Neoadjuvant Concurrent Chemoradiotherapy Research Articles

A Phase II Trial of Adjuvant Durvalumab Following Trimodality Therapy for Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma: A Big Ten Cancer Research Consortium Study.

BackgroundMost patients with resectable locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma (AC) receive concurrent chemoradiation (CRT) followed by esophagectomy. The majority of patients do not achieve pathologic complete response (pCR) with neoadjuvant CRT, and the relapse rate is high among these patients.MethodsWe conducted a phase II study (ClinicalTrials.gov Identifier: NCT02639065) evaluating the efficacy and safety of PD-L1 inhibitor durvalumab in patients with locally advanced esophageal and GEJ AC who have undergone neoadjuvant CRT followed by R0 resection with evidence of persistent residual disease in the surgical specimen. Patients received durvalumab 1500 mg IV every 4 weeks for up to 1 year. The primary endpoint was 1-year relapse free survival (RFS). Secondary endpoint was safety and tolerability of durvalumab following trimodality therapy. Exploratory endpoints included correlation of RFS with PD-L1 expression, HER-2 expression, and tumor immune cell population.ResultsThirty-seven patients were enrolled. The majority (64.9%) had pathologically positive lymph nodes. The most common treatment related adverse events were fatigue (27%), diarrhea (18.9%), arthralgia (16.2%), nausea (16.2%), pruritus (16.2%), cough (10.8%), and increase in AST/ALT/bilirubin (10.8%). Three (8.1%) patients developed grade 3 immune mediated adverse events. One-year RFS was 73% (95% CI, 56–84%) with median RFS of 21 months (95% CI, 14–40.4 months). Patients with GEJ AC had a trend toward superior 1-year RFS compared to those with esophageal AC (83% vs. 63%, p = 0.1534). There was a numerical trend toward superior 1-year RFS among patients with PD-L1 positive disease compared to those with PD-L1 negative disease, using CPS of ≥10 (100% vs. 66.7%, p = 0.1551) and ≥1 (84.2% vs. 61.1%, p = 0.1510) cutoffs. A higher relative proportion of M2 macrophages and CD4 memory activated T cells was associated with improved RFS (HR = 0.16; 95% CI, 0.05–0.59; p = 0.0053; and HR = 0.37; 95% CI, 0.15–0.93, p = 0.0351, respectively).ConclusionsAdjuvant durvalumab in patients with residual disease in the surgical specimen following trimodality therapy for locally advanced esophageal and GEJ AC led to clinically meaningful improvement in 1-year RFS compared to historical control rate. Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting. Higher proportion of M2 macrophages and CD4 memory activated T cells was associated with superior RFS.

Feasibility of an Interactive Health Coaching Mobile App to Prevent Malnutrition and Muscle Loss in Esophageal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy: Prospective Pilot Study.

BackgroundExcessive muscle loss is an important prognostic factor in esophageal cancer patients undergoing neoadjuvant chemoradiotherapy (NACRT), as reported in our previous research.ObjectiveIn this pilot study, we prospectively tested the feasibility of a health coaching mobile app for preventing malnutrition and muscle loss in this patient population.MethodsBetween July 2019 and May 2020, we enrolled 38 male patients with esophageal cancer scheduled for NACRT. For 8 weeks from the start of radiotherapy (RT), the patients used Noom, a health coaching mobile app that interactively provided online advice about food intake, exercise, and weight changes. The skeletal muscle index (SMI) measured based on computed tomography and nutrition-related laboratory markers were assessed before and after RT. We evaluated the changes in the SMI, nutrition, and inflammatory factors between the patient group that used the mobile app (mHealth group) and our previous study cohort (usual care group). Additionally, we analyzed the factors associated with walk steps recorded in the app.ResultsTwo patients dropped out of the study (no app usage; treatment changed to a definitive aim). The use (or activation) of the app was noted in approximately 70% (25/36) of the patients until the end of the trial. Compared to the 1:2 matched usual care group by propensity scores balanced with their age, primary tumor location, tumor stage, pre-RT BMI, and pre-RT SMI level, 30 operable patients showed less aggravation of the prognostic nutritional index (PNI) (–6.7 vs –9.8; P=.04). However, there was no significant difference in the SMI change or the number of patients with excessive muscle loss (∆SMI/50 days >10%). In patients with excessive muscle loss, the walk steps significantly decreased in the last 4 weeks compared to those in the first 4 weeks. Age affected the absolute number of walk steps (P=.01), whereas pre-RT sarcopenia was related to the recovery of the reduced walk steps (P=.03).ConclusionsFor esophageal cancer patients receiving NACRT, a health care mobile app helped nutritional self-care with less decrease in the PNI, although it did not prevent excessive muscle loss. An individualized care model with proper exercise as well as nutritional support may be required to reduce muscle loss and malnutrition.

Effects of neoadjuvant chemoradiotherapy on infiltrating immune cells in the tumor microenvironment of rectal cancer

To detect the changes in the number and phenotype of tumor infiltrating immune cells in rectal cancer tissues before and after neoadjuvant concurrent chemoradiotherapy (CRT) and analyze their correlation with the clinicopathological parameters of the patients. The protein expressions of CD3, CD4, CD8, CD56 and Foxp3 in biopsy specimens and postoperative pathological specimens collected from 20 rectal cancer patients before and after neoadjuvant CRT were detected using ElivisionTM Plus immunohistochemistry, and the results were statistically analyzed. Compared with the measurements before the therapy, neoadjuvant CRT resulted in significant increments in CD3 (21.8% vs 48.8%, P < 0.001), CD4(16.5% vs 42.2%, P < 0.001), CD8(8.3% vs 33.4%, P < 0.001)and CD56(0 vs 7.6%, P=0.012), obvious reduction in Foxp3 expression(26.0% vs 15.3%, P=0.005), but no significant changes in CD4/CD8 ratio of(2.7 vs 5.1).Multivariate analysis showed that the increase of CD3-positive cells(HR=0.16, P=0.028)and CD8-positive cells(HR=0.03, P=0.001)was positively correlated with the disease-free survival of the patients after the operation. Neoadjuvant CRT can significantly increase the proportions of infiltrating immune cells positive for CD3, CD4, CD8 and CD56 and decrease the proportion of Treg lymphocytes in the tumor tissues in patients with rectal cancer.The patients with increased CD3-and CD8-positive T lymphocytes may have longer disease-free survival after the surgery.

Difference in Computed Tomography Image Quality between Central Vein and Peripheral Vein Enhancement in Treatment Naive Esophageal Cancer Patients.

Simple SummaryA chest CT via central vein enhancement not only eliminates peripheral vein regurgitation but also provides better image quality that facilitates precise clinical staging. A chest CT via central vein enhancement may be considered after tissue proof in order to better discriminate disease severity.The differences in chest computed tomography (CT) image quality may affect the tumor stage. The aim of this study was to compare the image quality and accuracy of chest CT via central vein and peripheral vein enhancement. Fifty consecutive patients were enrolled from a tertiary medical center in Taiwan from May 2016 to March 2019. All the patients received a chest CT via central vein enhancement prior to neoadjuvant concurrent chemoradiation in order to compare the chest CT that was obtained via the peripheral vein. In addition, blind independent central reviews of chest CT via central vein and peripheral vein enhancement were conducted. For T and N stage, chest CT via central vein enhancement had a greater consistency with endoscopic ultrasonography and positron-emission tomography-computed tomography findings (kappa coefficients 0.4471 and 0.5564, respectively). In addition, chest CT via central vein enhancement also showed excellent agreement in the blind independent central review (kappa coefficient 0.9157). The changes in the T and N stage resulted in stage migration in 16 patients. Chest CT via central vein enhancement eliminated peripheral vein regurgitation and also provided more precise clinical staging. This study is registered under the registered NCT number 02887261.

Deep Learning Analysis of CT Images Reveals High-Grade Pathological Features to Predict Survival in Lung Adenocarcinoma.

Simple SummaryThe high-grade pattern (micropapillary or solid pattern, MPSol) in lung adenocarcinoma affects the patient’s poor prognosis. We aimed to develop a deep learning (DL) model for predicting any high-grade patterns in lung adenocarcinoma and to assess the prognostic performance of model in advanced lung cancer patients who underwent neoadjuvant of definitive concurrent chemoradiation therapy (CCRT). Our model considering both tumor and peri-tumoral area showed area under the curve value of 0.8. DL model worked well in independent validation set of advanced lung cancer, stratifying their survival significantly. The subgroup with a high probability of MPSol estimated by the DL model showed a 1.76-fold higher risk of death. Thus, our DL model can be useful in estimating high-grade histologic patterns in lung adenocarcinomas and predicting clinical outcomes of patients with advanced lung cancer who underwent neoadjuvant or definitive CCRT.We aimed to develop a deep learning (DL) model for predicting high-grade patterns in lung adenocarcinomas (ADC) and to assess the prognostic performance of model in advanced lung cancer patients who underwent neoadjuvant or definitive concurrent chemoradiation therapy (CCRT). We included 275 patients with 290 early lung ADCs from an ongoing prospective clinical trial in the training dataset, which we split into internal–training and internal–validation datasets. We constructed a diagnostic DL model of high-grade patterns of lung ADC considering both morphologic view of the tumor and context view of the area surrounding the tumor (MC3DN; morphologic-view context-view 3D network). Validation was performed on an independent dataset of 417 patients with advanced non-small cell lung cancer who underwent neoadjuvant or definitive CCRT. The area under the curve value of the DL model was 0.8 for the prediction of high-grade histologic patterns such as micropapillary and solid patterns (MPSol). When our model was applied to the validation set, a high probability of MPSol was associated with worse overall survival (probability of MPSol >0.5 vs. <0.5; 5-year OS rate 56.1% vs. 70.7%), indicating that our model could predict the clinical outcomes of advanced lung cancer patients. The subgroup with a high probability of MPSol estimated by the DL model showed a 1.76-fold higher risk of death (HR 1.76, 95% CI 1.16–2.68). Our DL model can be useful in estimating high-grade histologic patterns in lung ADCs and predicting clinical outcomes of patients with advanced lung cancer who underwent neoadjuvant or definitive CCRT.

Long-term outcomes of an esophagus-preserving chemoradiotherapy strategy for patients with endoscopically unresectable stage I thoracic esophageal squamous cell carcinoma

Background and purposeTo assess the long-term outcomes of a multimodal approach for maximum esophagus preservation in operable patients with endoscopically unresectable stage I thoracic esophageal squamous cell carcinoma (ESCC). Materials and methodsThe medical records of patients with stage I thoracic ESCC treated with our protocol between 1992 and 2005 were retrospectively reviewed. Our protocol consisted of neoadjuvant concurrent chemoradiotherapy, followed by either additional definitive chemoradiotherapy for good responders (CRT group) or surgery for moderate or poor responders (CRT-S group) after an interim appraisal. ResultsA total of 51 patients were analysed. The median age of the patients was 67 years. The median follow-up period was 124.8 months. After the interim assessment, 49 and 2 cases were assigned to the CRT and CRT-S groups, respectively. In the intent-to-treat analyses, overall survival (OS), disease-free survival (DFS), cumulative incidence for death from esophageal cancer, and that for loss of esophageal function were 78.9%, 53.5%, 10.5%, and 20.4% at 5 years, and 55.2%, 27.8%, 18.2%, and 22.9% at 10 years, respectively. Grade 3 late toxicities occurred with the following incidences: esophageal stenosis in 1 case, esophageal ulcer in 1 case, and pericardial effusion in 2 cases. No grade 4 or higher toxicities were observed. ConclusionLong-term survival and esophagus preservation outcomes were favorable, with acceptable toxicities. Our results suggest that CCRT is an alternative treatment for majority of operable patients with endoscopically unresectable stage I thoracic ESCC in combination with salvage therapy.

Trimodality Versus Bimodality Therapy in Patients With Locally Advanced Esophageal Carcinoma: Commentary on the American Society of Clinical Oncology Practice Guidelines

In the recent guideline statement from the American Society of Clinical Oncology, experts reviewed relevant literature and provided treatment recommendations for multimodality treatment approaches. The guidelines recommend either preoperative concurrent neoadjuvant chemoradiotherapy (CRT) or perioperative chemotherapy for locally advanced adenocarcinoma and either preoperative CRT followed by esophagectomy or definitive CRT for squamous cell carcinoma. Whether radiation can be omitted in patients with adenocarcinoma or whether surgery can be omitted in patients with squamous cell carcinoma is a subject of ongoing debate and clinical trials.

The impact of neoadjuvant concurrent chemoradiation on exosomal markers (CD63 and CD9) expression and their prognostic significance in patients with rectal adenocarcinoma.

Introduction: Exosomes have pivotal roles in cancer development. The impact of neoadjuvant concurrent chemoradiation (NCCR) on exosomal markers (CD63 and CD9) expression and their prognostic significance in patients with rectal adenocarcinoma are yet to be explored.Materials and Methods: Between 2015 and 2018, 33 patients had rectal adenocarcinoma treated with NCCR and had pre-NCCR biopsy and post-NCCR resected rectum. CD63 and CD9 expression was assessed by immunohistochemistry (IHC). The short-term surrogate endpoint neoadjuvant rectal (NAR) score was used for assessment of prognostic significance. Un-Paired t-test was used for statistical analysis.Results: The mean tumor CD63 and CD9 scores in pre-NCCR biopsy vs. post-NCCR resected rectum were 106 vs. 165 (P = 0.0022) and 136 vs. 215 (P < 0.0001) respectively. The mean tumor CD63 and CD9 scores respectively in pre-NCCR biopsy was 99 and 130 in patients with low-intermediate NAR score compared to 117 and 144 in patients with high NAR score (P = 0.4934) (P = 0.5519). The mean tumor CD63 and CD9 scores respectively in post-NCCR resected rectum was 155 and 205 in patients with low-intermediate NAR score compared to 180 and 230 in patients with high NAR score (P = 0.3793) (P = 0.2837).Conclusions: The expression of the exosomal markers (CD63 and CD9) increased in patients with rectal adenocarcinoma after treatment with NCCR. The exosomal markers (CD63 and CD9) may have a prognostic significance. There was a trend for higher CD63 and CD9 expression in patients with high NAR score compared with low-intermediate NAR scores. The lack of statistical significance is likely due to the small sample size.

Upregulated MUC2 Is an Unfavorable Prognostic Indicator for Rectal Cancer Patients Undergoing Preoperative CCRT.

For locally advanced rectal cancer patients, introducing neoadjuvant concurrent chemoradiotherapy (CCRT) before radical resection allows tumor downstaging and increases the rate of anus retention. Since accurate staging before surgery and sensitivity prediction to CCRT remain challenging, a more precise genetic biomarker is urgently needed to enhance the management of such situations. The epithelial mucous barrier can protect the gut lumen, but aberrant mucin synthesis may defend against drug penetration. In this study, we focused on genes related to maintenance of gastrointestinal epithelium (GO: 0030277) and identified mucin 2 (MUC2) as the most significantly upregulated gene correlated with CCRT resistance through a public rectal cancer transcriptome dataset (GSE35452). We retrieved 172 records of rectal cancer patients undergoing CCRT accompanied by radical resection from our biobank. We also assessed the expression level of MUC2 using immunohistochemistry. The results showed that upregulated MUC2 immunoexpression was considerably correlated with the pre-CCRT and post-CCRT positive nodal status (p = 0.001 and p < 0.001), advanced pre-CCRT and post-CCRT tumor status (p = 0.022 and p < 0.001), vascular invasion (p = 0.015), and no or little response to CCRT (p = 0.006). Upregulated MUC2 immunoexpression was adversely prognostic for all three endpoints, disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MeFS) (all p < 0.0001), at the univariate level. Moreover, upregulated MUC2 immunoexpression was an independent prognostic factor for worse DSS (p < 0.001), LRFS (p = 0.008), and MeFS (p = 0.003) at the multivariate level. Collectively, these results imply that upregulated MUC2 expression is characterized by a more advanced clinical course and treatment resistance in rectal cancer patients undergoing CCRT, revealing the potential prognostic utility of MUC2 expression.

Abstract 610: Paired alterations of 35-gene expressing profiles before and after neoadjuvant chemoradiation in esophageal squamous cell carcinoma patients impact clinical prognosis

Abstract Purpose: Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is widely used for treating locally advanced esophageal cancer in the thorax. The aim of this study was to evaluate alterations of the 35-gene expression profiles in irradiated esophageal tissues before and after chemoradiation. Materials and Methods: A total number of 50 patients with Esophageal squamous cell carcinoma (ESCC) received neoadjuvant CCRT were retrospectively reviewed. The prescribed radiation dose for gross tumor and metastatic lymph nodes or subclinical mucosal/submucosal disease and regional lymphatic basin were 48 Gy and 43.2 Gy, respectively. All patients underwent CCRT using the intensity-modulated radiation therapy in 24 fractions and received concurrent chemotherapy with cisplatin. A 35-gene expression profile derived from reported ESCC-specific next-generation sequencing was performed. Paired 35-gene expression profiles were analyzed using pre-CCRT biopsy and post-CCRT esophagectomy specimens. In vitro validation of differential expression genes by using human ESCC cell lines 81T and TE2 was performed using the same 35-gene panel. Results: The alterations in mutation of genes between pre-CCRT biopsy and post-CCRT surgical specimens (delta expression profiles) correlated with pathological complete remission, overall survival and progression free survival. Among the delta expression profiles, the most significant alterations with prognostic impact were noted in MYH4 (p.Gln1210fs) and TTN (p.Asp7145His). Mutation of MYH4 (p.Gln1210fs) and TTN (p.Asp7145His) were demonstrated with favorable and unfavorable impact on rate of pathological complete remission, respectively. The mutation of MYH4 was also noted in human ESCC cell lines 81T and TE2 cells. Conclusion: By using the 35-gene expression profiles, specific mutations correlated to prognosis in esophageal squamous cell carcinoma patients receiving neoadjuvant chemoradiation and esophagectomy were found. The role of MYH4 mutation in treatment outcome and development as therapeutic target of esophageal squamous cell carcinoma remains to be clarified. Citation Format: Yu-Jen Chen, Prerana Bhan, Terry Wu, Hang Chang, Chi-Jung Lee. Paired alterations of 35-gene expressing profiles before and after neoadjuvant chemoradiation in esophageal squamous cell carcinoma patients impact clinical prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 610.

P-54 Higher muscle mass is associated with better response to concurrent neoadjuvant chemoradiotherapy in rectal cancer patients

Sarcopenia (low muscle mass) is an emerging syndrome associated with poor outcome in cancer patients. We investigated the relationship between skeletal muscle index (SMI), psoas muscle index (PMI), and neoadjuvant rectal score (NAR) in a group of patients with locally advanced rectal adenocarcinoma, treated with neoadjuvant concurrent chemoradiotherapy (nCCRT) with capecitabine and surgery.

Abstract 538: Liquid biopsy approaches for determining pathologic response to neoadjuvant immunotherapy in esophageal cancer

Abstract We examined the utility of serial liquid biopsies to monitor clonal dynamics and predict pathologic response in patients with esophageal/gastroesophageal junction (E/GEJ) cancer undergoing treatment with neoadjuvant immunotherapy and concurrent chemoradiation (CA209-906; NCT03044613). Methods: Using Targeted Error Correction sequencing (TEC-Seq), we performed high-depth next generation sequencing on 79 serial plasma samples from 16 patients with operable stage II/III E/GEJ cancer undergoing treatment with neoadjuvant nivolumab, followed by nivolumab plus chemo-radiation and surgery as part of the CA209-906 trial. Liquid biopsies were evaluated pre-treatment, after each of two cycles of neoadjuvant nivolumab, and after concurrent nivolumab and chemoradiation immediately prior to surgery, for an average of 4 time points per patient. Deep sequencing of matched leukocyte DNA and whole exome sequencing (WES) of pre-treatment tumors was performed. The origin of plasma variants was determined by comparison to tumor WES (tumor-derived) and leukocyte TEC-Seq (clonal hematopoiesis (CH)-derived or germline) and their clonal dynamics over time were evaluated. Resected tumors were reviewed by central pathology and percent residual tumor was estimated. Patients were followed for an average of 2 years post-surgery. Results: Eight of 16 patients had detectable circulating tumor-derived DNA (ctDNA) at any time point. Additionally, 13 CH-derived mutations were detected in plasma of 8 patients. The number of CH-derived mutations was correlated with increasing patient age. Identification and removal of CH-derived mutations via comparison to matched leukocyte sequencing allowed for accurate assessment of kinetics of bona fide tumor-derived mutations in plasma. Tumor mutation burden as determined by tumor WES was not associated with pathological response (mean baseline mutations per exome 90 vs 81 for patients with residual disease &amp;gt;20% and &amp;lt;20% respectively). Detectable ctDNA at the last pre-surgery time point was found in 3 patients and was associated with residual tumor &amp;gt;20% (50% vs 23% with or without detectable ctDNA respectively). ctDNA clearance, defined as detectable ctDNA at one or more earlier time points that subsequently becomes undetectable before surgery, occurred in 5 patients and was associated with improved pathologic response (80% of patients with ctDNA clearance had residual tumor &amp;lt;=20% and no evidence of disease progression). Furthermore, of the three patients who did not have ctDNA clearance, two subsequently developed disease progression. Conclusion: Comprehensive analyses of ctDNA from E/GEJ patients undergoing neoadjuvant immunotherapy with concurrent chemoradiation revealed ctDNA dynamics that were associated with pathologic response and disease recurrence. These approaches may be used to identify patients at high risk for disease progression. Citation Format: Jenna VanLiere Canzoniero, Vincent Lam, Zineb Belcaid, Mara Lanis, Lamia Rhymee, Blair Landon, Archana Balan, Kristen Marrone, Patrick Forde, Benjamin Levy, David Ettinger, Heather Schneider, Hanika Rodavia, Richard Battafarano, Stephen Yang, Stephen Broderick, Jinny Ha, Blair Jobe, Ali Zaidi, Elizabeth Thompson, Julie Brahmer, Victor Velculescu, Ronan Kelly, Josephine Feliciano, Valsamo Anagnostou. Liquid biopsy approaches for determining pathologic response to neoadjuvant immunotherapy in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 538.

Abstract 438: Deep learning based radiomic biomarker for predicting the presence of high-grade histologic patterns in lung adenocarcinoma

Abstract Introduction: The presence of high-grade histologic patterns such as micropapillary or solid (MPSol) in patients with lung adenocarcinoma (ADC) is known to have a poor prognosis even if it is not the most predominant subtype. However, since it is difficult to determine the histologic pattern of the entire tumor with a small biopsy sample, there is a growing need for non-invasive biomarkers that can predict the histologic pattern of lung ADC. We developed a deep learning (DL)-based model as a radiomic biomarker that predicts high-grade ADC patterns and validated by applying it to the independent clinical dataset. Methods: A total of 290 early lung ADCs (from 275 patients) underwent curative surgical resection recruited from Samsung Medical Center were retrospectively analyzed as a training dataset. We developed a 3D convolutional DL model called morphologic-view context-view 3D network (MC3DN). Our model was developed to focus on morphologic characteristics of target lesion with contexture information observed around the lesion. Additional information about pathologic size and segmentation were trained together. An independent dataset of 416 patients with advanced lung cancer who underwent neoadjuvant concurrent chemoradiation therapy (CCRT) or definitive CCRT was analyzed to assess the prognostic performance of our model. Results: Of the training set, 54 (18.6%) lesions had MPSol pattern as the most or second predominant histologic pattern in the pathologic specimen. For the prediction of the presence of MPSol pattern, the area under the curve (AUC) value of the baseline MC3DN was 0.77. When training the model with pathologic size and segmentation together through multi-task learning, the AUC value increased to 0.80. When applied to the validation set, a high probability of MPSol estimated by DL model was associated with worse overall survival (probability of MPSol &amp;gt; 0.5 vs ≤ 0.5; 5-year OS rate 59.0% vs 73.6%, p=0.007). The subgroup with a high probability of MPSol showed 1.78 folds high risk for death (95% CI 1.17-2.72, p = 0.008). It was also significantly associated with overall survival after adjusting for other prognostic factors including age, sex, smoking, ECOG, and TNM stage (HR 1.61, 95% CI 1.05-2.47, p=0.029). Conclusion: MC3DN model through CT images could be useful in estimating any high-grade histologic pattern of lung ADCs and predicting clinical outcomes of patients with advanced lung cancer who underwent neoadjuvant or definitive CCRT. This model is also applied to inoperable patients and could be used to establish a treatment plan. Citation Format: Yeonu Choi, Jaehong Aum, Seunghwan Shin, Chan-Young Ock, Se-Hoon Lee, Hong Kwan Kim, Jhingook Kim, Ho Yun Lee. Deep learning based radiomic biomarker for predicting the presence of high-grade histologic patterns in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 438.

High SPINK4 Expression Predicts Poor Outcomes among Rectal Cancer Patients Receiving CCRT.

Background: Patients with rectal cancer can prospectively be favored for neoadjuvant concurrent chemoradiotherapy (CCRT) to downstage before a radical proctectomy, but the risk stratification and clinical outcomes remain disappointing. Methods: From a published rectal cancer transcriptome dataset (GSE35452), we highlighted extracellular matrix (ECM)-linked genes and identified the serine protease inhibitor Kazal-type 4 (SPINK4) gene as the most relevant among the top 10 differentially expressed genes associated with CCRT resistance. We accumulated the cases of 172 rectal cancer patients who received neoadjuvant CCRT followed by surgery and collected tumor specimens for the evaluation of the expression of SPINK4 using immunohistochemistry. Results: The results revealed that high SPINK4 immunoexpression was significantly related to advanced pre-CCRT and post-CCRT tumor status (both p < 0.001), post-CCRT lymph node metastasis (p = 0.001), more vascular and perineurial invasion (p = 0.015 and p = 0.023), and a lower degree of tumor regression (p = 0.001). In univariate analyses, high SPINK4 immunoexpression was remarkably correlated with worse disease-specific survival (DSS) (p < 0.0001), local recurrence-free survival (LRFS) (p = 0.0017), and metastasis-free survival (MeFS) (p < 0.0001). Furthermore, in multivariate analyses, high SPINK4 immunoexpression remained independently prognostic of inferior DSS and MeFS (p = 0.004 and p = 0.002). Conclusion: These results imply that high SPINK4 expression is associated with advanced clinicopathological features and a poor therapeutic response among rectal cancer patients undergoing CCRT, thus validating the prospective prognostic value of SPINK4 for those patients.

Machine learning model for predicting excessive muscle loss during neoadjuvant chemoradiotherapy in oesophageal cancer.

BackgroundExcessive skeletal muscle loss during neoadjuvant concurrent chemoradiotherapy (NACRT) is significantly related to survival outcomes of oesophageal cancer. However, the conventional method for measuring skeletal muscle mass requires computed tomography (CT) images, and the calculation process is labour‐intensive. In this study, we built machine‐learning models to predict excessive skeletal muscle loss, using only body mass index data and blood laboratory test results.MethodsWe randomly split the data of 232 male patients treated with NACRT for oesophageal cancer into the training (70%) and test (30%) sets for 1000 iterations. The naive random over sampling method was applied to each training set to adjust for class imbalance, and we used seven different machine‐learning algorithms to predict excessive skeletal muscle loss. We used five input variables, namely, relative change percentage in body mass index, albumin, prognostic nutritional index, neutrophil‐to‐lymphocyte ratio, and platelet‐to‐lymphocyte ratio over 50 days. According to our previous study results, which used the maximal χ 2 method, 10.0% decrease of skeletal muscle index over 50 days was determined as the cut‐off value to define the excessive skeletal muscle loss.ResultsThe five input variables were significantly different between the excessive and the non‐excessive muscle loss group (all P < 0.001). None of the clinicopathologic variables differed significantly between the two groups. The ensemble model of logistic regression and support vector classifier showed the highest area under the curve value among all the other models [area under the curve = 0.808, 95% confidence interval (CI): 0.708–0.894]. The sensitivity and specificity of the ensemble model were 73.7% (95% CI: 52.6%–89.5%) and 74.5% (95% CI: 62.7%–86.3%), respectively.ConclusionsMachine learning model using the ensemble of logistic regression and support vector classifier most effectively predicted the excessive muscle loss following NACRT in patients with oesophageal cancer. This model can easily screen the patients with excessive muscle loss who need an active intervention or timely care following NACRT.

Optimal cumulative cisplatin dose during concurrent chemoradiotherapy among children and adolescents with locoregionally advanced nasopharyngeal carcinoma: A real-world data study

PurposeTo identify an optimal cumulative cisplatin dose along with concurrent chemoradiotherapy (CC-CCD) for children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CALANPC) using real-world data. Materials and MethodsUsing an NPC-specific database at our center, 157 patients younger than 19 years old with non-disseminated CALANPC and receiving neoadjuvant chemotherapy (NAC) plus cisplatin-based concurrent chemoradiotherapy (CCRT) were enrolled. Confounding factors were controlled by conducting propensity score matching analysis. Primary endpoints include disease-free survival (DFS) and distant metastasis-free survival (DMFS). ResultsThe optimal threshold for CC-CCD with respect to DFS was 160 mg/m2 based on recursive partitioning analyses (RPA). Therefore, a uniform threshold of 160 mg/m2 (≥160 vs. <160 mg/m2) was selected to classify patients between high and low CC-CCD groups for survival analysis. Patients receiving low CC-CCD showed a significant decrease in 5-year DFS (76.6% vs 91.3%; P = 0.006) and DMFS (81.3% vs 93.5%; P = 0.009) compared to those receiving high CC-CCD. Multivariate analyses indicated that high CC-CCD as an favorable prognostic influence for DFS (P = 0.007) and DMFS (P = 0.008). Further matched analysis identified 65 pairs in both high and low CC-CCD groups. In the matched cohort, high CC-CCD was still identified as a favorable factor for prognosis in DFS (HR, 0.23; 95% CI, 0.08–0.70; P = 0.010) and DMFS (HR, 0.23; 95% CI, 0.06–0.82; P = 0.023). ConclusionCC-CCD exerts significant treatment effects and 160 mg/m2 CC-CCD may be adequate to provide antitumor effects for CALANPC receiving NAC plus CCRT.

The Prognostic Value of Programmed Death-ligand 1 (PD-L1) in Patients who Received Neoadjuvant Chemoradiation Therapy Followed by Surgery for Locally Advanced Non-small Cell Lung Cancer.

We analyzed the prognostic efficacy of programmed death-ligand 1 (PD-L1) in locally advanced non-small cell lung cancer (LA-NSCLC) patients. During 2005-2016, 211 patients underwent neoadjuvant concurrent chemoradiation therapy (CCRT) followed by surgical resection for LA-NSCLC at Asan Medical Center. PD-L1 expression and CD8+ tumor-infiltrating lymphocytes (TIL) were measured pre- and post-neoadjuvant CCRT and analyzed using immuno - histochemical staining. In total, 39 patients were enrolled. Overall survival (OS) and disease-free survival (DFS) were significantly longer in patients with increased PD-L1 expression and increased CD8+ TIL density post-neoadjuvant CCRT. Univariate Cox regression analysis confirmed that increased levels of PD-L1 and increased CD8+ TIL density were prognostic factors for OS and DFS. Multivariate Cox regression analysis confirmed that increased levels of PD-L1 was a prognostic factor for OS and increased CD8+ TIL density for DFS. Relative changes in PD-L1 expression post-neoadjuvant CCRT can be utilized to predict the prognosis of LA-NSCLC patients.

High FRMD3 expression is prognostic for worse survival in rectal cancer patients treated with CCRT.

Rectal cancer patients can conceivably obtain relief from neoadjuvant concurrent chemoradiotherapy (CCRT) for downstaging before resection, but the stratification of risk and clinical outcomes remains challenging. Therefore, identifying effective predictive biomarkers offers clinicians the opportunity to individually tailor early interventions, which would help optimize therapy. Using a public rectal cancer transcriptome dataset (GSE35452), we focused on cytoskeletal protein binding (GO: 0008092)-related genes and identified FERM domain containing 3 (FRMD3) as the most significant differentially expressed gene associated with CCRT resistance. We gathered 172 tumor samples from rectal cancer patients treated with neoadjuvant CCRT accompanied by curative resection and estimated the expression level of FRMD3 using immunohistochemistry. The results revealed that high FRMD3 immunoexpression was remarkably associated with advanced pre-CCRT and post-CCRT tumor status (p = 0.004 and p < 0.001), pre-CCRT and post-CCRT lymph node metastasis (both p < 0.001), more perineurial invasion (p = 0.023), and a smaller extent of tumor regression (p = 0.018). High FRMD3 immunoexpression was remarkably correlated with inferior disease-specific survival (DSS) (p = 0.0001), local recurrence-free survival (LRFS) (p = 0.0003), and metastasis-free survival (MeFS) (p = 0.0023) at the univariate level. Furthermore, in multivariate analysis, high FRMD3 immunoexpression remained independently predictive of inferior DSS (p = 0.002), LRFS (p = 0.005), and MeFS (p = 0.015). These results suggest that high FRMD3 expression is related to advanced clinicopathological features and inferior therapeutic responses in rectal cancer patients treated with CCRT, validating the promising prognostic value of FRMD3 expression.

Locally Advanced Breast Cancer (LABC): Real-World Outcome of Patients From Cancer Institute, Chennai.

PURPOSEThere are sparse data on the outcome of patients with locally advanced breast cancer (LABC). This report is on the prognostic factors and long-term outcome from Cancer Institute, Chennai.METHODSThis is an analysis of untreated patients with LABC (stages IIIA-C) who were treated from January 2006 to December 2013.RESULTSOf the 4,577 patients with breast cancer who were treated, 2,137 patients (47%) with LABC were included for analysis. The median follow-up was 75 months (range, 1-170 months), and 2.3% (n = 49) were lost to follow-up at 5 years. The initial treatment was neoadjuvant concurrent chemoradiation (NACR) (77%), neoadjuvant chemotherapy (15%), or others (8%). Patients with triple-negative breast cancer had a pathologic complete response (PCR) of 41%. The 10-year overall survival was for stage IIIA (65.1%), stage IIIB (41.2%), and stage IIIC (26.7%). Recurrence of cancer was observed in 27% of patients (local 13% and distant 87%). Multivariate analysis showed that patients with a tumor size > 10 cm (hazard ratio [HR], 2.19; 95% CI, 1.62 to 2.98; P = .001), hormone receptor negativity (HR, 1.45; 95% CI, 1.22 to 1.72; P = .001), treatment modality (neoadjuvant chemotherapy, HR, 0.56; 95% CI, 0.43 to 0.73; P = .001), lack of PCR (HR, 2.36; 95% CI, 1.85 to 3.02; P = .001), and the presence of lymphovascular invasion (HR, 1.97; 95% CI, 1.60 to 2.44; P = .001) had decreased overall survival.CONCLUSIONNACR was feasible in inoperable LABC and gave satisfactory long-term survival. PCR was significantly higher in patients with triple-negative breast cancer. The tumor size > 10 cm was significantly associated with inferior survival. However, this report acknowledges the limitations inherent in experience of management of LABC from a single center.

Pediatric Rectal Cancer

Pediatric rectal adenocarcinoma is a rare disease with an incidence of 1.3 cases per million children; these numbers have been on the rise in the past two decades. Standard management guidelines are yet to be established because of their rarity and complex range of issues that need to be simultaneously addressed. Here, we demonstrate the treatment approach in a 10-year-old girl who presented with bleeding per rectum and was diagnosed with low rectal cancer; the histopathology was moderately differentiated adenocarcinoma. After discussions by a multidisciplinary team, she underwent laparoscopic bilateral ovarian transposition followed by neoadjuvant concurrent chemoradiation therapy. On follow-up, she achieved a complete clinical response that was evaluated by triple assessment (clinical examination, pelvic magnetic resonance imaging, and colonoscopy). For the past three years, the patient is being followed up using the watch and wait strategy, which is not standard in pediatric patients, and has remained disease-free. We believe that this novel perspective will enable the future development of individualized yet standardized management protocols; thus, it may help in minimizing morbidities. We discuss the complexity involved in treating pediatric rectal cancers by quoting the current case, being the first of its kind, to the best of our knowledge.