Neoadjuvant Radiotherapy Research Articles

A CT-based radiomics classification model for the prediction of histological type and tumour grade in retroperitoneal sarcoma (RADSARC-R): a retrospective multicohort analysis

Retroperitoneal sarcomas are tumours with a poor prognosis. Upfront characterisation of the tumour is difficult, and under-grading is common. Radiomics has the potential to non-invasively characterise the so-called radiological phenotype of tumours. We aimed to develop and independently validate a CT-based radiomics classification model for the prediction of histological type and grade in retroperitoneal leiomyosarcoma and liposarcoma. A retrospective discovery cohort was collated at our centre (Royal Marsden Hospital, London, UK) and an independent validation cohort comprising patients recruited in the phase 3 STRASS study of neoadjuvant radiotherapy in retroperitoneal sarcoma. Patients aged older than 18 years with confirmed primary leiomyosarcoma or liposarcoma proceeding to surgical resection with available contrast-enhanced CT scans were included. Using the discovery dataset, a CT-based radiomics workflow was developed, including manual delineation, sub-segmentation, feature extraction, and predictive model building. Separate probabilistic classifiers for the prediction of histological type and low versus intermediate or high grade tumour types were built and tested. Independent validation was then performed. The primary objective of the study was to develop radiomic classification models for the prediction of retroperitoneal leiomyosarcoma and liposarcoma type and histological grade. 170 patients recruited between Oct 30, 2016, and Dec 23, 2020, were eligible in the discovery cohort and 89 patients recruited between Jan 18, 2012, and April 10, 2017, were eligible in the validation cohort. In the discovery cohort, the median age was 63 years (range 27-89), with 83 (49%) female and 87 (51%) male patients. In the validation cohort, median age was 59 years (range 33-77), with 46 (52%) female and 43 (48%) male patients. The highest performing model for the prediction of histological type had an area under the receiver operator curve (AUROC) of 0·928 on validation, based on a feature set of radiomics and approximate radiomic volume fraction. The highest performing model for the prediction of histological grade had an AUROC of 0·882 on validation, based on a radiomics feature set. Our validated radiomics model can predict the histological type and grade of retroperitoneal sarcomas with excellent performance. This could have important implications for improving diagnosis and risk stratification in retroperitoneal sarcomas. Wellcome Trust, European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group, the National Institutes for Health, and the National Institute for Health and Care Research Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research.

A Modified NAR Scoring Model Incorporating Immune Infiltration Characteristics to Better Predict Long-Term Survival Following Neoadjuvant Radiotherapy in Rectal Cancer.

(1) Background: The neoadjuvant rectal (NAR) score has been developed as a prognostic tool for survival in locally advanced rectal cancer (LARC). However, the NAR score only incorporates weighted cT, ypT, and ypN categories. This long-term follow-up study aims to modify a novel prognostic scoring model and identify a short-term endpoint for survival. (2) Methods: The prognostic factors for overall survival (OS) were explored through univariate and multivariate analyses. Based on Cox regression modeling, nomogram plots were constructed. Area under the curve (AUC) and concordance indices were used to evaluate the performance of the nomogram. Receiver operating characteristic (ROC) analysis was conducted to compare the efficiency of the nomogram with other prognostic factors. (3) Results: After a long-term follow-up, the 5-year OS was 67.1%. The mean NAR score was 20.4 ± 16.3. Multivariate analysis indicated that CD8+ T-cell, lymphovascular invasion, and the NAR score were independent predictors of OS. The modified NAR scoring model, incorporating immune infiltration characteristics, exhibited a high C-index of 0.739 for 5-year OS, significantly outperforming any individual factor. Moreover, the predictive value of the nomogram was superior to the AJCC stage and pathological complete regression at 3-year, 5-year, and 10-year time points, respectively. Over time, the model's predictions of long-term survival remained consistent and improved in accuracy. (4) Conclusions: The modified NAR scoring model, incorporating immune infiltration characteristics, demonstrates high accuracy and consistency in predicting OS.

Great Debate: Chemoradiation Should be Added to Chemotherapy as a Neoadjuvant Treatment Strategy for Resectable Gastric Adenocarcinoma.

Most patients with resectable gastric cancer present with locally advanced disease and warrant neoadjuvant chemotherapy based on level 1 evidence. However, the incremental benefit of adding radiation to chemotherapy as a neoadjuvant treatment strategy for these patients is less clear. While awaiting the results of two ongoing randomized clinical trials attempting to specifically address this question (TOPGEAR and CRITICS-II), this article presents the debate between two gastric cancer surgery experts supporting each side of the argument on the use or omission of neoadjuvant radiation in this setting. On the one hand, neoadjuvant radiation may be better tolerated compared with modern triplet chemotherapy and may be associated with higher rates of major pathologic response. Additionally, there is evidence to suggest that radiation may offer a survival benefit when the tumor is located at the gastroesophageal junction or there is concern for a margin-positive resection. However, in the setting of adequate surgery, no survival benefit has been demonstrated by adding radiation to modern chemotherapy, likely reflecting the fact that death from gastric cancer is a result of distant recurrence, which is not addressed by local treatment such as radiotherapy. While awaiting the results of the TOPGEAR and CRITICS-II trials, this discussion of current evidence can facilitate the refinement of an optimal neoadjuvant therapy strategy in patients with resectable gastric cancer.

Novel Tumor Organoid-Based Mouse Model to Study Image Guided Radiation Therapy of Rectal Cancer After Noninvasive and Precise Endoscopic Implantation

PurposePreoperative (neoadjuvant) radiation therapy (RT) is an essential part of multimodal rectal cancer therapy. Recently, total neoadjuvant therapy (TNT) which combines simultaneous radio-chemotherapy with additional courses of chemotherapy (CTx) has emerged as an effective approach. TNT achieves a pathological complete remission in approximately 30% of resected patients, opening avenues for treatment strategies that avoid radical organ resection. Furthermore, recent studies have demonstrated that anti-PD-1 immunotherapy (IT) can induce clinical complete responses in patients with specific genetic alterations. Overall, there is significant potential to enhance outcomes through intensifying, personalizing, and de-escalating treatment approaches. However, the heterogeneous response rates to RT or TNT and strategies to sensitize patients without specific genetic changes to IT remain poorly understood. Materials and MethodsWe developed a novel orthotopic mouse model of rectal cancer which is based on precisely defined endoscopic injections of tumor organoids that reflect tumor heterogeneity. Subsequently, we employed endoscopic- and computed tomography-guided RT, and validated rectal tumor growth and response rates to therapy using small animal magnetic resonance imaging and endoscopic follow-up. ResultsRectal tumor formation was successfully induced in all mice following two organoid injections. Clinically relevant RT regimens with 5 × 5 Gy significantly delayed clinical signs of tumor progression and significantly improved survival. Consistent with human disease, rectal tumor progression correlated with the development of liver and lung metastases. Notably, longterm survivors after RT showed no evidence of tumor recurrence, as demonstrated by in vivo radiological tumor staging and histopathological examination. ConclusionsOur novel mouse model combines orthotopic tumor growth via non-invasive and precise rectal organoid injection and small animal RT. This model holds significant promise for investigating the impact of tumor cell-intrinsic aspects, genetic alterations of the host, or exogenous factors (e.g., nutrition or microbiota) on RT outcomes. Furthermore, it allows for the exploration of combination therapies involving CTx, IT or novel targeted therapies.

Survival outcomes of different neoadjuvant treatment regimens in patients with locally advanced rectal cancer and MRI-detected extramural venous invasion.

MRI-detected extramural venous invasion (mrEMVI) is associated with poor survival outcomes in patients with locally advanced rectal cancer (LARC). An mrEMVI-positive status is considered a strong indication for neoadjuvant treatment, but the optimal regimen is unknown. We retrospectively compared pathological and survival outcomes of 584 patients diagnosed with mrEMVI-positive rectal cancer between January 2013 and October 2021, and receiving either neoadjuvant chemotherapy (NCT) alone, neoadjuvant chemoradiotherapy (nCRT) alone, or nCRT plus NCT, prior to total mesorectal excision. Propensity score matching (PSM) was used to balance clinical bias between groups, which were compared using chi-square testing and Kaplan-Meier curves. Median follow-up was 33.9 (range, 10.2-100.4) months. The 3-year overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS) rates for all patients were 90.4%, 57.5%, 61.1%, and 85.7%, respectively. Of 584 mrEMVI-positive patients at the time of diagnosis, 457 (78.3%) were EMVI-negative on surgical pathology, and they had significantly better 3-year OS, DMFS, DFS, and LRFS rates (all p < 0.001) than patients who remained EMVI-positive. After PSM was applied, patients receiving nCRT alone had significantly better 3-year OS (96.8% vs. 86.5%, p = 0.005) and DMFS (67.1% vs. 53.5%, p = 0.03) rates than those receiving NCT alone. Patients receiving NCT plus nCRT had higher pathological complete response (PCR) (10.8% vs. 2.7%, p = 0.04) and downstaging (33.8% vs. 5.3%, p < 0.001) rates than those receiving nCRT alone, but survival rates did not differ (all p > 0.05). Most EMVI-positive patients with LARC converted to EMVI-negative after neoadjuvant treatment, resulting in improved OS and DFS. Patients receiving nCRT had more favorable survival outcomes than those receiving NCT, suggesting the importance of including neoadjuvant radiotherapy. Patients receiving NCT in addition to nCRT had higher rates of PCR and downstaging, but their survival rates were not better.

Challenges in the Management of Complex Soft-Tissue Sarcoma Clinical Scenarios.

With nearly 15,000 new cases of soft-tissue sarcoma (STS) in the United States each year, early diagnosis and therapeutic management is imperative for successful patient outcomes. Primary STS is conventionally treated with a combination of wide-margin resection, neoadjuvant or adjuvant radiation therapy, and, in specific cases, adjuvant chemotherapy. However, in situations of complex disease presentation, guidelines for treatment are less clearly outlined. Limited metastatic disease, local recurrence, fungating STSs, and unplanned or incomplete resections of STSs present unique challenges for the multidisciplinary care team. The management of complex STS clinical scenarios usually involves limb-salvage resection or amputation as well as some combination of radiation therapy and/or ablative interventional radiology techniques. As a result, a multidisciplinary team approach is essential for treating patients in these challenging scenarios, with a recent focus on the integration of plastic and reconstructive surgery into the treatment algorithm.

Multi-institutional review of adverse events associated with irreversible electroporation in the treatment of locally advanced pancreatic cancer

BackgroundIrreversible electroporation is a novel approach for treating locally advanced pancreatic adenocarcinoma. However, this ablative technique is not without risk and has the potential to precipitate adverse events. The aim of this study was to delineate risk factors that increase this risk, as well as to elucidate the risk profile associated with irreversible electroporation in the setting of locally advanced pancreatic adenocarcinoma. MethodsA review of our prospective multi-institutional database from December 2015 to March 2022 of patients with locally advanced pancreatic adenocarcinoma who underwent irreversible electroporation was analyzed for adverse events. These were then compared with a control population of patients undergoing pancreatectomy for adenocarcinoma. ResultsAdverse events occurred in 51 patients of the 201 patients treated with irreversible electroporation compared with 78 of the 200 patients treated with pancreatectomy. The irreversible electroporation group had a significantly greater incidence of postoperative ascites in stage 3C patients. The most common complications in the irreversible electroporation group were infectious (n = 13), gastrointestinal bleed (n = 11), and ascites (n = 7). Multivariate analysis demonstrated increased risk of severe (grade ≥3) adverse events in the irreversible electroporation cohort who received high dose, neoadjuvant radiation (hazard ratio, 2.4; 95% confidence interval, 1.4–5.4), irreversible electroporation electrodes bracketing the superior mesenteric artery, superior mesenteric vein, and portal venous vein (hazard ratio, 1.9; 95% confidence interval, 1.3–3.4), and who had a bile duct stent in place for >6 months (hazard ratio, 1.7; 95% confidence interval, 1.2–5.6). There were similar rates of 90-day mortality in both groups, irreversible electroporation 2.4% vs pancreatectomy 2.8%. ConclusionThis study revealed a 25% rate of adverse events associated with irreversible electroporation in locally advanced pancreatic adenocarcinoma, which was significantly less (P = .004) than the 39% rate of adverse events associated with pancreatectomy in early-stage disease. Certain unique adverse events in the irreversible electroporation group have been established and should be understood in the care of these patients.

ASO Author Reflections: A Role for Neoadjuvant Radiation in the Treatment of Locally Advanced Gastric Cancer?

ASO Author Reflections: A Role for Neoadjuvant Radiation in the Treatment of Locally Advanced Gastric Cancer?

Évaluation de facteurs prédictifs de réponse pathologique à la radiothérapie néoadjuvante des sarcomes des tissus mous

PurposeConserving surgery combined with radiotherapy in presence of local recurrence risk factors is standard treatment of soft tissue sarcomas, a group of rare and heterogeneous tumours. Radiotherapy is performed before or after surgery. In neoadjuvant setting, late radiation-induced toxicity is reduced and pathological response to radiotherapy could be achieved. A complete pathological response to radiotherapy has recently been shown to predict better survival. Our study aims at identifying predictive factors of pathological response to neoadjuvant radiotherapy (clinical, radiological or histological) of soft tissue sarcomas. Patients and methodsClinical, imaging (MRI: perilesional oedema, necrosis, tumour heterogeneity, vasculonervous relationships) and pathological (pathological subtype, tumour grade, anticipated/obtained resection quality) data were retrospectively collected. Tumour response (imaging and pathological), patient outcome, acute and late radiation-induced toxicity, predictive factors of pathological response to neoadjuvant radiotherapy were studied. The 2-test or exact-Fisher test (qualitative variables) and by Student's t-test or Kruskal-Wallis test (quantitative variables) were used for statistical analysis. ResultsFrom April 2017 to April 2021, neoadjuvant radiotherapy (50Gy in 25 fractions) followed by surgical excision was performed to 36 consecutive patients with liposarcomas (n=17/36), or undifferentiated sarcomas (n=8/36). MRI response was complete in 1 patient, partial in 9 patients (n=9/36, 25%), stable in 21 patients (n=21/36, 58%) or in progression in 5 patients (n=5/36, 14%). Pathological response was observed in 22 patients (61%). No grade 3-4 acute radiation-induced toxicity was observed. Regarding late toxicity, 28% of patients had grade 1–2 oedema (n=10/36), 39% had a grade 1 fibrosis (n=14/36), and 30% grade 1 pain (n=11/36). No predictive factors of response to radiotherapy was statistically significant. ConclusionsNeoadjuvant radiotherapy is well-tolerated. No clinical, radiological or pathological predictive factors was identified for radiotherapy tumour response.

Towards deep-learning (DL) based fully automated target delineation for rectal cancer neoadjuvant radiotherapy using a divide-and-conquer strategy: a study with multicenter blind and randomized validation

PurposeManual clinical target volume (CTV) and gross tumor volume (GTV) delineation for rectal cancer neoadjuvant radiotherapy is pivotal but labor-intensive. This study aims to propose a deep learning (DL)-based workflow towards fully automated clinical target volume (CTV) and gross tumor volume (GTV) delineation for rectal cancer neoadjuvant radiotherapy.Materials & methodsWe retrospectively included 141 patients with Stage II-III mid-low rectal cancer and randomly grouped them into training (n = 121) and testing (n = 20) cohorts. We adopted a divide-and-conquer strategy to address CTV and GTV segmentation using two separate DL models with DpuUnet as backend-one model for CTV segmentation in the CT domain, and the other for GTV in the MRI domain. The workflow was validated using a three-level multicenter-involved blind and randomized evaluation scheme. Dice similarity coefficient (DSC) and 95th percentile Hausdorff distance (95HD) metrics were calculated in Level 1, four-grade expert scoring was performed in Level 2, and head-to-head Turing test in Level 3.ResultsFor the DL-based CTV contours over the testing cohort, the DSC and 95HD (mean ± SD) were 0.85 ± 0.06 and 7.75 ± 6.42 mm respectively, and 96.4% cases achieved clinical viable scores (≥ 2). The positive rate in the Turing test was 52.3%. For GTV, the DSC and 95HD were 0.87 ± 0.07 and 4.07 ± 1.67 mm respectively, and 100% of the DL-based contours achieved clinical viable scores (≥ 2). The positive rate in the Turing test was 52.0%.ConclusionThe proposed DL-based workflow exhibited promising accuracy and excellent clinical viability towards automated CTV and GTV delineation for rectal cancer neoadjuvant radiotherapy.

Short-course radiation with consolidation chemotherapy does not increase operative morbidity compared to long-course chemoradiation: A retrospective study of the US rectal cancer consortium.

Neoadjuvant short-course radiation and consolidation chemotherapy (SC TNT) remains less widely used for rectal cancer in the United States than long-course chemoradiation (LCRT). SC TNT may improve compliance and downstaging; however, a longer radiation-to-surgery interval may worsen pelvic fibrosis and morbidity with total mesorectal excision (TME). A single, US-center retrospective analysis has shown comparable risk of morbidity after neoadjuvant short-course radiation with consolidation chemotherapy (SC TNT) and long-course chemoradiation (LCRT). Validation by a multi-institutional study is needed. The US Rectal Cancer Consortium database (2010-2018) was retrospectively reviewed for patients with nonmetastatic, rectal adenocarcinoma treated with neoadjuvant LCRT or SC TNT before TME. The primary endpoint was severe postoperative morbidity. Cohorts were compared by univariate analysis. Multivariable logistic regression modeled the odds of severe complication. Of 788 included patients, 151 (19%) received SC TNT and 637 (81%) LCRT. The SC TNT group had fewer distal tumors (33.8% vs. 50.2%, p < 0.0001) and more clinical node-positive disease (74.2% vs. 47.6%, p < 0.0001). The intraoperative complication rate was similar (SC TNT 5.3% vs. 4.4%, p = 0.65). There was no difference in overall postoperative morbidity (38.4% vs. 46.3%, p = 0.08). Severe morbidity was similar with low anterior resection (9.1% vs. 15.3%, p = 0.10) and abdominoperineal resection (24.4% vs. 29.7%, p = 0.49). SC TNT did not increase the odds of severe morbidity relative to LCRT on multivariable analysis (OR 0.64, 95% CI 0.37-1.10). SC TNT does not increase morbidity after TME for rectal cancer relative to LCRT. Concern for surgical complications should not discourage the use of SC TNT when aiming to increase the likelihood of complete clinical response.

LBA25 Neoadjuvant short-course radiotherapy followed by camrelizumab plus chemotherapy versus long-course chemoradiotherapy followed by chemotherapy in locally advanced rectal cancer: A randomized phase III trial (UNION)

LBA25 Neoadjuvant short-course radiotherapy followed by camrelizumab plus chemotherapy versus long-course chemoradiotherapy followed by chemotherapy in locally advanced rectal cancer: A randomized phase III trial (UNION)

A RARE CLINICAL CASE SERIES OF LEIOMYOSARCOMA OF SOFT TISSUE ORIGIN AT OUR INSTITUTE

Introduction:- LMS is a type of rare cancer that grows in the smooth muscles of the body. LMS is a aggressive cancer. LMS incidence is between 5-10% of soft tissues sarcoma cases and is more common in adults. It often present as an enlarging painless mass. Imaging with proper Biopsy and IHC aids in the diagnosis and management incudes a multidisciplinary approach. Objectives:- Due to rarity of this disease case series of LMS of soft tissue origin is documented here. Material and Methods:- 3 cases of primary LMS of soft tissue origin is documented in this case series along with history, imaging, diagnosis and treatment. 1. LMS of Lung – A 51 year old female patient presented with complaints of cough and difficulty in breathing since 3-4 months. Patient was planned with chemotherapy. 2. LMS of Pelvis – A 44 year old female patient presented in OPD with complaints of pain in leg due to nerve compression. Patient underwent surgery followed by which chemotherapy was given. 3. LMS of Pararenal Space – A 33 year old female presented with dull aching pain in left lumbar region since 2-3 months. Patient managed with surgery, chemotherapy and radiotherapy. Conclusion:- Due to rarity of the sites of LMS mentioned in the case series little is known about its clinical behaviour and treatment outcome. A multidisciplinary approach is needed for the optimal management of the disease. Surgery with a curative intent is the corner stone of treatment for localized disease along with the combination of neoadjuvant or adjuvant chemotherapy and radiotherapy. Due to its aggressive behaviour and rarity, further researches are required for the definitive treatment.

The Association of Time Interval between Surgery and Neoadjuvant Chemoradiation Therapy with pCR and Overall Survival for Locally Advanced Rectal Adenocarcinoma

To determine the best time interval between neoadjuvant radiation therapy (RT) and surgery that is associated with the highest rate of complete pathological response (pCR) and evaluate its impact on overall survival (OS) for locally advanced rectal adenocarcinoma. We hypothesize that the longer interval the higher pCR and a higher pCR is associated with a higher OS. The National Cancer Database (NCDB) was used to extract data on patients diagnosed with stage II and III adenocarcinoma of the anus, rectum, or rectosigmoid between 2004-2019 and who had ≤ 24 weeks' time interval between neoadjuvant RT and surgery. Multivariable logistic regression analysis was used to determine factors associated with achieving pCR and odds ratios (OR) were reported as a measure of association between the covariates of interest and the outcome of achieving pCR. Multivariable Cox regression analysis was conducted to estimate hazard ratios (HR) and their associated 95% confidence intervals. The multivariable analyses were adjusted for age at diagnosis, sex, race, income, education, facility type, insurance status, comorbidity score, place of living, chemotherapy's sequence with surgery and RT, and year of diagnosis. Among 28,656 patients, 4,455 (15.6%) achieved pCR. In the multivariable logistic regression analysis, patients who received surgery between 5-8 weeks, 9-12 weeks, 13-16 weeks, 17-20 weeks, or 21-24 weeks after the completion of RT were more likely to achieve pCR compared to < = 4 weeks (ORs: 1.63, 2.16, 1.82, 1.73, 1.75, respectively, p<0.001 for all) with OR being the highest for the 9-12 weeks interval. In the multivariable Cox regression analysis, patients who achieved pCR had comparable OS regardless of when the surgery took place between < = 4 to 24 weeks after completing RT compared to < = 4 weeks after RT. Among patients who did not achieve pCR, OS was only similar if surgery was received between 5-8 weeks or 9-12 weeks after RT compared to < = 4 weeks after RT (HR: 0.90, p = 0.19 and HR: 1.02, p = 0.78 respectively). However, surgery between 13-16 weeks after RT, 71-20 weeks or 21-24 weeks after RT was associated with worse OS compared to < = 4 weeks after RT (HRs: 1.30, 1.67, 1.79, respectively, p<0.01). In the current study, we found that among patients who achieve pCR, OS does not depend on the time interval between the completion of RT and receipt of surgery, while among patients who do not achieve pCR, delaying surgery >12 weeks is associated with reduced OS. An interval of 9-12 weeks was the best optimal time as it was associated with the highest OR of achieving pCR and better OS compared to other interval times.

Development of a Screening Nomogram for Regional Lymph Node Metastasis Development in Muscle Invasive Bladder Cancer after Multiagent Systemic Therapy

A reliable method of identifying clinically node negative bladder cancer patients at greater risk of developing lymph node metastasis and may require intensified therapy is needed. The purpose of this study was to create a nomogram to quantify the risk for regional lymphatic involvement in non-metastatic muscle invasive bladder cancer. Usingthe National Cancer Database, patients with clinical T2-4N0M0 urothelial carcinoma of the bladder between the years of 2004 - 2020 were selected. All patients completed multiagent chemotherapy followed by surgery for pathologic nodal staging to determine presence or absence of nodal disease. No neoadjuvant radiation therapy was allowed and patients with history of prior malignancies were excluded. Following a 70:30 training to testing data split, baseline variables were assessed using univariate logistic regression. Variables were selected for inclusion in the multivariate logistic regression model using a combination of previously reported findings in the literature and/or if found to have a p-value < 0.05 on univariate analysis. A nomogram was constructed using this final model with assessment using calibration plots and the area under the receiver operating characteristics curve (AUC), respectively. An empiric cut point was chosen at 95% sensitivity to identify patients at "high" and "low" risk for pathologic nodal disease with overall assessment in both cohorts using chi-square. A total of 6194patients were identified for study with a median age of 65 years (IQR = 58 - 71 years). Most patients were male (68.0%) with T2 disease (81.2%). The final multivariate model included age at time of diagnosis (OR = 0.99; 95% CI = 0.99 - 1.00; p = 0.172), time from diagnosis to initiation of chemotherapy (OR = 1.00; 95% CI = 1.00 - 1.01; p = 0.005), papillary histology (OR = 0.85; 95% CI = 0.72 - 1.01; p = 0.068), and clinical T stage (Table 1). Model calibration demonstrated excellent goodness-of-fit with good discrimination (AUC = 0.644). Within the training data, high risk patients were seen to have a twofold increase in pathologic nodal disease (N = 835/3924, 21.2%) when compared to those identified as low risk (N = 38/347, 9.9%) (p < 0.001). Validation within the testing data set demonstrated similar results with pathologic node rates of 22.8% and 7.8% for high- and low-risk patients, respectively (AUC = 0.645, p < 0.001). This study demonstrates a clinically applicable risk stratification tool for identifying patients at risk for developing lymphadenopathy in T2-4 bladder cancer and may help guide future research in selecting patients eligible for escalation of therapy. Future studies should aim to externally validate this tool within prospective cohorts, and seek to determine if this nomogram may provide further prognostic utility.

Neoadjuvant Radiation Therapy in the Treatment of Breast Cancer

Radiation therapy improves locoregional control and increases breast cancer patient's survival. Its neoadjuvant setting is a rarely used alternative that favors tumor resectability and, in addition, allows immediate breast reconstruction. This study aims to characterize locally advanced breast cancer patients that were treated with neoadjuvant radiotherapy (naRT), its indications and results. Medical records were reviewed retrospectively. All patients diagnosed with breast cancer treated with curative-intent naRT in a Chilean oncologic hospital between January 2017 and 2019 were included. Inflammatory breast cancer cases and sarcomas were excluded. We described demographic, clinical and treatment characteristics, naRT indications and outcomes. Information was collected from 112 patients (98% women) referred from 7 public hospitals. The median age was 57 years [28-85 years]. At diagnosis, 78% corresponded to clinical stage cT4b, and 83% had cN+ axilla (axillary biopsy was performed in 44 cases, 35 were positive). 53% were classified as luminal B, 19% as triple negative, 17% as luminal A, and 11% as HER2 enriched. 98% of patients began treatment with neoadjuvant systemic therapy (91 patients received chemotherapy and 19 patients hormone therapy). naRT indications were: immediate breast reconstruction in 23% and contraindication or unsatisfactory response to systemic therapy in 77%. In 99% of naRT the dose was 45-50 Gy to the breast/chest wall and peripheral lymphatics. 86% of patients underwent surgery (14 patients did not undergo surgery due to disease progression or because they refused surgery and 2 patients were on the waiting list at the time of follow up). Immediate breast reconstruction was performed in 31 patients with a median age of 45 years, all of them were derived from 2 referral centers that suggest this altered sequence of treatments. Surgical biopsies of 96 patients were reviewed: 13% had pathological complete response in the breast/chest wall, 55% in the axilla, and 12% at both levels. 30% of post-surgical complications were reported in the subgroup of patients who continued follow-up in our institution (total of 47 patients). With a median follow-up of 29 months, 18% of the patients had died from breast cancer. naRT is not only an option when systemic therapy is not a good alternative, but also favors resectability of locally advanced tumors making pathological complete response and immediate breast reconstruction possible in selected cases, obtaining an oncological and reconstructive objective in the same surgery.

Gamma Secretase Inhibition Sensitizes Pancreatic Adenocarcinoma Tumors to RT In Vivo

Pancreatic adenocarcinoma (PDAC) is an extremely aggressive cancer that lacks curative treatment options. Almost half of patients present with unresectable disease limiting treatment to non-curative options. Patients treated with neoadjuvant radiation therapy (RT) exhibit increases in fibrosis and epithelial-to-mesenchymal transition (EMT). ADAM10, an extracellular sheddase, can stimulate stromal fibrosis, EMT, and radioresistance. ADAM10 also mediates EMT through Notch signaling by cleaving its extracellular domain. Further cleavage by gamma secretase produces the Notch intracellular domain (NICD), which translocates to the nucleus and activates downstream transcriptional targets. Here, we explore whether inhibition of Notch cleavage by gamma secretase radiosensitizes PDAC tumors. Bilateral flank subcutaneous PDAC isografts were produced in 40 mice using PK5L1940 KPC cells. Intraperitoneal injections of the gamma secretase inhibitor, DAPT (5 mg/kg), were delivered daily for 7 days, starting 3 days prior to RT. A single dose of 20 Gy was administered to each flank tumor, and volumes were measured twice weekly. Colony formation assays of KPC cells were performed after RT, in the presence or absence of DAPT. Since stromal fibrosis can mediate radio-resistance in the tumor microenvironment (TME), the effect of tumor cells on Notch pathway activation in mouse fibroblasts (3T3 cells) was investigated using a luciferase reporter assay. Thus, 3T3 cells transfected with a Notch pathway luciferase reporter were incubated with PDAC cells for 48 h, followed by measurement of luciferase activity. In vivo, the combination of DAPT and RT significantly delayed tumor growth, and some tumors were completely eradicated. Mean tumor size for the combination at 21 days was 21 mm3 (range = 0-53, p = 0.005), while tumor size was 577 mm3 (range = 217-955, p = 0.69) for DAPT alone, 435 mm3 for RT alone (range = 51-932, p = 0.79), and 367 mm3 for untreated vehicle (range = 97-1144). Surprisingly, DAPT did not reduce clonogenic survival in vitro. Both ADAM10 knockout and DAPT decreased NICD cleavage and transcription of the downstream target Hes1 in vivo and in vitro. Co-culture with PDAC cells increased Notch luciferase reporter activity in fibroblasts. This effect was not mimicked by PDAC-conditioned media, suggesting a requirement for intercellular contact. Notch pathway inhibition sensitizes PDAC tumors to RT in vivo, but not in vitro, suggesting involvement of the TME. Indeed, co-culture with PDAC cells stimulates notch signaling in fibroblasts, suggesting non-cell autonomous mechanisms mediating fibrosis in the TME driving radioresistance. Future studies will determine if ADAM10 inhibition targeting PDAC cells and/or gamma secretase inhibition targeting the TME enhances radiation sensitivity in vivo by blocking fibroblast Notch signaling.

Neoadjuvant Stereotactic MR-Guided Ablative Radiation Therapy (SMART) and Surgical Outcomes in Patients with Pancreatic Cancer

The benefit of neoadjuvant radiation therapy for patients undergoing surgery for pancreatic ductal adenocarcinoma (PDAC) remains unclear. Stereotactic MR-guided adaptive radiation therapy (SMART) treatment to ablative doses is a newer technique that is well tolerated and has increased local control in unresectable pancreatic cancer. For resectable pancreatic cancer, neoadjuvant SMART has the potential to decrease local recurrence risk and positive margin rates. However, there is concern for perioperative risks associated with ablative dose treatments. We report the efficacy and safety of surgical resection in patients who have received neoadjuvant SMART at our institution. We conducted a retrospective analysis of all consecutive patients diagnosed with PDAC who had noted vascular involvement of the celiac axis, superior mesenteric, and/or portal vessels between January 2016 and December 2022 at a single, high-volume, academic institution. Perioperative events were defined according to the Clavien-Dindo classification. The Kaplan Meier method was applied to estimate disease free survival (DFS) and overall survival (OS). Seventeen patients with PDAC and vessel involvement at time of diagnosis who received SMART were included. Median follow-up time was 14.3 months; all patients underwent surgery, at a median time after radiation of 28 days (range: 15 - 90). Median length of postoperative stay was 7 days (range: 3 - 15). Five patients (29%) underwent vascular resection. Fifteen patients (88%) achieved R0 resection, with two R1 resections noted at the SMA and pancreatic neck respectively. Seven patients (41%) had adverse events attributable to surgery, with the majority being defined as abscess or infection (n = 5; 29%). One (6%) Clavien-Dindo grade III or higher toxicity was observed - a cortical cerebrovascular event following surgery. No major bleeding events requiring surgical intervention were noted. At time of event censorship, there were no observable locoregional failures. The median DFS and OS were not reached; however, 1-year DFS and OS were 62% and 87%, respectively. Neoadjuvant SMART appears to be safe, with low rates of surgical complications and promising outcomes. Further identification of patients for this approach requires additional investigation.

Association between Tumor Volume Change on MRI with Surgical Margin Status, Pathological Response, and Local Control Following Pre-Operative Radiation Therapy for Soft Tissue Sarcoma

The clinical significance of radiographic progression during pre-operative radiation therapy (RT) for soft tissue sarcoma (STS) remains unclear. We sought to evaluate associations between radiographic change on T1 post-contrast (T1c) and T2 weighted magnetic resonance imaging (MRI) with percent pathological response (PR%), positive surgical margins (+SM), and local control (LC). We retrospectively identified patients with STS undergoing neoadjuvant RT who had both pre- and post-RT MRI prior to surgical resection. Gross tumor volumes were contoured on pre- and post-RT T1c and T2 MRI sequences and relative change in volume from baseline was calculated. Radiographic classification was defined as response (>30% reduction), progression (>30% increase), or stable (≤30% reduction or ≤30% increase). Chi squared, Fishers Exact, and Kruskal Wallis (KW) tests were used to assess differences between groups. Linear and binary logistic regression models used to assess associations between MRI response and PR% and +SM, respectively. LC was modeled with Kaplan Meier methods and log rank tests. A total of 68 STS patients were identified, with a median follow up of 49 months (range 7-229). With a median age of 60.5 years (25-88) and tumor size of 10.8cm (2.7-25.7), the most common histologies were undifferentiated pleomorphic sarcoma (UPS; 32.4%) and myxoid liposarcoma (ML; 16.2%), and were primarily grade 2-3 disease (89.7%). With a median RT dose of 50 Gy in 25 fractions (44-60Gy), the median radiographic volume change was 2% (-86.4 to 953.6%) and -2.1% (-89.6 to 962.5%) for T1c and T2, respectively. Radiographic classification of response/stable/progression was 25.4%/49.2%/25.4% and 27.9%/52.5%/19.7% for T1c and T2, respectively. Histology (ML vs. UPS) and grade (1 vs. 3) were predictors for radiographic response on both T1c (72.7% vs 18.8%, p = 0.03 and 71.4% vs. 10.4%, p = 0.03) and T2 (71.5% vs. 18.2%, p = 0.02 and 71.4% vs. 14.6%, p = 0.002), respectively. With 6 +SM (8.8%), the rate of +SM for response/stable/progression was 20%/10.3%/0% in T1c (p = 0.2) and 5.9%/12.5%/0% in T2 (p = 0.5). As a continuous variable, neither relative change on T1c (p = 0.2) or T2 (p = 0.4) were associated with +SM. With an overall median PR% of 64% (0-100%), the median PR% was significantly different for response/stable/progression for both T1c (95%/42%/73%, p = 0.02) and T2 (95%/50%/87.5%, p = 0.04). Radiographic change on neither T1c (p = 0.4) or T2 (p = 0.5) were associated with PR% on a continuous basis. With a total of 4 local recurrences, there was no significant difference in LC by radiographic classification on either T1c (p = 0.65) or T2 (p = 0.85). While radiographic response may be correlated with pathological response, radiographic progression on either T1c or T2 following neoadjuvant RT was not associated with a detriment in surgical margins or local control. These findings suggest that STS radiographic "pseudoprogression" is not associated with worse outcome.

Effect of Interval between Neoadjuvant Chemotherapy and Radiation Therapy on Metastasis Risk for Inoperable Non-Metastatic Pancreatic Adenocarcinoma

In inoperable pancreatic cancer patients requiring radiotherapy (RT) after neoadjuvant chemotherapy (CT), there can be delays in starting radiation due to multiple complications. However, pancreatic cancer can progress rapidly during short intervals without treatment. We hypothesize that longer intervals between neoadjuvant chemotherapy and radiation could expediate the development of metastatic disease. We identified patients with inoperable non-metastatic borderline resectable or locally advanced pancreatic cancer treated with neoadjuvant CT followed by RT from 2011 to 2021 at a single institution. Patients who completed palliative RT as defined by a biologic effective dose (BED) of less than 50 Gy, or those who were lost to follow-up within 3 months after completing RT without documented disease progression were excluded. The interval between RT and CT was defined as the time between last date of CT administration and initiation of RT. The primary endpoint was metastasis-free survival (MFS) after RT completion. Differences in MFS between patients who started RT within or after 4, 6, and 8 weeks of completing CT were examined utilizing log rank analysis of MFS generated via the Kaplan-Meier method. At a median follow-up of 5.45 months, twenty-three patients were included. Most patients were male (61%) with cT4 (61%), cN0 (83%) pancreatic adenocarcinoma. Almost all patients completed combination neoadjuvant CT (91%) followed by either intensity modulated RT to 50.4 Gy in 28 fractions with capecitabine (n = 9) or stereotactic body RT to 33-40 Gy in 5 fractions (n = 14). Eleven (48%) patients received adjuvant CT after radiation therapy. The median time between last CT and RT initiation was 34 days (range 13-142). The MFS of patients who initiated RT within 4 weeks of CT compared to after was higher but not significant (16.8 vs 9.9 months, p = 0.144). Those who received RT within 6 or 8 weeks of completing CT exhibited significantly longer MFS compared to later than 6 (16.0 vs 6.9 mo, p = 0.016) or 8 weeks (15.1 vs 2.1 mo, p = 0.004). There was no statistical correlation between MFS and other variables (CA 19-9 before radiation, T-stage, receipt of adjuvant CT, BED). These results suggest that a longer interval between CT and RT is associated with the risk of developing metastatic disease sooner but requires validation in a prospective cohort. Root causes of delays in starting radiation (e.g., insurance authorization) should be investigated as well.