Neoadjuvant Concurrent Chemoradiotherapy Research Articles

Efficacy and safety of bevacizumab in neoadjuvant and concurrent chemoradiotherapy for refractory cervical cancer patients.

A platinum-based concurrent chemoradiotherapy (CCRT) is the standard treatment for refractory cervical cancer (CC). However, the recurrence of disease and the occurrence of metastasis remain prevalent. We observed the long-term efficacy and safety of bevacizumab combined with neoadjuvant chemotherapy (NACT) and CCRT in refractory CC. A total of 62 patients with refractory CC were enrolled in this study from January 2016 to December 2019. The NACT regimen included bevacizumab (7.5 mg/kg), docetaxel (75 mg/m2), and cisplatin (75 mg/m2), administered tri-weekly for 2 cycles. The CCRT regimen included bevacizumab (7.5 mg/kg) and cisplatin (75 mg/m2), administered tri-weekly for 2 cycles. A dose of 45-50 Gy was prescribed for external beam radiotherapy (EBRT), while 30-35 Gy in 4-5 fractions was prescribed for brachytherapy (BT). Among the patients, 21 patients (33.9%) were at stages IIB-IIIB, 8 patients (12.9%) were at stage IIIC1, 19 patients (30.6%) were at stage IIIC2, and 14 patients (22.6%) were at stage IVB. Pelvic, para-aortic, supraclavicular, and inguinal lymph node metastases were discovered in 41 patients (66.1%). The median follow-up was 49.8 months (12.3-82.7 months). The median tumor volumes pre-treatment, after NACT, and before BT were 84.64 ± 53.15 cm3, 1.64 ± 13.15 cm3, and 0 ± 1.5 cm3, respectively. Complete clinical response (cCR) rates after NACT and EBRT were 35.5% and 66.1%, respectively. Four years after the diagnosis, the overall survival (OS) rate was 78.6%, the local region-free survival (LRFS) rate was 91.3%, the disease-free survival (DFS) rate was 70.6%, and the distant metastasis-free survival (DMFS) rate was 81.4%. A total of 29 patients (46.8%) experienced grade 3/4 hematological toxicity, 3 patients (4.8%) experienced grade 3 gastrointestinal toxicities, and none experienced grade 5 adverse events. Bevacizumab combined with NACT and CCRT significantly improved cCR and OS in refractory CC with acceptable toxicity.

The Expression of TP63 as a Biomarker of Early Recurrence in Resected Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemoradiotherapy.

Esophageal cancer ranks among the ten most common cancers worldwide. Despite the adoption of neoadjuvant concurrent chemoradiotherapy (nCCRT) followed by surgery as the standard treatment approach in recent years, the local recurrence rate remains high. In this study, we employed RNA-seq to investigate distinctive gene expression profiles in esophageal squamous cell carcinoma (ESCC) with or without recurrence following a standard treatment course. Our findings indicate that recurrent ESCC exhibits heightened keratinizing and epidermis development activity compared to non-recurrent ESCC. We identified TP63 as a potential candidate for distinguishing clinical outcomes. Furthermore, immunohistochemistry confirmed the trend of TP63 overexpression in ESCC recurrence. Patients with elevated TP63 expression had poorer overall survival and lower 3-year recurrence-free survival. This study underscores the potential of TP63 as a biomarker for detecting cancer recurrence and suggests its role in guiding future treatment options.

Adjuvant Pembrolizumab in Patients with Stage IIIA/N2 Non-Small Cell Lung Cancer Completely Resected after Neoadjuvant Concurrent Chemoradiation: A Prospective, Open-Label, Single-Arm, Phase 2 Trial.

Optimal treatment for stage IIIA/N2 non-small cell lung cancer (NSCLC) is controversial. We aimed to assess the efficacy and safety of adjuvant pembrolizumab for stage IIIA/N2 NSCLC completely resected after neoadjuvant concurrent chemoradiation therapy (CCRT). In this open-label, single-center, single-arm phase 2 trial, patients with stage IIIA/N2 NSCLC received adjuvant pembrolizumab for up to two years after complete resection following neoadjuvant CCRT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety. As an exploratory biomarker analysis, we evaluated the proliferative response of blood CD39+PD-1+CD8+ T cells using fold changes in the percentage of proliferating Ki-67+ cells from days 1 to 7 of cycle 1 (Ki-67D7/D1). Between October 2017 and October 2018, 37 patients were enrolled. Twelve (32%) and three (8%) patients harbored EGFR and ALK alterations, respectively. Of 34 patients with programmed cell death ligand 1 assessment, 21 (62%), 9 (26%), and 4 (12%) had a tumor proportion score of <1%, 1-50%, and ≥50%, respectively. The median follow-up was 71 months. The median DFS was 22.4 months in the overall population, with a five-year DFS rate of 29%. The OS rate was 86% at two years and 76% at five years. Patients with tumor recurrence within six months had a significantly lower Ki-67D7/D1 among CD39+PD-1+CD8+ T cells than those without (p=0.036). No new safety signals were identified. Adjuvant pembrolizumab may offer durable disease control in a subset of stage IIIA/N2 NSCLC patients after neoadjuvant CCRT and surgery.

Effect of neoadjuvant concurrent three-dimensional conformal chemoradiotherapy with conventional two-dimensional chemoradiotherapy in locally advanced rectal cancer

Background: Rectal carcinoma is a prevalent clinical condition, and treatment hinges on factors like tumor specifics, staging, grading, and histopathological characteristics. While surgery remains the primary treatment, neoadjuvant chemoradiotherapy, particularly using 3D-CRT, has proven effective in reducing local recurrence rates for locally advanced cases. Alternatively, 2D-RT is considered for neoadjuvant treatment. This study aimed to compare the impact of neoadjuvant concurrent three-dimensional conformal chemoradiotherapy with conventional two-dimensional chemoradiotherapy in the context of locally advanced rectal cancer. Methods: In this multicentre quasi-experimental study, 60 patients with biopsy-proven adenocarcinoma and clinically confirmed locally advanced rectal cancer, were divided into Group A (receiving oral capecitabine with three-dimensional conformal radiotherapy) and Group B (receiving the same capecitabine dose with 50 Gy two-dimensional radiotherapy). After surgery within 6-12 weeks, outcomes were analysed. Results: After neoadjuvant chemoradiotherapy, clinical complete response rates were 16.7% in Group A and 10.0% in Group B, with a higher pathological complete response in Group A (10.0% vs. 3.3%). Tumor downsizing occurred in 83.3% of Group A and 73.3% of Group B, and sphincter-sparing surgery was achieved in 73.3% of Group A and 56.7% of Group B. Grade 2 toxicities included anemia (10.0% vs. 13.3%), leucopenia (13.3% vs. 20.0%), diarrhoea (10.0% vs. 16.7%), proctitis (13.3% vs. 40.0%), and urinary toxicity (10.0% vs. 20.0%). Grade-1 toxicities were nausea (20.0% vs. 40.0%), vomiting (20.0% vs. 36.7%), mucositis (56.7% vs. 60.0%), hand-foot syndrome (33.3% vs. 40.0%), and urinary toxicity (43.3% vs. 56.67%), with significant proctitis in Group A (p=0.012). Other toxicities showed non-significant p-values (&gt;0.05). Conclusions: Tumour response was not statistically significant between the patients of concurrent 3D-CRT and 2D-RT Arms. But the patients of 3D-CRT arm showed better response arithmetically. Also, there was an observable significant reduction of toxicities (lower gastrointestinal) in the 3D-CRT arm.

Retrospective Evaluation of the Efficacy of Total Neoadjuvant Therapy and Chemoradiotherapy Neoadjuvant Treatment in Relation to Surgery in Patients with Rectal Cancer.

Background and Objective: In the therapeutic strategy of rectal cancer, radiotherapy has consolidated its important position and frequent use in current practice due to its indications as neoadjuvant, adjuvant, definitive, or palliative treatment. In recent years, total neoadjuvant therapy (TNT) has been established as the preferred regimen compared to concurrent neoadjuvant chemoradiotherapy (CRT). In relation to better outcomes, the percentage of patients who achieved pathological complete response (pCR) after neoadjuvant treatment is higher in the case of TNT. This study aimed to analyze the response to TNT compared to neoadjuvant CRT regarding pCR rate and the change in staging after surgical intervention. Materials and Methods: We performed a retrospective study on 323 patients with rectal cancer and finally analyzed the data of 201 patients with neoadjuvant treatment, selected based on the inclusion and exclusion criteria. Patients received CRT neoadjuvant therapy or TNT neoadjuvant therapy with FOLFOX or CAPEOX. Results: Out of 157 patients who underwent TNT treatment, 19.74% had pathological complete response, whereas in the group with CRT (n = 44), those with pCR were 13.64%. After neoadjuvant treatment, the most frequent TNM classifications were ypT2 (40.30%) and ypN0 (79.10%). The statistical analysis of the postoperative disease stage, after neoadjuvant therapy, showed that the most frequent changes were downstaging (71.14%) and complete response (18.41%). Only four patients (1.99%) had an upstaging change. The majority of patients (88.56%) initially presented clinical evidence of nodal involvement whereas only 20.9% of the patients still presented regional disease at the time of surgical intervention. Conclusions: By using TNT, a higher rate of stage reduction is obtained compared to the neoadjuvant CRT treatment. The post-neoadjuvant-treatment imagistic evaluation fails to accurately evaluate the response. A better response to TNT was observed in young patients.

The Neoadjuvant Administration of PD-1 Inhibitor plus Concurrent Chemoradiotherapy in Patients with Locally Advanced Esophageal Squamous-Cell Carcinoma

Objective. Programmed cell death-1 (PD-1) inhibitors have shown potency for neoadjuvant therapy in several cancers, while their administration combined with concurrent chemoradiotherapy (CCRT) as a neoadjuvant therapy for locally advanced esophageal squamous-cell carcinoma (ESCC) is seldom reported. The current study aimed to investigate the pathological response, survival, and safety of neoadjuvant PD-1 inhibitor plus CCRT in locally advanced ESCC patients. Methods. Twenty-five locally advanced ESCC patients who underwent PD-1 inhibitor plus CCRT neoadjuvant therapy were retrospectively reviewed. Data regarding radiological response, pathological response, disease-free survival (DFS), overall survival (OS), and adverse events were retrieved. Results. Two (8.0%), 14 (56.0%), 9 (36.0%), and 0 (0.0%) patients had a clinical response of complete response, partial response, stable disease, and progressive disease after neoadjuvant therapy by radiological evaluations, respectively. Notably, 25 (100.0%) patients had successful tumor resections, 24 (96.0%) patients realized R0 resection, and 13 (52.0%) patients achieved pathological complete response (pCR) by pathological evaluations. Regarding survival profiles, the 1-year and 2-year accumulating DFS rates were 90.0% and 74.6%, respectively; then, the 1-year and 2-year accumulating OS rates were 95.5% and 90.4%, respectively. The top prevalent adverse events were fatigue (48.0%), nausea and vomiting (40.0%), leukopenia (36.0%), neutropenia (36.0%), and peripheral neuropathy (36.0%). In addition, grades 3-4 adverse events included peripheral neuropathy (12.0%), nausea and vomiting (4.0%), leukopenia (4.0%), neutropenia (4.0%), anemia (4.0%), and pruritus (4.0%). Conclusion. Neoadjuvant PD-1 inhibitor plus CCRT shows a good efficacy and acceptable tolerance for locally advanced ESCC treatment, but further large-scale study validation is needed.

Risk Factor Analysis of Morbidity and 90-Day Mortality of Curative Resection in Patients with Stage IIIA-N2 Non-Small Cell Lung Cancer after Induction Concurrent Chemoradiation Therapy.

Major pulmonary resection after neoadjuvant concurrent chemoradiation therapy (nCCRT) is associated with a substantial risk of postoperative complications. This study investigated postoperative complications and associated risk factors to facilitate the selection of suitable surgical candidates following nCCRT in stage IIIA-N2 non-small cell lung cancer (NSCLC). We conducted a retrospective analysis of patients diagnosed with clinical stage IIIA-N2 NSCLC who underwent surgical resection following nCCRT between 1997 and 2013. Perioperative characteristics and clinical factors associated with morbidity and mortality were analyzed using univariable and multivariable logistic regression. A total of 574 patients underwent major lung resection after induction CCRT. Thirty-day and 90-day postoperative mortality occurred in 8 patients (1.4%) and 41 patients (7.1%), respectively. Acute respiratory distress syndrome (n=6, 4.5%) was the primary cause of in-hospital mortality. Morbidity occurred in 199 patients (34.7%). Multivariable analysis identified significant predictors of morbidity, including patient age exceeding 70 years (odds ratio [OR], 1.8; p=0.04), low body mass index (OR, 2.6; p=0.02), and pneumonectomy (OR, 1.8; p=0.03). Patient age over 70 years (OR, 1.8; p=0.02) and pneumonectomy (OR, 3.26; p<0.01) were independent predictors of mortality in the multivariable analysis. In conclusion, the surgical outcomes following nCCRT are less favorable for individuals aged over 70 years or those undergoing pneumonectomy. Special attention is warranted for these patients due to their heightened risks of respiratory complications. In high-risk patients, such as elderly patients with decreased lung function, alternative treatment options like definitive CCRT should be considered instead of surgical resection.

Lymph node volume predicts survival in esophageal squamous cell carcinoma treated with neoadjuvant chemoradiotherapy and surgery.

Large primary tumor volume has been identified as a poor prognostic factor of esophageal squamous cell carcinoma (ESCC) treated with definitive concurrent chemoradiotherapy (CCRT). However, when neoadjuvant CCRT and surgery are adopted, the prognostic impact of primary tumor and lymph node (LN) volume on clinical outcomes in ESCC remains to be elucidated. This study included 107 patients who received neoadjuvant CCRT and surgery for ESCC. The volume of the primary tumor and LN was measured using radiotherapy planning computed tomography scans, and was correlated with overall survival (OS), disease-free survival (DFS), and cancer failure pattern. The median OS was 24.2 months (IQR, 11.1-93.9) after a median follow-up of 18.4 months (IQR, 8.1-40.7). The patients with a baseline LN volume > 7.7 ml had a significantly worse median OS compared to those with smaller LN volume (18.8 vs. 46.9 months, p = 0.049), as did those with tumor regression grade (TRG) 3-5 after CCRT (13.9 vs. 86.7 months, p < 0.001). However, there was no association between OS and esophageal tumor volume (p = 0.363). Multivariate analysis indicated that large LN volume (HR 1.753, 95% CI 1.015-3.029, p = 0.044) and high TRG (HR 3.276, 95% CI 1.556-6.898, p = 0.002) were negative prognostic factors for OS. Furthermore, large LN volume was linked to increased locoregional failure (p = 0.033) and decreased DFS (p = 0.041). In conclusion, this study demonstrated that large LN volume is correlated with poor OS, DFS, and locoregional control in ESCC treated with neoadjuvant CCRT and esophagectomy.

Neoadjuvant chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in elderly patients with stage III-IVa nasopharyngeal carcinoma: A real-world study based on medical comorbidities.

To evaluate the outcomes and toxicities of adding neoadjuvant chemotherapy (NAC) to concurrent chemoradiotherapy (CCRT) in elderly (≥65 years) patients with locoregionally advanced nasopharyngeal carcinoma (LANPC, stage III-IVa). Using an NPC-specific database, 245 elderly patients with stage III-IVa NPC, receiving CCRT +/- NAC, and an Adult Co-morbidity Evaluation 27 (ACE-27) score <2 were included. Recursive partitioning analysis (RPA) based on TNM stage and Epstein-Barr virus (EBV) DNA were applied for risk stratification. The primary end point was disease-free survival (DFS). Two risk groups were generated by the RPA model. In the high-risk group (EBV DNA < 4000 copy/ml with stage IVa & EBV DNA ≥4000 copy/ml with stage III-IVa), patients treated with NAC plus CCRT achieved improved 5-year DFS rates compared to those who received CCRT alone (56.9% vs. 29.4%; p = 0.003). But we failed to observe the survival benefit of additional NAC in the low-risk group (EBV DNA <4000 copy/ml with stage III). The most common severe acute toxic effects were leucopenia (46.8% vs. 24.4%) and neutropenia (43.7% vs. 20.2%) in the NAC plus CCRT group versus CCRT group with statistically significant differences. The addition of NAC to CCRT was associated with better DFS for the high-risk group of elderly LANPC patients with ACE-27 score <2. However, the survival benefit of additional NAC was not observed in low-risk patients.

Quality of Life in Locally Advanced Carcinoma Rectum Patients During Various Phases of NACRT: An Indian Perspective.

In low- and middle-income countries (LMICs) including India, cancer patients have a poor prognosis because of late diagnosis and cases already grown to advanced stages, low cancer awareness and skewed cancer care facilities. In India, the incidence of colorectal cancer (CRC) is ranked the 4th most common (6.4%) in males and the 5th most common (3.4%) in females. The improvement in the cure rate of rectal cancer has increased life expectancy, and assessment of the quality of life (QoL) in these patients has become a fundamental requirement. Little is known about how the patients perceive these adverse effects during curatively intended radiotherapy. Although studies have investigated the various adverse effects that can occur with radiotherapy and chemotherapy in carcinoma rectum patients, these have not yet been critically appraised and synopsized to form a comprehensive review of their prevalence and effects on QoL. The study was designed to explore the QoL issues in locally advanced carcinoma rectum patients during various phases of neoadjuvant concurrent chemo-radiotherapy (NACCRT). The study was performed over a period of 2years at a single super speciality cancer hospital in North India. Patients were selected as per the inclusion criteria and followed up with a standard questionnaire incorporating various aspects depicting QoL. The interview technique was used for collecting QoL data at four points, at baseline, midway during treatment, at the end of treatment and 4weeks after completion of NACCRT, using EORTC QLQ C30, for QLQ CR29. Special care was taken to avoid observer bias in cases of language issues, and interpreters' services were utilised, and compared with the baseline pre-treatment scores, patients reported a statistically significant and large clinically meaningful change in the global health status, social functioning, fatigue (FACIT-F), appetite loss, anxiety, sore skin and male and female sexual function at the post-treatment time point. Statistically significant changes with moderate clinically meaningful changes were reported for the functional scales-physical, role and emotional functioning of the QLQ C30 questionnaire and body image and weight of the CR29 questionnaire. Similar moderate clinical changes were found in the symptom scales-fatigue, nausea and vomiting, insomnia, constipation and diarrhoea of QLQ C30 and stool frequency, embarrassment with bowel function, impotence and dyspareunia. These parameters returned to almost the pre-treatment values after 4weeks of completion of NACRT. Since QoL is a relatively subjective variable, differences in human race, culture, education and social environment will have impacts on the results. International cooperation is needed to study the QoL in patients with multiple cultural backgrounds. The existing QoL questionnaire tools have been designed with Western countries in mind, and we did face multiple social issues. We suggest that many similar multicentre studies shall be required to essentially tap the accurate QoL-related issues keeping in mind the diverse social, economic, racial and educational backgrounds. As we deal with the ever-increasing cancer menace and better life expectancy, QoL issues shall be a major determinant of treatment success besides primary treatment. These factors should form an integral part of treatment modality, and adequate counselling must be performed prior to initiation of care.

Role of Oxaliplatin in the Neoadjuvant Concurrent Chemoradiotherapy in Locally Advanced Rectal Cancer: a Review of Evidence.

The treatment of locally advanced rectal cancer (LARC) is a challenging situation for radiation oncologists and colorectal surgeons. Most current approaches recommend neoadjuvant fluorouracil or capecitabine-based chemoradiotherapy followed by surgery as a standard of care. Intensification of concurrent chemotherapy by adding oxaliplatin to fluorouracil or capecitabine backbone to get better outcomes is the matter that has remained unresolved. In this review, we searched Medline and Google Scholar databases and selected 28 prospective phase II and III clinical trials that addressed this question. We discussed the potential advantages and drawbacks of incorporating oxaliplatin into concurrent chemoradiation therapy. We tried to define whether adding oxaliplatin to concurrent chemoradiation with excellent performance and high-risk features benefits some subpopulations. The available literature suggests that by adding oxaliplatin there are some benefits in enhancing response to neoadjuvant chemoradiotherapy, however, without any translated improvements in long-term outcomes including overall and disease-free survival.

Correlation of maintenance chemotherapy and improved survival in patients with locally advanced unresectable pancreatic head adenocarcinoma receiving neoadjuvant chemotherapy and concurrent chemoradiotherapy

Correlation of maintenance chemotherapy and improved survival in patients with locally advanced unresectable pancreatic head adenocarcinoma receiving neoadjuvant chemotherapy and concurrent chemoradiotherapy

Predictive Value of the Interaction between CEA and Hemoglobin in Neoadjuvant CCRT Outcomes in Rectal Cancer Patients.

The adoption of neoadjuvant concurrent chemoradiotherapy (CCRT) has reshaped the therapeutic landscape, but response prediction remains challenging. This study investigates the interaction between pre-CCRT carcinoembryonic antigen (CEA) and post-CCRT hemoglobin (Hb) levels in predicting the response of locally advanced rectal cancer (LARC) to CCRT. Retrospective data from 93 rectal cancer patients receiving neoadjuvant CCRT were analyzed. Univariate analyses assessed clinical factors associated with tumor regression grade (TRG) and T-stage outcomes. Machine learning identified predictive biomarkers. Interaction effects between CEA and Hb were explored through subgroup analyses. Post-CCRT Hb varied between pre-CCRT CEA groups. The interaction between pre-CCRT CEA and post-CCRT Hb influenced TRG. Males with normal pre-CCRT CEA and anemia showed better treatment responses. Females with elevated pre-CCRT CEA and post-CCRT anemia exhibited poorer responses. The interaction effect between them was significant, indicating that their relationship with TRG was not additive. Inflammatory biomarkers, WBC, neutrophil count, and post-CCRT platelet level correlated with CCRT response. Contrasting with previous findings, anemia was a predictor of better treatment response in males with normal pre-CCRT CEA. The interaction between pre-CCRT CEA and post-CCRT Hb levels predicts the response of LARC to CCRT. CEA, Hb, and sex should be considered when assessing treatment response. Inflammatory biomarkers contribute to response prediction. Understanding these complex relationships can enhance personalized treatment approaches in rectal cancer patients.

Effect of Neoadjuvant Concurrent Chemoradiation on Operability and Survival in Locally Advanced Inoperable Breast Cancer

PurposeInoperable locally advanced breast cancers (LABC) are treated with neoadjuvant chemotherapy (NACT). We studied the use of neoadjuvant concurrent chemoradiation (NACCRT) in patients with inoperable LABC. Patients and MethodsFrom May 2017 to Dec 2021, the study recruited patients with Stage III inoperable LABC. The treatment included 4 cycles of Adriamycin and Cyclophosphamide and 4 cycles of Paclitaxel, along with concurrent radiotherapy to a total dose of 46 Gy. Thereafter, all patients were evaluated for surgery, and additional treatments were given based on receptor status. The effects of NACCRT on the pathological complete response (pCR), operability, and survival were analyzed. ResultsThe study involved 202 female patients with a median age of 52 years. Of these, 23.7% had IIIA, 65.3% had IIIB, and 10.8% had IIIC disease. Hormone-receptor (HR) positive disease was observed in 44.6% of patients, triple-negative breast cancer (TNBC) in 24.8%, and HER2-positive disease in 30.7%. Modified radical mastectomy (MRM) was performed in 88.1% of patients, 8.5% remained inoperable, and 3.4% declined surgery. Among the patients who underwent MRM, 36.5% of patients had a pCR. Patients who were operable and underwent MRM had complete resections and had negative margins. pCR was observed in 16% with HR-positive disease, 45.6% with TNBC, and 60.7% with HER2-positive disease. Grade 3 skin reactions were observed in 19.3%. Postoperative wound morbidity requiring hospitalization was observed in 10.6% of patients.After a median follow-up of 42 months, the 4-year EFS and OS were 63.4% and 71.5%, respectively. HER2-positive patients who achieved pCR had significantly improved EFS and OS. ConclusionsOur study shows that using NACCRT can improve operability and survival outcomes in patients with inoperable LABC.

Neoadjuvant Chemotherapy With/Without Radiotherapy for Locally Advanced Rectal Cancer: A Nationwide Retrospective Cohort Study.

The role of neoadjuvant radiotherapy in the management of patients with locally advanced rectal cancer (LARC) who have undergone neoadjuvant systemic therapy has been the subject of recent debate. We identified eligible rectal cancer patients diagnosed between 2011 and 2020 using data from the Taiwan Cancer Registry. In our primary analysis, we applied propensity score weighting (PSW) to balance observable potential confounders. We then compared the hazard ratio (HR) of death the neoadjuvant concurrent chemoradiotherapy (nCCRT) group and the neoadjuvant chemotherapy without radiotherapy (nCT) group. Additionally, we conducted a comprehensive assessment of other outcomes and performed various supplementary analyses. The primary analysis included 2,298 patients. The overall survival did not exhibit statistically significant differences, with a PSW-adjusted HR of 0.72 (95% confidence interval=0.33-1.56, p=0.40) when comparing the nCCRT group to the nCT group. These findings were consistent with those of other long-term outcomes and supplementary analyses. In patients with LARC who have undergone neoadjuvant systemic therapy, the addition of radiotherapy did not yield statistically significant differences in long-term clinical outcomes.

Immune changes in hilar tumor draining lymph nodes following node sparing neoadjuvant chemoradiotherapy of localized cN0 non-small cell lung cancer

BackgroundWhile much progress has been accomplished in the understanding of radiation-induced immune effects in tumors, little is known regarding the mechanisms involved at the tumor draining lymph node (TDLN) level. The objective of this retrospective study was to assess the immune and biological changes arising in non-involved TDLNs upon node sparing concurrent chemoradiotherapy (CRT) of non-small cell lung cancer (NSCLC) tumors.MethodsPatients with proven localized (cN0M0) NSCLC, treated by radical surgery plus lymph node dissection with (CRT+) or without (CRT-) neoadjuvant chemoradiotherapy, whereby radiotherapy was targeted on the primary tumor with no significant incidental irradiation of the non-involved TDLN station (stations XI), were identified. Bulk RNA sequencing of TDLNs was performed and data were analyzed based on differential gene expression (DGE) and gene sets enrichment.ResultsSixteen patients were included and 25 TDLNs were analyzed: 6 patients in the CRT+ group (12 samples) and 10 patients in the CRT- group (13 samples). Overall, 1001 genes were differentially expressed between the two groups (CRT+ and CRT-). Analysis with g-profiler revealed that gene sets associated with antitumor immune response, inflammatory response, hypoxia, angiogenesis, epithelial mesenchymal transition and extra-cellular matrix remodeling were enriched in the CRT+ group, whereas only gene sets associated with B cells and B-cell receptor signaling were enriched in the CRT- group. Unsupervised dimensionality reduction identified two clusters of TDLNs from CRT+ patients, of which one cluster (cluster 1) exhibited higher expression of pathways identified as enriched in the overall CRT+ group in comparison to the CRT- group. In CRT+ cluster 1, 3 out of 3 patients had pathological complete response (pCR) or major pathological response (MPR) to neoadjuvant CRT, whereas only 1 out of 3 patients in the other CRT+ cluster (cluster 2) experienced MPR and none exhibited pCR.ConclusionNeoadjuvant node sparing concurrent CRT of NSCLC patients is associated with distinct microenvironment and immunological patterns in non-involved TDLNs as compared to non-involved TDLNs from patients with non-irradiated tumors. Our data are in line with studies showing superiority of lymph node sparing irradiation of the primary tumor in the induction of antitumor immunity.

Predicting Treatment Response of Esophageal Cancer Treated by Concurrent Chemoradiotherapy Using Pre- and Posttreatment 18F-FDG PET Metabolic Characteristics.

This study hypothesizes that metabolic characteristics of esophageal tumors can be used to predict treatment response, which considers changes in the primary tumor and lymph nodes, for patients receiving neoadjuvant concurrent chemoradiotherapy (CCRT). This study retrospectively included 60 esophageal cancer patients receiving CCRT followed by surgery. All patients received 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) examinations prior to CCRT and in the interval between CCRT and surgery. On the pre-treatment FDG PET/CT images, the maximum standardized uptake value (SUVMaxPre) within the primary tumor was identified. By computerized methods, the CT images of pre- and post-treatment FDG PET/CT were registered. Then, the coordinates of SUVMaxPre were transformed to the post-treatment FDG PET images and delineated a sphere with a diameter of 5 cm to indicate the tumor position. After excluding air, the sphere was partitioned into several metabolic volumes by the optimal dichotomy of high and low metabolic FDG uptakes. Finally, the volume with the shortest distance to the center was adopted and represented by the maximum standardized uptakes (SUVMaxPost). Two additional features, SUVDiff and SUVDiffR, were defined as SUVMaxPost - SUVMaxPre and (SUVMaxPost - SUVMaxPre) / SUVMaxPre. Besides, for defining treatment response, the patients with and without residual tumors were defined as ypT+ and ESOCR based on the histopathology results of surgery. The ESOCR was further classified into pCR to indicate the absence of lymph node metastasis and LNM for remaining. Finally, the area under the receiver operating characteristic curve analysis (AUC) was conducted to assess the features' ability to differentiate two treatment responses. Kruskal-Wallis test was used to evaluate the differences in features between treatment responses. Of the 60 patients, 55 were men (92%), and the mean age was 58. The number of tumors at the esophagus's upper, middle, and lower third were 8, 18, and 34, respectively. Ninety-eight percent of the tumors were squamous cell carcinomas (59/60). The patient numbers of ypT+ and ESOCR were 43 and 17 of which contained 13 pCR and 4 LNM. The SUVDiff and SUVDiffR exhibited a significant ability to identify the ESOCR with AUC = .337 (p = .05) and AUC = .290 (p = .012), respectively. In addition, a statistically significant difference was found among the three groups of ypT+, pCR, and LNM on SUVMaxPre (H = 6.252 and p = .044), SUVDiff (H = 7.948 and p = .019), and SUVDiffR (H = 8.405 and p = .015). In the post-hoc tests corrected by the Bonferroni, the difference between ypT+ and LNM was significant on these features. The metabolic characteristics extracted from pre- and post-treatment FDG PET/CT images could indicate treatment response and disease progression. Further studies are warranted.

Impact of Neoadjuvant Concurrent Chemoradiation (NACCRT) on Operability and Survival in Locally Advanced Inoperable Breast Cancer

Inoperable locally advanced breast cancers (LABC) are treated with neoadjuvant chemotherapy (NACT). However, many patients remain inoperable after NACT due to an inadequate response. We, therefore, investigated the role of neoadjuvant concurrent chemoradiation (NACCRT) in this setting. Patients with inoperable Stage III LABC were prospectively recruited in the study between May 2017 and December 2021. NACT consisted of 4 cycles of q3weekly Adriamycin (60 mg/m2) and Cyclophosphamide (600mg/m2), and 4 cycles of q3weekly Paclitaxel (175 mg/m2). Concurrent radiotherapy with 6 MV X-rays was given using a 3D conformal technique to a total dose of 46 Gy (2 Gy/fraction, 5 days/week) to the involved breast, axilla, supraclavicular fossa, and internal mammary chain (upper 3 intercostal spaces) along with the first two cycles of paclitaxel. A 0.5 cm bolus was used to boost the skin till the appearance of hyperpigmentation. All patients were assessed for surgery after the completion of the planned neoadjuvant treatment. Adjuvant treatments were given based on the receptor status. The impact of neoadjuvant CTRT on the pathological complete response (pCR), operability, and survival was analyzed. Event-free survival (EFS) and Overall Survival (OS) were analyzed using the Kaplan-Meier method. The study enrolled 202 female patients with a median age of 52 years, with 23.7% having IIIA, 65.3% IIIB, and 10.8% having IIIC disease. Hormone-receptor (HR) positive disease was observed in 90/202 (44.6%) patients, triple-negative (TNBC) in 50/202 (24.8%) and Her2/neu positive in 62/202 (30.7%) patients. Modified radical mastectomy was performed in 88.1% of patients, with 8.5% remaining inoperable and 3.4% declining surgery due to clinical complete response (cCR). Among the patients who underwent MRM, 65/178 (32.2%) patients had a pCR. pCR was observed in 13/81 (16%) with HR-positive disease, 21/46 (45.6%) with TNBC, and 31/51 (60.7%) patients with Her2/neu-positive disease. Grade 3 skin reactions were observed in 39/202 (19.3%). Postoperative wound morbidity requiring hospitalization was observed in 19/178 (10.6%) patients. The median follow-up was 42 months, with 4-year EFS and OS of 63.8% and 71.5%, respectively. Six out of 7 patients who were in cCR and declined surgery are alive and remain in cCR. On subgroup analysis of Her 2 positive patients, pCR was significantly associated with improved EFS and OS (89.8% vs 33.3%, p = 0.001 and 89.1% vs 44.4%, p = 0.001 respectively). Our study demonstrates the feasibility and efficacy of NACCRT in improving operability, pCR rates and survival outcomes in patients with inoperable LABC. The results suggest that NACCRT can be considered for use in clinical practice with careful patient selection. These findings contribute to the ongoing efforts to optimize treatment for this patient population and warrant further investigation in larger, randomized trials.

A Prospective Study of Bevacizumab and Neoadjuvant Concurrent Chemoradiation in Locally Advanced Esophageal Squamous Cell Carcinoma: Paradoxical Increase in Circulating Vascular Endothelial Growth Factor-A and Effect on Outcome

In the prior prospective biomarker study, high serum vascular endothelial growth factor-A (VEGF-A) was associated with a poor prognosis. We conducted a prospective phase II trial of adding Bevacizumab, an anti-VEGF-A monoclonal antibody, to neoadjuvant concurrent chemoradiation (neoCCRT) for patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). This prospective biomarker study aims to evaluate the expressions of angiogenesis-associated circulating biomarkers before and after neoCCRT and compare clinical outcomes for patients receiving platinum/5-fluorouracil (PF) with or without Bevacizumab. Patients with biopsy-proven resectable non-T4 LA-ESCC were enrolled for the prospective phase II trial investigating PF-neoCCRT plus Bevacizumab (BPF group). A parallel patient cohort enrolled in a prospective biomarker study receiving PF-neoCCRT was included in the present analysis as the control group (PF group). Radiotherapy was delivered with 40 Gy in 20 fractions. All patients had restaging workups after enoCCRT and underwent radical esophagectomy if the disease remained resectable. Serums were collected before and after neoCCRT. The serum concentrations of angiogenesis-associated biomarkers were determined by the multiplex enzyme-linked immunosorbent assay. Survival analyses were performed by the Kaplan-Meier method. The t-test and log-rank test were used to compare differences in biomarker expression and survival between groups. From 2016 to 2019, 43 patients (BPF/PF group: 21/22) were enrolled in the study. Twenty patients in each group had serum samples available for biomarker analysis. 15 out of 21 patients in the BPF group and 20 out of 22 patients in the PF group underwent radical esophagectomy. Six patients in the BPF group and nine patients in the PF group achieved pathological complete responses. The median overall survival for the BPF and PF group was 20.8 months and not-reached, respectively (hazard ratio = 1.33, long rank p = 0.58). In the BPF group, the serum VEGF-A level was significantly increased from an average value of 446 pg/mL to 723 pg/mL after neoCCRT (p = 0.037), while its level was decreased from 815 ng/mL to 380 pg/mL in the PF group (p = 0.104). In addition, the expression value of circulating Angiopoietin-1 was not changed in the BPF group (before neoCCRT, mean value = 828 pg/mL; after neoCCRT, mean value 762 pg/mL, p = 0.67). In contrast, serum Angiopoietin-1 level was reduced from an average value of 659 pg/mL before neoCCRT to 271 pg/mL after neoCCRT (p = 0.002) in the PF group. The addition of Bevacizumab to PF-neoCCRT did not improve pathological or survival outcomes in patients with resectable LA-ESCC. Adding a single dose of Bevacizumab paradoxically increases circulating VEGF-A while maintaining the Angiopoietin-1 serum level after neoCCRT. Further investigation by using additional VEGF-A inhibition may be required to achieve sustained angiogenesis blocked for tumor control.

Long-Term Outcomes and Toxicity in Esophageal Cancer Patients after Neoadjuvant or Definitive Concurrent Chemotherapy with Proton Beam Therapy

Proton-beam therapy (PT) is increasingly utilized over three dimensional-conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) photon irradiation for the treatment of various malignancies due to better toxicity reduction. We investigated the long-term outcomes and toxicity in esophageal cancer (EC) patients treated with PT as part of their neoadjuvant concurrent chemoradiation followed by surgery (nCRT) or definitive concurrent chemoradiation (dCRT) treatment regimen. All consecutively treated, American Joint Committee on Cancer 7th edition clinical stage I-IV EC patients from 2006 to 2022 were retrospectively analyzed. Standard RT dose for most patients was 50.4 Gy/28 fractions. nCRT patients had surgery within 4 months post-RT. Kaplan-Meier method was used to determine overall survival (OS), locoregional recurrence-free survival (LRRFS) and distant metastatic-free survival (DMFS). Acute and chronic RT-related toxicities were graded with Common Terminology Criteria for Adverse Events version 4.0. There were 510 EC PT patients: 204 (40%) had nCRT and 306 (60%) had dCRT. Most lesions were located in the lower esophagus, of adenocarcinoma histology and treated with passive scatter PT. Overall median follow-up was 72 months. Median, 3- and 5-year OS for all patients were 43 months, 54.1% and 44.9%, respectively. Median LRRFS and DMFS were not reached. Esophagitis was the most common grade ≥3 (G3+) toxicity (59 patients; 28.9%, including a G4 and a G5 toxicity), followed by nausea (29 patients; 14.2%) and esophageal stricture (26 patients, 12.7%). With nCRT, median, 3- and 5-year OS were 80 months, 64.7% and 56.1%, respectively, while the median LRRFS and DMFS were not reached again. Their most common G3+ toxicity was esophagitis in 14 patients (6.9%) followed by nausea (8 patients; 3.9%). An nCRT patient developed G4 RT pneumonitis. Pathological complete response (pCR) was observed in 58 patients (28.4%). Surgery-related pulmonary, cardiac and gastrointestinal complications were reported in 38 (18.6%), 40 (19.6%) and 43 (21.1%) patients, respectively. dCRT patients had a median follow-up of 65 months, and median, 3- and 5-year OS of 32 months, 46.7% and 37.0%, respectively. Although the median LRRFS was not reached, the median DMFS was 74 months. The most observed dCRT G3+ toxicity was esophagitis (45 patients, 22.1%: including both G4 and G5 patients) and then esophageal stricture (23 patients, 11.3%). A dCRT patient developed G4 fistula. To our knowledge, this is the largest single-institutional study on EC long-term outcomes and toxicity using PT. Our cohort reveals good outcomes and mostly mild CRT-related toxicities. Trimodality nCRT with protons demonstrates excellent outcomes relative to the CROSS trial (49.4 months) with identical pCR rate (29% in CROSS) and similar toxicity profile. nCRT with protons should be studied rigorously in the current randomized phase III trial NRG GI006.