherapy, perioperative outcomes and long-term survival were collected. Pathological regression was assessed using Mandard tumour regression grade (TRG). The peri-operative, pathological, and long-term outcomes of patients who completed four cycles of neoadjuvant FLOT was compared with those who had reduced dose or early cessation. Statistical analysis used IBM SPSS, with Mann-Whitney U and Chi squared for variable analysis and univariate cox regression for survival. Results Eighty patients were included with a median age of 66 (47-79), 84% were male. Full dose completion was achieved by 57 (71%) patients, 20 (25%) had dose reduction and 7(8%) did not complete four cycles. Age, anaerobic threshold and VO2 max were not significantly different between those completing or not completing neoadjuvant chemotherapy (p=0.460, p=0.624, p=0.104 respectively); or requiring dose reductions (p=0.317, p=0.587, p=0.82). Median TRG across all three groups was 3. Median follow up was 55.4 months and mean overall survival was 53.4 months. No difference in survival was observed between those who completed or did not complete neoadjuvant FLOT (p=0.45). Conclusion Completion of neoadjuvant chemotherapy was lower in this cohort of patients than FLOT4-AIO. Rates of pathological complete response were similar. This translated into similar mean overall survival. Median survival was unable to be calculated as survival exceeds 50% at the time of our study. The use of FLOT has translated well into the routine neoadjuvant clinical setting with acceptable short- and long-term outcomes.

Correlation of PD-L1 expression with CD8+ T cells and oxidative stress-related molecules NRF2 and NQO1 in esophageal squamous cell carcinoma.

Oxidative stress and the immune microenvironment both contribute to the pathogenesis of esophageal squamous cell carcinoma (ESCC). However, their interrelationships remain poorly understood. We aimed to examine the status of key molecules involved in oxidative stress and the immune microenvironment, as well as their relationships with each other and with clinicopathological features and prognosis in ESCC. The expression of programmed death-ligand 1 (PD-L1), CD8, nuclear factor erythroid-2 related factor-2 (NRF2), and NAD(P)H quinone oxidoreductase 1 (NQO1) was detected using immunohistochemistry in tissue samples from 176 patients with ESCC. We employed both combined positive score (CPS) and tumor proportion score (TPS) to evaluate PD-L1 expression and found a positive correlation between CPS and TPS. Notably, PD-L1 expression, as assessed by either CPS or TPS, was positively correlated with both NRF2 nuclear score and NQO1 score in stage II-IV ESCC. We also observed a positive correlation between the density of CD8+ T cells and PD-L1 expression. Furthermore, high levels of PD-L1 CPS, but not TPS, were associated with advanced TNM stage and lymph node metastases. Moreover, both PD-L1 CPS and the nuclear expression of NRF2 were found to be predictive of shorter overall survival in stage II-IV ESCC. By using the Mandard-tumor regression grading (TRG) system to evaluate the pathological response of tumors to neoadjuvant chemotherapy (NACT), we found that the TRG-5 group had higher NRF2 nuclear score, PD-L1 CPS, and TPS in pre-NACT biopsy samples compared with the TRG-3 + 4 group. The NQO1 scores of post-NACT surgical specimens were significantly higher in the TRG-5 group than in the TRG 3 + 4 group. In conclusion, the expression of PD-L1 is associated with aberrant NRF2 signaling pathway, advanced TNM stage, lymph node metastases, and unfavorable prognosis. The dysregulation of PD-L1 and aberrant activation of the NRF2 signaling pathway are implicated in resistance to NACT. Our findings shed light on the complex interrelationships between oxidative stress and the immune microenvironment in ESCC, which may have implications for personalized therapies and improved patient outcomes.

Safety and efficacy of intensified preoperative management of locally advanced gastrorsophageal junction cancer (INPROVE).

e16110 Background: The optimal management of locally advanced gastroesophageal junction adenocarcinoma (LAGEJad) is not fully established yet. Both neoadjuvant chemoradiotherapy (CRT) and perioperative taxane-based triplet chemotherapy (CT) are acknowledged treatment options for Siewert I and II cancers. In this retrospective study, we aimed to assess the safety and outcomes of an intensified preoperative regimen combining taxane-based triplet CT and CRT. Methods: We conducted a retrospective analysis of a cohort comprising 16 consecutive HER2 negative patients (pts) with LAGEJad treated at the Centro di Riferimento Oncologico of Aviano between 2019 and 2022. All pts received induction CT (iCT) consisting of fluoropyrimidine, oxaliplatin and docetaxel, followed by CRT (45Gy/25Fr) with simultaneous boost and concomitant CT. Surgery (Ivor-Lewis or McKeown) was performed 8 weeks post-CRT. Clinico-pathological (CP) and treatment features were analyzed using logistic regression to assess their association with response to iCT-CRT. The association of iCT-CRT with survival outcomes was investigated using the Kaplan-Meier method. Results: Key CP data are summarized in Table 1. Median age was 59 years, all pts were male. At diagnosis, 81.2% of pts exhibited cT3+ and cN+ disease. All pts received iCT and CRT. The rate of partial responses was 50% after iCT and 68.8% after CRT. Overall, 12 pts underwent surgery, all achieving R0 resections within a median timeframe of 9 [8.5;11] weeks post-CRT. Among them, 25% had a pathologic complete response, while 62.5% attained a Mandard tumor regression grade (TRG) of 1-2. No new safety signals emerged from iCT (only 2 pts had ≥G3 diarrhea) or CRT (≥G3 mucositis occurred in 6.2% and anemia in 6.2% of pts). No significant surgical delays were observed, although 5 pts experienced post-operative complications (4 grade I, 1 grade IIa). There were no statistically significant associations between CP variables and response to the iCT-CRT. Relapses were seen in 8 pts (2 locoregionally); 3-year survival was 46%. Median event-free survival was 5 [5;11] months, while median overall survival 34 [14;NR] months. Conclusions: The intensification of preoperative treatment in pts with LAGEJad is active and safe: the surgical schedule was not significantly delayed, and the safety profile remained comparable to standard regimens, with no major complications reported. Randomized clinical trials are ongoing to assess the clinical benefits of this approach. [Table: see text]

Neoadjuvant/adjuvant pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo for gastric/gastroesophageal junction (G/GEJ) adenocarcinoma: Major pathologic response (mPR) in KEYNOTE-585.

4073 Background: Pathologic tumor downstaging (pDS) is more accurate than clinical staging for prognosis; generally, patients (pts) with downstaged tumors have lower recurrence rates and improved overall survival (OS). mPR is an important surrogate end point in non–small cell lung cancer, but data are scarce in gastric cancer. In the randomized phase 3 KEYNOTE-585 trial (NCT03221426), neoadjuvant or adjuvant pembro + chemo (cisplatin + capecitabine [XP] or cisplatin + 5-fluorouracil [FP]) was not superior to pbo + chemo (XP or FP) for event-free survival (EFS) in the intention-to-treat (ITT) population of pts with locally advanced G/GEJ adenocarcinoma; pembro + chemo significantly improved pathologic complete response (pCR) vs pbo + chemo (difference, 10.9%; 95% CI, 7.5-14.8; P<0.00001). In this post hoc analysis we examined the utility of mPR and pDS as surrogate end points in KEYNOTE-585. Methods: Pts with untreated localized G/GEJ adenocarcinoma (including Siewert type 2 or 3 tumors) and ECOG PS 0 or 1 who planned to undergo surgery after preoperative chemo were eligible. The main cohort of KEYNOTE-585 received pembro or pbo + XP or FP; the safety cohort received pembro or pbo + docetaxel, oxaliplatin, FP, and leucovorin (FLOT). Objectives for the post hoc analysis were the relation between mPR (≤10% residual viable tumor, comparable to Mandard tumor regression grade 1 or 2) and EFS per RECIST v1.1 per investigator and OS, plus the percentage of pts who had improved survival, by stage, compared with downstaging in the pTNM group. Overall downstaging was derived by comparing answers to questions regarding primary tumor and nodal involvement from clinical and pathologic assessments for each pt. Pts could have tumor downstaging, nodal downstaging, or both. If both, the number of levels downstaged for tumor and nodes were added together to calculate a total number of levels downstaged. The database cutoff was February 9, 2023. Results: A total of 1007 pts were analyzed (n=502, pembro + chemo; n=505, pbo + chemo); 44.0% and 34.1%, respectively, had pathologic nodal stage N0. The incidence of mPR (grade 1/2 tumor regression) was 31.5% with pembro + chemo vs 22.2% with pbo + chemo. In pts who had mPR, the HRs (95% CI) for EFS and OS were 0.6 (0.4-1.0) and 0.7 (0.4-1.2), respectively, for pembro + chemo vs pbo + chemo. Downstaging results are shown (Table). Conclusions: In this post hoc analysis, pts with mPR had numerically improved PFS and OS with pembro + chemo vs pbo + chemo; these findings were consistent with analysis of the ITT population. Further studies in this population are warranted. Clinical trial information: NCT03221426 . [Table: see text]

Effect of Tumor Regression Grade on Survival and Disease-Free Interval in Patients Operated on for Locally Advanced Rectal Cancer.

Colorectal cancer is the fourth leading cause of cancer-related death in both men and women in our population. In this regard, rectal cancer accounts for more than half of colorectal cancer deaths, and its incidence is expected to increase in the coming years. There have been significant changes in neoadjuvant therapy regimens, with promising results, as demonstrated by the recent RAPIDO and PRODIGE23 studies. Around 40% of patients diagnosed with locally advanced rectal cancer show some degree of response to neoadjuvant treatment, with complete tumor regression observed in up to one in five patients. Retrospective observational study. A total of 181 patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy followed by surgery were analyzed. Clinical and pathological data were collected from the patients, including assessment of tumor regression through histopathological studies after surgery. The Mandard tumor regression grading system was used to categorize tumor response into different grades. The results showed a significant association between the degree of tumor regression and several important clinical outcomes. Specifically, patients with higher tumor regression had significantly better disease-free survival than those with less regression (p = 0.004). In addition, tumor regression was also correlated with the incidence of local recurrence (p = 0.018) and distant metastasis (p = 0.032). These associations suggest that tumor responsiveness to neoadjuvant therapy may influence the long-term progression of the disease. Regarding tumor deposits and the presence of lymphadenopathy, these factors were also found to be significantly associated with clinical outcomes. Patients with tumor deposits had a higher incidence of local recurrence (p = 0.025) and distant metastases (p = 0.041), while the presence of lymphadenopathy increased the risk of local recurrence (p = 0.013). These findings highlight the importance of evaluating not only tumor regression but also other pathological markers to predict prognosis and guide clinical management. The degree of tumor regression was not an independent predictor of survival compared to other variables such as nodal stage and presence of tumor deposits. This indicates that while tumor regression is an important factor, other elements also play a crucial role in determining the prognosis of patients with locally advanced rectal cancer. This study provides additional evidence for the importance of tumor regression, tumor deposits, and lymphadenopathy as predictors of clinical outcomes in patients with rectal cancer treated with neoadjuvant chemoradiotherapy.

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

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

Impact of Neoadjuvant Radiochemotherapy on Pathological Complete Response for Locally Advanced Rectal Cancer: A Mono Institutional Experience.

Neoadjuvant radiochemotherapy followed by surgery is a standard of care in locally advanced rectal cancer (LARC). Only a subgroup of patients can obtain a pathological complete response (pCR) and achieve good local control. However, the role of pCR on patient survival is debated. The aim of the study was to evaluate the impact of pCR on clinical outcomes and toxicities in LARC patients treated with dose intensification and concomitant capecitabine treatment in a neoadjuvant radiochemotherapy schedule. This was a single Institution retrospective study including 178 patients. Mandard tumor regression grade (TRG) and pTNM staging system were used to classify pathological response and define pathological complete response (pCR). Patients were divided in: pCR (pT0N0) and Not-pCR (pT>0N>0), according to pTNM and in good responders (TRG1-2) and partial/not responders (TRG3-5), according to Mandard TRG. The Kaplan-Meier method was used to estimate OS, CSS, DFS and LC. A low severe toxicity rate was observed. Acute Grade 3 lower bowel toxicity and Grade 3 cutaneous toxicity were reported in 2 (1.1%) patients, respectively. Late Grade >3 lower bowel toxicity was reported in 6 patients (3%) and late Grade >3 cutaneous toxicity was registered in one patient. No other severe acute and late toxicities were reported. The 5- and 10-year OS, CSS, DFS and LC rates were 85% and 75%, 94% and 92%, 83% and 81%, 88% and 88%, respectively. We observed a pCR rate of 36% and a good responders rate of 62%, in our study population. Both groups showed better rates for each analyzed clinical outcome. Neoadjuvant radiochemotherapy with dose intensification in LARC patients resulted in favorable long-term oncological outcomes, pCR rate showed an optimal impact on OS and DFS with an acceptable toxicity.

Digitally assessed lymphocyte infiltration in rectal cancer biopsies is associated with pathological response to neoadjuvant therapy

A frequently used treatment strategy in locally advanced rectal cancer (RC) is neoadjuvant therapy followed by surgery. Patients treated with neoadjuvant therapy achieve varying pathological response, and currently, predicting the degree of response is challenging. This study examined the association between digitally assessed histopathological features in the diagnostic biopsies and pathological response to neoadjuvant therapy, aiming to find potential predictive biomarkers. 50 patients with RC treated with neoadjuvant chemotherapy and/or radiotherapy followed by surgery were included. Deep learning-based digital algorithms were used to assess the epithelium tumor area percentage (ETP) based on H&E-stained slides, and to quantify the density of CD3+ and CD8+ lymphocytes, as well as the CD8+/CD3+ lymphocyte percentage, based on immunohistochemically stained slides, from the diagnostic tumor biopsies. Pathological response was assessed according to the Mandard method. A good pathological response was defined as tumor regression grade (TRG) 1–2, and a complete pathological response was defined as Mandard TRG 1. Associations between the ETP and lymphocyte densities in the diagnostic biopsies and the pathological response were examined. The density of CD8+ lymphocytes, and the CD8+/CD3+ lymphocyte percentage, were associated with both good and complete response to neoadjuvant therapy, while the density of CD3+ lymphocytes was associated with complete response. The ETP did not correlate with response to neoadjuvant therapy. It is well-known that infiltration of lymphocytes in colorectal cancer is a prognostic biomarker. However, assessment of CD8+ and CD3+ lymphocytes in the diagnostic tumor biopsies of patients with RC may also be useful in predicting response to neoadjuvant therapy.

Concurrent clinical and pathological response predicts favorable prognosis of patients with gastric cancer after neoadjuvant therapy: a real-world study

BackgroundResponse of locally advanced gastric cancer (LAGC) to neoadjuvant therapy (NAT) may be associated with prognosis, but which of the clinical or pathological evaluation can accurately predict a favorable prognosis is still controversial. This study aims to compare the effect of clinical and pathological response on the prognosis of patients with gastric cancer.MethodsThis study retrospectively analyzed LAGC patients who underwent NAT followed by surgery in the China National Cancer Center from January 2004 to January 2021. Clinical and pathological responses after NAT were evaluated using RECIST 1.1 and Mandard tumor regression grade system (TRG) respectively. Complete response (CR) and partial response (PR) assessed by computed tomography were regarded as clinical response. For histopathology regression assessment, response was defined as Mandard 1, 2, 3 and non-response as Mandard 4, 5. Furthermore, we combined clinical and pathological evaluation results into a variable termed “comprehensive assessment” and divided it into four groups based on the presence or absence of response (concurrent response, only clinical response, only pathological response, both non-response). The association between the prognosis and clinicopathological factors was assessed in univariate and multivariate Cox regression analysis.ResultsIn total, 238 of 1073 patients were included in the study after screening. The postoperative pathological response rate and clinical response rate were 50.84% (121/238) and 39.92% (95/238), respectively. 154 patients got consistent results in clinical and pathological evaluation (66 were concurrent response and 88 were both non-response), while the other 84 patients did not. The kappa value was 0.297(p < 0.001), which showed poor consistency. Multivariate Cox regression analysis revealed that comprehensive assessment (P = 0.03), clinical N stage(P < 0.001), vascular or lymphatic invasion (VOLI) (HR 2.745, P < 0.001), and pre-CA724(HR 1.577, P = 0.047) were independent factors for overall survival in patients with gastric cancer. Among four groups in the comprehensive assessment, concurrent response had significantly better survival (median OS: 103.5 months) than the other groups (P = 0.008).ConclusionConcurrent clinical and pathological response might predict a favorable prognosis of patients with gastric cancer after neoadjuvant therapy, further validation is needed in prospective clinical trials with larger samples.

Prognostic Value of Mandard's Tumor Regression Grade (TRG) in Post Chemo-Radiotherapy Cervical Cancer.

In locally advanced cervical cancer (LACC), definitive chemo-radiotherapy is the standard treatment, but chemo-radiotherapy followed by surgery could be an alternative choice in selected patients. We enrolled 244 patients affected by LACC and treated with CT-RT followed by surgery in order to assess the prognostic role of the histological response using the Mandard scoring system. Results: A complete pathological response (TRG 0) was observed in 118 patients (48.4%), rare residual cancer cells (TRG2) were found in 49 cases (20.1%), increased number of cancer cells but fibrosis still predominating (TRG3) in 35 cases (14.3%), and 42 (17.2%) were classified as non-responders (TRG4-5). TRG was significantly associated with both OS (p < 0.001) and PFS (p < 0.001). The survival curves highlighted two main prognostic groups: TRG1-TRG2 and TRG3-TRG4-5. Main responders (TRG1-2) showed a 92% 5-year overall survival (5y-OS) and a 75% 5-year disease free survival (5y-DFS). Minor or no responders showed a 48% 5y-OS and a 39% 5y-DFS. The two-tiered TRG was independently associated with both DFS and OS in Cox regression analysis. Conclusion. We showed that Mandard TRG is an independent prognostic factor in post-CT/RT LACC, with potential benefits in defining post-treatment adjuvant therapy.

ApoA-I and ApoB levels, and ApoB-to-ApoA-I ratio as candidate pre-treatment biomarkers of pathomorphological response to neoadjuvant therapy in gastric and esophago-gastric junction adenocarcinoma.

&lt;b&gt;&lt;br&gt;Introduction:&lt;/b&gt; Neoadjuvant chemotherapy (NAC) is a part of the current standard of care in a locally advanced gastric adenocarcinoma (GA) and esophagogastric junction adenocarcinoma (EGJA), but only patients with good pathomorphological response (pR) to NAC benefit from prolonged overall survival.&lt;/br&gt; &lt;b&gt;&lt;br&gt;Aim:&lt;/b&gt; The study aims to evaluate ApoA-I and ApoB as candidate pre-treatment biomarkers of pR to NAC in patients with GA and EGJA.&lt;/br&gt; &lt;b&gt;&lt;br&gt;Materials and methods:&lt;/b&gt; Serum samples were collected from 18 patients with GA and 9 with EGJA before the initiation of NAC to determine the ApoA-I and ApoB levels. After NAC tumor regression grade (TRG) was evaluated in resected specimens according to the Mandard's tumor regression grading system and correlated with pre-treatment ApoA-I and ApoB serum concentration, and ApoB-to-ApoA-I serum concentration ratio.&lt;/br&gt; &lt;b&gt;&lt;br&gt;Results:&lt;/b&gt; We found a positive correlation of ApoA-I level and pR (95% CI: -0.863 to -0.467; P &lt; 0.0001), a negative correlation of ApoB level and pR (95% CI: 0.445 to 0.857; P &lt; 0.0001), a negative correlation of ApoB-to-ApoA-I ratio and pR (95% CI: 0.835 to 0.964; P &lt; 0.0001).&lt;/br&gt; &lt;b&gt;&lt;br&gt;Conclusions:&lt;/b&gt; ApoA-I and ApoB levels, and ApoB-to-ApoA-I ratio are candidate pre-treatment predictors of pR to NAC in GA and may help to guide personalized therapy.&lt;/br&gt;Our work fits into the dynamically developing trend of personalized treatment. It describes a potentially important rationale for further evaluation of apolipoprotein A-I and apolipoprotein B as predictors of cancer response to neoadjuvant therapy.

Size and depth of residual tumor after neoadjuvant chemoradiotherapy in rectal cancer - implications for the development of new imaging modalities for response assessment.

With the shift towards organ preserving treatment strategies in rectal cancer it has become increasingly important to accurately discriminate between a complete and good clinical response after neoadjuvant chemoradiotherapy (CRT). Standard of care imaging techniques such as CT and MRI are well equipped for initial staging of rectal tumors, but discrimination between a good clinical and complete response remains difficult due to their limited ability to detect small residual vital tumor fragments. To identify new promising imaging techniques that could fill this gap, it is crucial to know the size and invasion depth of residual vital tumor tissue since this determines the requirements with regard to the resolution and imaging depth of potential new optical imaging techniques. We analyzed 198 pathology slides from 30 rectal cancer patients with a Mandard tumor regression grade 2 or 3 after CRT that underwent surgery. For each patient we determined response pattern, size of the largest vital tumor fragment or bulk and the shortest distance from the vital tumor to the luminal surface. The response pattern was shrinkage in 14 patients and fragmentation in 16 patients. For both groups combined, the largest vital tumor fragment per patient was smaller than 1mm for 38% of patients, below 0.2mm for 12% of patients and for one patient as small as 0.06mm. For 29% of patients the vital tumor remnant was present within the first 0.01mm from the luminal surface and for 87% within 0.5mm. Our results explain why it is difficult to differentiate between a good clinical and complete response in rectal cancer patients using endoscopy and MRI, since in many patients submillimeter tumor fragments remain below the luminal surface. To detect residual vital tumor tissue in all patients included in this study a technique with a spatial resolution of 0.06mm and an imaging depth of 8.9mm would have been required. Optical imaging techniques offer the possibility of detecting majority of these cases due to the potential of both high-resolution imaging and enhanced contrast between tissue types. These techniques could thus serve as a complimentary tool to conventional methods for rectal cancer response assessment.

463. THE IMPACT OF PATHOLOGICAL TUMOR RESPONSE FOLLOWING NEOADJUVANT CHEMOTHERAPY AND CHEMORADIOTHERAPY FOR ESOPHAGEAL ADENOCARCINOMA. A RETROSPECTIVE MULTICENTER COHORT STUDY

Abstract Background Two multimodal strategies are available for the treatment of esophageal cancer: neoadjuvant chemotherapy (CT) and chemoradiotherapy (CTRT). The higher rate of pathological complete response (pCR) after CTRT is an argument to support this treatment. However, previous studies have failed to demonstrate a survival benefit of CTRT for adenocarcinoma (ADC) and the correlation between pathological tumor response (pTR) and survival is unclear. Methods This multicenter retrospective cohort study included data from 2 high-volume centers. Only patients with ADC who underwent CT or CTRT and surgery between 2012 and 2019 were included. The correlation between pTR and survival after both treatments was evaluated using Kaplan–Meier analysis. The 5-year overall (OS) and disease-free survivals (DFS) of patients showing pCR after the 2 treatments were compared. pTR was assessed using the Mandard tumor regression grade (TRG). Results Overall, 424 patients were included, 236 received CT and 188 CTRT. The incidence of pCR was 12.7% in the CT group and 26.1% after CTRT (p = 0.0005). At 5-years the OS rate after CT was 85.6% for TRG1 patients, 75.5% for TRG2, 57% for TRG3 and 42% for TRG4–5 (p = 0.004). After CTRT it was 72.8% for TRG1, 60.8% for TRG2, 39% for TRG3 and 27% for TRG4–5 (p = 0.0003) (figure 1). The OS of patients with pCR was not significantly different after CT and CTRT (p = 0.65). The 5-years DFS of pCR patients was higher in the CT group (86% vs. 70%, p = 0.05). Conclusion Despite a lower rate of pCR, both OS and, especially, DFS of pCR patients were improved after CT compared to CTRT. TRG showed to be significantly associated with survival in both treatment groups. The effectiveness of long-term disease control after CT and CTRT should be further analyzed in ADC.

Pretreatment Microvessel Density for Predicting of Tumor Responsiveness to Neoadjuvant Chemoradiotherapy of Locally Advanced Rectal Cancer.

This study aimed to assess whether pretreatment tumor tissue microvessel density (MVD) could be a potential predictive marker for Mandard response in LARC treated with nCRT. A retrospective analysis was performed in pretreatment paraffin-embedded specimens of 31 pathologically confirmed rectal adenocarcinoma. All patients received nCRT and subsequent total mesorectal resection. Tumor MVD was determined by an average number of counted CD34-stained endothelial cells from two selected fields at 200x magnification in each slide and categorized into two groups: low MVD (</=60) and high MVD (> 60). The tumor response was determined using the Mandard tumor regression grading system. The subjects were grouped according to their TRG into responder (TRG 1-3) and non-responder (TRG 4-5). Twenty out of thirty-one patients (64.5%) were defined as responders. Eleven patients (35.5%) were defined as non-responders. MVD was significantly associated with tumor responsiveness to nCRT (p < 0.05). High MVD was shown to be an independent risk factor associated with tumor resistance to nCRT (OR, 22.58; 95% CI, 1.943-262.34; p = 0.013). A strong correlation was found between MVD and TRG (correlation coefficient value of 0.642, p <0.01), between MVD and vascular invasion (correlation coefficient value of 0.618, p <0.01), and between nodal involvement and vascular invasion (correlation coefficient value of 0.521, p <0.01). A moderate correlation was found between nodal involvement and vascular invasion (correlation coefficient value of 0.406, p <0.05). High MVD in pretreatment tumor tissue was significantly associated with the tumor resistance to nCRT.

Evaluation of Pathological Response Rate and Complications of FOLFOX versus FLOT Regimen in Perioperative Chemotherapy for Resectable Gastric Cancer: A Prospective Study.

Previous studies have shown that the perioperative and postoperative chemotherapy can lead to an improvement in the prognosis of patients with resectable gastric cancer (GC). There is no preference for postoperative chemotherapy with the two common treatment regimens, FLOT and FOLFOX, in these patients. The aim of this study was to compare FOLFOX and FLOT regimens in perioperative chemotherapy in resectable GC based on pathological response and complications. This prospective cohort study was conducted on 112 patients with resectable GC who were admitted to Firozgar Hospital affiliated with Iran University of Medical Sciences, Tehran, Iran between 2021 to 2022. Given the inclusion criteria, 80 patients were enrolled in the present study. Patients were divided into 2 groups based on the type of treatment regimen, FOLFOX (40 patients) and FLOT (40 patients). Tumor response was classified using Mandard Tumor regression grading system criteria into five categories of TRG1 to 5. Also, the side effects were classified according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0. The rate of complete pathological response in FOLT group was significantly higher than FOLFOX group (35.0% vs 2.5%, p: 0.001). The frequency of neurological complications and hair loss in the FOLT group was significantly higher than the FOLFOX group (P<0.05). While no significant difference was observed in the frequency of hematological, Gastroenterological, hepatic, renal and stomatitis complications in the both groups (p>0.05). Our study showed that perioperative FLOT regimen has a better pathological response than FOLFOX regimen. The frequency of neurological complications and hair loss was significantly higher in patients treated with FLOT regimen. Thus, perioperative FLOT regimen may be recommended for treating GC patients.

Development and multicenter validation of a multiparametric imaging model to predict treatment response in rectal cancer

ObjectivesTo develop and validate a multiparametric model to predict neoadjuvant treatment response in rectal cancer at baseline using a heterogeneous multicenter MRI dataset.MethodsBaseline staging MRIs (T2W (T2-weighted)-MRI, diffusion-weighted imaging (DWI) / apparent diffusion coefficient (ADC)) of 509 patients (9 centres) treated with neoadjuvant chemoradiotherapy (CRT) were collected. Response was defined as (1) complete versus incomplete response, or (2) good (Mandard tumor regression grade (TRG) 1–2) versus poor response (TRG3-5). Prediction models were developed using combinations of the following variable groups:(1) Non-imaging: age/sex/tumor-location/tumor-morphology/CRT-surgery interval(2) Basic staging: cT-stage/cN-stage/mesorectal fascia involvement, derived from (2a) original staging reports, or (2b) expert re-evaluation(3) Advanced staging: variables from 2b combined with cTN-substaging/invasion depth/extramural vascular invasion/tumor length(4) Quantitative imaging: tumour volume + first-order histogram features (from T2W-MRI and DWI/ADC)Models were developed with data from 6 centers (n = 412) using logistic regression with the Least Absolute Shrinkage and Selector Operator (LASSO) feature selection, internally validated using repeated (n = 100) random hold-out validation, and externally validated using data from 3 centers (n = 97).ResultsAfter external validation, the best model (including non-imaging and advanced staging variables) achieved an area under the curve of 0.60 (95%CI=0.48–0.72) to predict complete response and 0.65 (95%CI=0.53–0.76) to predict a good response. Quantitative variables did not improve model performance. Basic staging variables consistently achieved lower performance compared to advanced staging variables.ConclusionsOverall model performance was moderate. Best results were obtained using advanced staging variables, highlighting the importance of good-quality staging according to current guidelines. Quantitative imaging features had no added value (in this heterogeneous dataset).Clinical relevance statementPredicting tumour response at baseline could aid in tailoring neoadjuvant therapies for rectal cancer. This study shows that image-based prediction models are promising, though are negatively affected by variations in staging quality and MRI acquisition, urging the need for harmonization.Key PointsThis multicenter study combining clinical information and features derived from MRI rendered disappointing performance to predict response to neoadjuvant treatment in rectal cancer.Best results were obtained with the combination of clinical baseline information and state-of-the-art image-based staging variables, highlighting the importance of good quality staging according to current guidelines and staging templates.No added value was found for quantitative imaging features in this multicenter retrospective study. This is likely related to acquisition variations, which is a major problem for feature reproducibility and thus model generalizability.

Total Lymph Node Yield Is Associated with Prolonged Survival after Neoadjuvant Chemotherapy in ypN0 Gastric Cancer Patients

Introduction: Lymph node status after neoadjuvant chemotherapy (NAC) plays the main role in predicting the survival of gastric cancer (GC) patients who underwent curative gastrectomy after NAC. NAC can reduce the number of involved lymph nodes. However, it is unknown whether other variables are associated with the survival outcomes for ypN0 GC patients. It is unknown whether lymph node yield (LNY) has prognostic value in ypN0 GC patients treated with NAC plus surgery. Methods: In this retrospective study, we reviewed the data of patients treated with NAC plus gastrectomy and identified those with ypN0 disease. The LNY cut-off was calculated using the X-tile program to determine the greatest actuarial survival difference. Patients were categorized into the downstaged N0 (cN+/ypN0) and natural N0 (cN0/ypN0) groups based on nodal status. Multivariate analysis was used to identify the prognostic factors and the association between LNY and prognosis. Results: A total of 211 GC patients with ypN0 status were included. The optimal LNY cut-off was 23. Kaplan-Meier analysis revealed no significant difference in overall survival between the natural and downstaged N0 groups, while ypN0 GC patients with an LNY of ≥24 had significantly longer overall survival than those with an LNY of ≤23. Univariate analysis identified that LNY, cT stage, tumor location, ypT stage, perineural invasion, lymphovascular invasion, tumor size, Mandard tumor regression grade, and extent of gastrectomy were significantly associated with overall survival. Multivariate analysis confirmed that perineural invasion (hazard ratio, 4.246; p < 0.001), lymphovascular invasion (hazard ratio, 2.694; p = 0.048), and an LNY of ≥24 (hazard ratio, 0.394; p = 0.011) were independent prognostic factors. Conclusions: Patients with natural and downstaged ypN0 GC had similar overall survival after NAC. LNY was an independent prognostic factor in these patients, and an LNY of ≥24 predicted prolonged overall survival.

Association of dynamic contrast-enhanced MRI and 18F-Fluorodeoxyglucose PET/CT parameters with neoadjuvant therapy response and survival in esophagogastric cancer

IntroductionBetter predictive markers are needed to deliver individualized care for patients with primary esophagogastric cancer. This exploratory study aimed to assess whether pre-treatment imaging parameters from dynamic contrast-enhanced MRI and 18F-fluorodeoxyglucose (18F-FDG) PET/CT are associated with response to neoadjuvant therapy or outcome. Materials and methodsFollowing ethical approval and informed consent, prospective participants underwent dynamic contrast-enhanced MRI and 18F-FDG PET/CT prior to neoadjuvant chemotherapy/chemoradiotherapy ± surgery. Vascular dynamic contrast-enhanced MRI and metabolic 18F-FDG PET parameters were compared by tumor characteristics using Mann Whitney U test and with pathological response (Mandard tumor regression grade), recurrence-free and overall survival using logistic regression modelling, adjusting for predefined clinical variables. Results39 of 47 recruited participants (30 males; median age 65 years, IQR: 54, 72 years) were included in the final analysis. The tumor vascular-metabolic ratio was higher in patients remaining node positive following neoadjuvant therapy (median tumor peak enhancement/SUVmax ratio: 0.052 vs. 0.023, p = 0.02). In multivariable analysis adjusted for age, gender, pre-treatment tumor and nodal stage, peak enhancement (highest gadolinium concentration value prior to contrast washout) was associated with pathological tumor regression grade. The odds of response decreased by 5% for each 0.01 unit increase (OR 0.95; 95% CI: 0.90, 1.00, p = 0.04). No 18F-FDG PET/CT parameters were predictive of pathological tumor response. No relationships between pre-treatment imaging and survival were identified. ConclusionPre-treatment esophagogastric tumor vascular and metabolic parameters may provide additional information in assessing response to neoadjuvant therapy.

Perioperative Cetuximab with Cisplatin and 5-Fluorouracil in Esogastric Adenocarcinoma: A Phase II Study

While perioperative chemotherapy provides a survival benefit over surgery alone in gastric and gastroesophageal junction (G/GEJ) adenocarcinomas, the results need to be improved. This study aimed to evaluate the efficacy and safety of perioperative cetuximab combined with 5-fluorouracil and cisplatin. Patients received six cycles of cetuximab, cisplatin, and simplified LV5FU2 before and after surgery. The primary objective was a combined evaluation of the tumor objective response (TOR), assessed by computed tomography, and the absence of major toxicities resulting in discontinuation of neoadjuvant chemotherapy (NCT) (45% and 90%, respectively). From 2011 to 2013, 65 patients were enrolled. From 64 patients evaluable for the primary endpoint, 19 (29.7%) had a morphological TOR and 61 (95.3%) did not stop NCT prematurely due to major toxicity. Sixty patients (92.3%) underwent resection. Sixteen patients (/56 available, 28.5%) had histological responses (Mandard tumor regression grade ≤3). After a median follow-up of 44.5 months, median disease-free and overall survival were 24.4 [95% CI: 16.4-39.4] and 40.3 months [95% CI: 27.5-NA], respectively. Adding cetuximab to the NCT regimen in operable G/GEJ adenocarcinomas is safe, but did not show enough efficacy in the present study to meet the primary endpoint (NCT01360086).