Cancer Therapy Research Articles

Radiation dose at the eye lens of patients undergoing radiation therapy for head and neck cancer.

Linear accelerator irradiation, the most common treatment for head and neck cancer, requires accurate prediction of lens radiation doses to ensure patient safety. The eye lens, being highly radiosensitive and vulnerable to scattered radiation, is at increased risk of developing cataracts. This study compared radiation doses calculated by the treatment planning system (TPS) with those measured in vivo using optically stimulated luminescence (OSL) dosimeters placed on the eyes of 18 patients undergoing radiotherapy for various head and neck cancers. Bland-Altman analysis was used to assess the agreement between the two methods. The results showed that TPS-calculated doses were significantly higher than OSL-measured doses, with TPS values averaging twice as high. However, in three cases, the measured OSL doses exceeded the TPS predictions. The Bland-Altman plot revealed poor agreement between the two methods. The mean doses to the left and right eye lenses were 182cGy and 170cGy, respectively, with the highest recorded doses being 492cGy for the left eye and 513cGy for the right eye. Patients with nasopharyngeal cancer received the highest doses, and four patients had doses in the 3-5Gy range, increasing their risk of cataracts. These findings emphasize the importance of validating TPS accuracy in clinical practice to ensure optimal patient care. Further research is necessary to explore the discrepancies between dose measurements and enhance TPS precision, improving clinical outcomes and patient safety in radiation therapy.

Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle

Abstract Cyclin dependent kinase 2 (CDK2) regulates cell cycle and is an emerging target for cancer therapy. There are relatively small numbers of tumor models that exhibit strong dependence on CDK2 and undergo G1 cell cycle arrest following CDK2 inhibition. The expression of P16INK4A and cyclin E1 determines this sensitivity to CDK2 inhibition. The co-expression of these genes occurs in breast cancer patients highlighting their clinical significance as predictive biomarkers for CDK2-targeted therapies. In cancer models that are genetically independent of CDK2, pharmacological inhibitors suppress cell proliferation by inducing 4N cell cycle arrest and increasing the expressions of phospho-CDK1 (Y15) and cyclin B1. CRISPR screens identify CDK2 loss as a mediator of resistance to a CDK2 inhibitor, INX-315. Furthermore, CDK2 deletion reverses the G2/M block induced by CDK2 inhibitors and restores cell proliferation. Complementary drug screens define multiple means to cooperate with CDK2 inhibition beyond G1/S. These include the depletion of mitotic regulators as well as CDK4/6 inhibitors cooperate with CDK2 inhibition in multiple phases of the cell cycle. Overall, this study underscores two fundamentally distinct features of response to CDK2 inhibitors that are conditioned by tumor context and could serve as the basis for differential therapeutic strategies in a wide range of cancers.

Ingenol mebutate in cancer therapy: mechanisms, clinical applications and future directions.

Ingenol mebutate (IM), a diterpene ester derived from Euphorbia species, has demonstrated promising anticancer properties through direct cytotoxicity and immune modulation. Despite initial clinical success, its therapeutic use has been curtailed due to safety concerns, including potential links to increased skin cancer risk. This review evaluates the mechanisms of action, preclinical and clinical efficacy, safety, and limitations of IM as an anticancer agent, identifying areas for further development. A comprehensive literature review was performed using Google Scholar to identify English-language articles published from 2010 to 2023. Keywords included "Ingenol mebutate," "PEP005," and "cancer therapy." Articles focusing on IM's pharmacological properties, therapeutic mechanisms, clinical studies, and safety profile were included. IM exerts anticancer effects through dual mechanisms: mitochondrial dysfunction leading to necrosis and immune-mediated cytotoxicity via protein kinase C activation. Preclinical studies show efficacy against pancreatic, colorectal, and epithelial cancers and clinical studies have reported success in treating actinic keratosis and nonmelanoma skin cancers. Challenges include intense local skin reactions and safety concerns, particularly its potential association with increased skin malignancy risk. IM represents a promising therapeutic agent due to its rapid and potent anticancer effects. However, optimizing its safety profile and exploring advanced delivery methods are critical to expanding its clinical applications. Further studies are required to establish its long-term efficacy and potential for broader use in oncology.

Current understanding of PEAK family members in regulation of cellular signaling pathways and cancer therapy.

Cancer evades therapy by multiple mechanisms, leading to uncontrolled cell growth and metastasis. Targeted therapies have shown promise in treating cancer by focusing on pathways within cancer cells. The PEAK family, comprising PEAK1 (SgK269), PEAK2 (SgK223/Pragmin), and the latest addition, PEAK3 (C19orf35), plays a crucial role in modulating cellular processes. Dysregulation and hyperactivity of these proteins, through overexpression or mutations, are associated with a wide range of cancers. This review delves into the different roles of the PEAK family members in regulating cell signaling pathways and highlights their potential in cancer therapy.

Bufalin targets the SRC-3/c-Myc pathway in chemoresistant cells to regulate metastasis induced by chemoresistance in colorectal cancer

BackgroundMetastasis and chemoresistance are often major challenges in advanced-stage colorectal cancer. Bufalin has a therapeutic effect on both metastasis and drug resistance, but how bufalin affects chemoresistance-mediated metastasis remains unclear.MethodsThe role of BU in the inhibition of EMT and angiogenesis induced by chemoresistant cells using wound healing assays, invasion assays, HUVEC tube formation and adhesion assays. Western blot and immunofluorescence were used to explore the potential molecular changes. BU can precisely regulate c-Myc expression by targeting SRC-3 in chemoresistant cells was confirmed by Western blot. In vivo experiments were conducted to validate that both BU and cinobufacini can ameliorate drug resistance-promoted EMT and angiogenic effects.ResultsBufalin inhibited resistance-induced epithelial-mesenchymal transition (EMT) and angiogenesis. Targeting of the SRC-3 protein by bufalin reduced the expression level of c-Myc and inhibited the prometastatic effect mediated by chemoresistance, and overexpression of SRC-3 or c-Myc reversed the inhibitory effect of bufalin on chemotherapeutic resistance, promoting metastasis. Moreover, the clinical drug cinobufacini and its main active monomer bufalin reduced liver metastasis of colorectal cancer caused by chemoresistance in vivo.ConclusionBufalin can target the SRC-3/c-Myc signaling pathway to affect the prometastatic effect of chemoresistant cells, suggesting that bufalin may be used as a new adjuvant antimetastatic therapy for colorectal cancer.

Targeted therapy and immunotherapy for gastric cancer: rational strategies, novel advancements, challenges, and future perspectives

Gastric cancer (GC) is one of the most common malignant tumors worldwide, and its treatment has been a focus of medical research. Herein we systematically review the current status of and advancements in targeted therapy and immunotherapy for GC, which have emerged as important treatment strategies in recent years with great potential, and summarize the efficacy and safety of such treatments. Targeted therapies against key targets in GC, including epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR), have shown remarkable therapeutic efficacies by inhibiting tumor progression and/or blood supply. In particular, markable breakthroughs have been made in HER2-targeting drugs for HER2-positive GC patients. To address intrinsic and acquired resistances to HER2-targeting drugs, novel therapeutic agents including bispecific antibodies and antibody–drug conjugates (ADC) targeting HER2 have been developed. Immunotherapy enhances the recognition and elimination of cancer cells by activating body anticancer immune system. Programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) antibodies are the most commonly used immunotherapeutic agents and have been used with some success in GC treatment. Innovative immunotherapy modalities, including adoptive immune cell therapy, tumor vaccines, and non-specific immunomodulators therapy, and oncolytic viruses have shown promise in early-stage clinical trials for GC. Clinical trials have supported that targeted therapy and immunotherapy can significantly improve the survival and quality of life of GC patients. However, the effects of such therapies need to be further improved and more personalized, with advancement in researches on tumor immune microenvironment. Further studies remain needed to address the issues of drug resistance and adverse events pertaining to such therapies for GC. The combined application of such therapies and individualized treatment strategies should be further explored with novel drugs developed, to provide more effective treatments for GC patients.

Predicting axillary residual disease after neoadjuvant therapy in breast cancer using baseline MRI and ultrasound.

To predict axillary node residual disease in women treated for node-positive breast cancer (BC) by neoadjuvant therapy (NAT), using breast BI-RADS MRI features and axillary ultrasound at baseline. In this single-center, retrospective study, women with node-positive BC who underwent NAT between 2016 and 2021 were included. Pre-treatment axillary US and breast MRIs were evaluated using the BI-RADS lexicon and T2 features, including Breast Edema Score. Univariate and multivariate logistic regression analyses were conducted for the prediction of axillary residual disease (ARD). A multivariable model based on logistic regression was trained and evaluated on randomly split train and test sets (7:3 ratio). Out of the 141 women, 41% had post-NAT ARD. Axillary metastasis was independently associated with luminal subtype (odds ratio (OR), 25.5; p < 0.001), anterior tumor location (OR, 14.1; p = 0.008), and cortical thickening ≥ 7 mm (OR, 6.09; p = 0.002). Intratumoral T2 high signal intensity was protective (OR, 0.16; p = 0.006), while Ki67 had a marginal association (p = 0.064). In the training and test sets, the model, which is available online, achieved AUCs of 0.860 (95% CI: 0.783-0.936) and 0.843 (95% CI: 0.714-0.971), respectively. Anterior depth location and cortical thickening greater than 7 mm were also independently associated with post-NAT axillary burden. Adjusting for BC subtype and KI-67 index, the anterior third location of BC, a cortical thickness greater than 7 mm, and the absence of intratumoral T2 hyperintensity is predictive of ARD after NAT. Question What baseline imaging-based predictive models can identify patients at risk of persistent nodal disease after neoadjuvant therapy? Findings Baseline US cortical thickness superior to 7 mm, anterior tumor location, and absence of an intratumoral high signal on T2-weighted MRI predict residual axillary disease. Clinical relevance Our predictive model, available online at: litoic.shinyapps.io/LNPred_Apps , including breast cancer subtype, Ki-67 index level, breast cancer location, intratumoral signal intensity on T2WI, and initial lymph node thickness, could guide post-NAT axillary management.

Isoacteoside alleviates hepatocellular carcinoma progression by inhibiting PDHB-mediated reprogramming of glucose metabolism

Pyruvate dehydrogenase B (PDHB) is an important component of the pyruvate dehydrogenase complex and is implicated in altering tumor metabolism and promoting malignancy. However, the specific impact of PDHB on hepatocellular carcinoma (HCC) metabolic reprogramming and its role in tumor progression remain to be elucidated. In our investigation, we have discerned a pronounced elevation in PDHB expression within HCC, intricately linked to delayed tumor staging, heightened tumor grading, and diminished prognostic outcomes. PDHB overexpression drives tumor growth and metastasis in vitro and in vivo. Mechanistically, PDHB mediates metabolic reprogramming by binding to the promoter regions of SLC2A1, GPI, and PKM2, promoting glycolysis-related gene transcription, contributes to HCC sorafenib resistance. In addition, Isoacteoside is a targeted inhibitor of PDHB and exert antitumor effects on HCC. In the mouse xenograft model, the combination of isoacteoside and sorafenib shows significantly better effects than sorafenib alone. In summary, our study validates PDHB as an oncogenic drug resistance-related gene capable of predicting HCC tumor progression. PDHB and Isoacteoside could be potential avenues for targeted and combination therapies in liver cancer.

Direct-Acting Antivirals Induce Lymphoproliferative Disease Response in HCV-Infected Patients With Indolent B-Cell Non-Hodgkin's Lymphoma: A Prospective Observational Study.

B-cell non-Hodgkin lymphoma (NHL) in one of the most serious extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. No prospective studies have been conducted in the United States (US) on the impact of direct-acting antivirals (DAAs) in HCV-infected patients with indolent B-cell NHL not requiring chemotherapy. In this prospective study, we evaluated the general characteristics of US patients with HCV-associated indolent B-cell NHL and the oncologic impact of only DAA treatment without systemic cancer therapy in those patients. We enrolled patients seen at our center during 2014-2021; we analyzed only chemotherapy-naïve patients treated with DAAs. Patients who required immediate conventional treatment for lymphoma were excluded from the study. The primary endpoints were sustained virologic response at 12weeks (SVR12) and lymphoproliferative disease response, classified as complete response, partial response, stable disease, or progressive disease. The secondary endpoints were overall response rate (ORR) of NHL, duration of response (DOR), overall survival (OS), and progression-free survival (PFS). Nine patients met the study criteria and were analyzed. Most patients were male (n=6), White (n=6), younger than 65years (n=6), and non-cirrhotic (n=8); had HCV genotype 1 (n=5); and had been infected for more than 30years (n=7). All patients achieved SVR12. Six patients (67%) had complete response, and 3 (33%) had progressive disease. The ORR was 67%. The median DOR was 51months (range 16-81months). The 5-year DOR, OS, and PFS rates were 100%, 83%, and 67%, respectively. HCV-associated NHL is a late extrahepatic complication of HCV. Infected patients with indolent NHL have an excellent virologic responses to DAAs and most of them experienced a favorable oncologic response after HCV eradication without chemotherapy.

A Spatially Distributed Microneedle System for Bioorthogonal T Cell-Guided Cancer Therapy.

Chimeric antigen receptor (CAR)-T cell therapy represents a promising strategy for cancer treatment. However, the diversity of solid tumor antigens and the poor infiltration of CAR-T cells significantly hinder the efficacy of CAR-T therapies against tumors. Here, a spatially distributed microneedle system (SDMNS) is developed that leverages bioorthogonal reactions to activate and guide endogenous T cells to tumors for effective destruction. The SDMNS consists of two dissolving microneedles, each loaded with complementary bioorthogonal groups and applied separately to lymph nodes and tumor sites. One microneedle loaded with two dibenzocyclooctyne (DBCO)-modified antibodies activates T cells and labels them with bioorthogonal groups in lymph nodes. The other microneedle, containing N-azidoacetylmannosamine-tetraacylated (Ac4ManNAz) for glycometabolic labeling of tumor cells, and the T cell chemotactic factor IP10, is applied directly to the tumor site. The in vivo studies demonstrate that SDMNS effectively directs the migration and infiltration of endogenous activated T cells into the tumors. Through a bioorthogonal click reaction, DBCO-modified T cells conjugate with azide (N3)-modified tumor cells, eliciting robust antitumor immune responses and durable immune memory. The SDMNS offers a novel strategy to overcomes tumor heterogeneity by facilitating the directed migration of endogenous T cells.

Ternary Schottky Junction for Sonocatalytic Water Splitting in Gas-Immunotherapy-Mediated Cancer Treatment.

Hydrogen therapy has shown new potential in cancer treatment, particularly in high-pressure and hypoxic areas, where it demonstrates the ability to alter the tumor microenvironment and regulate tumor metabolism. Hydrogen disrupts the mitochondrial function of cancer cells, interferes with their energy metabolism, and ultimately leads to energy depletion and apoptosis. In this study, a sonocatalyst (BPM), is designed to generate hydrogen and oxygen in situ within tumors, further enhancing the therapeutic efficacy. The mesocrystalline structure of BPM, composed of bismuth fluoride, polyoxometalates, and molybdenum carbide, significantly improves charge separation and electron transfer efficiency under ultrasound irradiation, resulting in an efficient water-splitting reaction. By simultaneously generating hydrogen and oxygen within the tumor microenvironment and depleting glutathione, BPM effectively triggers oxidative stress and alleviates hypoxia, thereby disrupting mitochondrial function and inhibiting energy metabolism in cancer cells. Additionally, BPM enhances antitumor immune responses by promoting dendritic cell maturation, activating T lymphocytes, and polarizing macrophages toward the M1 phenotype, reversing the immunosuppressive state of the tumor microenvironment. The results indicate that BPM holds potential for gas-immunotherapy combination treatments, offering a multifunctional strategy to improve cancer therapy outcomes.

Pharmacophore-based identification and in Silico characterization of microbial metabolites as potential modulators of Wnt signaling pathway in colorectal cancer therapy.

Aberrant activation of the Wnt/β-catenin signaling pathway, primarily driven by APC mutation and AXIN degradation via Tankyrase, contributes significantly to colorectal cancer (CRC) progression and metastasis. The accumulation of β-catenin, resulting from the dysregulated ubiquitination, underscores the need for alternative therapeutic strategies targeting Tankyrase and β-catenin. This present study explores microbial metabolites as a source of novel anti-cancer agents, leveraging their unique bioactivity and structural diversity, often exhibiting superior target specificity and lower toxicity than synthetic drugs. Through a computational drug discovery pipeline, a large library of 27641 microbial metabolites was initially screened based on multiple drug-likeliness criteria, resulting in the selection of 2527 compounds. Among the screened compounds, an integrated computational workflow comprising molecular docking, molecular dynamic simulations (MDS), MM/PBSA analysis, and Principal component analysis (PCA) identified Terreustoxin I (T1) as a potential Tankyrase inhibitor. In contrast, compound 10- phenyl-[12]-cytochalasin Z16 (B1) demonstrated a strong binding affinity within the β-catenin active site. Under physiological conditions, these lead compounds were evaluated for conformational stability, binding efficacy, and dynamic behavior. Additionally, ADMET profiling, physiochemical properties, and bioactivity score predictions confirmed the identified compounds' pharmacokinetic suitability and reduced toxicity profile. In silico, cytotoxicity predictions showed significant activity against SW480 and HCT90 colorectal cell lines, with additional anti-neoplastic and anti-leukemic properties, strengthening their candidacy as effective anti-cancer agents. These findings provide a foundation for further experimental validation and development of novel CRC therapies with improved safety and efficacy potential.

Optogenetically Activatable MLKL as a Standalone Functional Module for Necroptosis and Therapeutic Applications in Antitumoral Immunity.

Necroptosis plays a crucial role in the progression of various diseases and has gained substantial attention for its potential to activate antitumor immunity. However, the complex signaling networks that regulate necroptosis have made it challenging to fully understand its mechanisms and translate this knowledge into therapeutic applications. To address these challenges, an optogenetically activatable necroptosis system is developed that allows for precise spatiotemporal control of key necroptosis regulators, bypassing complex upstream signaling processes. The system, specifically featuring optoMLKL, demonstrates that it can rapidly assemble into functional higher-order "hotspots" within cellular membrane compartments, independent of RIPK3-mediated phosphorylation. Moreover, the functional module of optoMLKL significantly enhances innate immune responses by promoting the release of iDAMPs and cDAMPs, which are critical for initiating antitumor immunity. Furthermore, optoMLKL exhibits antitumor effects when activated in patient-derived pancreatic cancer organoids, highlighting its potential for clinical application. These findings will pave the way for innovative cancer therapies by leveraging optogenetic approaches to precisely control and enhance necroptosis.

Etoposide-induced cancer cell death: roles of mitochondrial VDAC1 and calpain, and resistance mechanisms.

Etoposide is an inhibitor of DNA topoisomerase II, an enzyme essential for DNA transcription, replication, and chromosome segregation. It is well accepted that etoposide triggers cell death due to DNA damage. Our results indicate that multiple molecular mechanisms contribute to etoposide-induced apoptosis, including the overexpression of the mitochondrial voltage-dependent anion channel 1 (VDAC1) and its oligomerization, forming a mega-channel that releases pro-apoptotic proteins, thereby activating apoptosis. Etoposide induces C-terminal truncation of VDAC1 (VDAC1-ΔC) via the proteolytic actions of calpain-1 and asparagine endopeptidase (AEP). A calpain-specific inhibitor effectively prevented etoposide-induced VDAC1-ΔC formation, apoptosis, and the nuclear translocation of apoptosis-inducing factor (AIF). Additionally, etoposide upregulates the expression levels of apoptosis regulators (p53, Bax, p21, AIF) and of the proteases calpain and AEP. Etoposide-induced apoptosis and VDAC1 truncation are cell-type dependent and associated with calpain levels and activity. Etoposide-induced VDAC1-ΔC formation and apoptosis are tightly linked: as both display similar patterns of concentration- and time-dependence, both are inhibited by calpain and AEP inhibitors, as well as the VDAC1 oligomerization inhibitor VBIT-4, and are dependent on intracellular Ca2+. These findings highlight the complexity of etoposide's actions in different cellular contexts, suggest possible mechanisms of resistance, offer potential biomarkers for guiding etoposide treatment in cancer patients, and propose targeting VDAC1 and calpain as promising therapeutic strategies in cancer therapy.

ATP-Dependent Chromatin Remodeler CSB Couples DNA Repair Pathways to Transcription with Implications for Cockayne Syndrome and Cancer Therapy

ATP-Dependent Chromatin Remodeler CSB Couples DNA Repair Pathways to Transcription with Implications for Cockayne Syndrome and Cancer Therapy

Pinosylvin as a promising natural anticancer agent: mechanisms of action and future directions in cancer therapy.

Cancer is a major global health challenge, with rising incidence necessitating alternative therapies. Pinosylvin, a natural phenolic compound in pine species, has demonstrated notable anticancer properties, making it a promising candidate for cancer treatment. This review synthesizes findings from extensive literature searches across databases, including PubMed and Scopus, to explore pinosylvin's efficacy against cancers like nasopharyngeal, prostate, colorectal, fibrosarcoma, and oral cancers. In vitro and in vivo studies indicate that pinosylvin disrupts cancer cell processes, such as migration and invasion, by targeting molecular pathways including MAPK, ERK, and PI3K. Its anti-inflammatory, antioxidant, and antimicrobial effects further support its therapeutic potential. Pinosylvin's anticancer mechanisms involve inhibiting cancer proliferation and metastasis while inducing apoptosis. These effects may be attributed to the compound's ability to modulate critical enzymes and pathways, underscoring its potential as a natural anticancer agent. However, further research, including clinical trials, is required to fully establish its efficacy and applicability in cancer treatment protocols.

Divide and Conquer—Targeted Therapy for Triple-Negative Breast Cancer

Divide and Conquer—Targeted Therapy for Triple-Negative Breast Cancer

Evolving Role of PET Imaging in Assessing Vascular and Central Nervous System Complications of Radiation Therapy in Head and Neck Cancer.

Radiation therapy for head and neck cancer is a cornerstone of treatment but can come with significant and lasting complications. Reduced vascularity and fibrosis heighten the risks of stroke, infection, and diminished quality of life. Advances in imaging technologies, such as fluorodeoxyglucose PET and sodium fluoride-PET, have emerged as critical tools for diagnosing and monitoring vascular inflammation and calcification, enabling earlier interventions and improved patient management. This review examines the pathophysiology of RT-induced damage, with a focus on vascular and connective tissue complications, and highlights the evolving role of PET imaging in early detection and management of these effects.

A novel ypN-TRG staging system for gastric cancer patients after neoadjuvant therapy based on the metro-ticket paradigm: a multicenter and large sample retrospective analysis.

Conventional ypT category evaluates the depth of invasion after neoadjuvant therapy (NAT) for gastric cancer (GC) and has limited prognostic value. Tumor regression grade (TRG) measures the extent of tumor response to treatment, and when combined with the ypN category, it may enhance the prediction of patient outcomes. This study aims to develop a new staging system by integrating TRG and ypN category to better evaluate the prognosis of GC patients receiving NAT. This retrospective analysis included 962 patients who underwent radical gastrectomy after NAT, with 513 in the development cohort (from one center) and 449 in the external validation cohort (from five centers). The ypN-TRG staging system was established by calculating the distance from the origin on a cartesian plane incorporating the ypN (x-axis) stage and TRG (y-axis) grade, and five sub-stages were delineated. In the development cohort, 3-year overall survival rates according to ypN-TRG stage I, IIA, IIB, IIIA, IIB were 87.6%, 80.2%, 70.7%, 47.3%, 21.5%, p < 0.01. Compared with ypTNM, the ypN-TRG staging system performed better in terms of the prognostic discrimination power (C-index), goodness-of-fit (AIC, BIC), model improvement (NRI, IDI), and model stability (time-AUC). Multivariate Cox regression analysis confirmed the superiority of ypN-TRG over ypTNM staging. In the external validation cohort, ypN-TRG staging was a better predictor of OS and DFS in patients with GC. The ypN-TRG staging system is superior to the AJCC eighth edition ypTNM staging system in accurately assessing the prognosis of patients with GC after NAT.

Radio(chemo)therapy in anal cancer: evaluation of sex-specific disparities across AJCC stages.

This study aimed to investigate sex differences in anal squamous cell carcinomas (ASCC), with aparticular focus on the prognostic significance of the American Joint Committee on Cancer (AJCC) 9thedition staging system for oncological outcome. Aretrospective analysis was conducted in 188 patients with histologically confirmed ASCC who underwent definitive (chemo)radiotherapy between 2004 and 2020. Patient- and tumor-related data were collected. Tumor stage groups were classified according to the AJCC 9thedition. Overall survival (OS), disease-free survival (DFS), freedom from recurrence (FFR), and colostomy-free survival (CFS) were analyzed using the Kaplan-Meier method for univariate testing and Cox regression models for multivariate analysis. Differences between sexes were assessed. The cohort included 134 females and 54males, with amedian follow-up of 83months. Females exhibited significantly better OS (p = 0.01), DFS (p = 0.01), and CFS (p = 0.03). For male patients, there was aclear trend towards better OS (p = 0.08), DFS (p = 0.10), and FFR (p = 0.09) in earlier tumors as well as significantly better CFS (p = 0.04). In contrast, in the female subgroup, there were no significant differences in OS (p = 0.64), DFS (p = 0.52), and CFS (p = 0.25) with respect to tumor stage. In multivariate analysis, male sex, older age, and advanced tumor stages were significant risk factors for poorer OS, DFS, and CFS. This study highlights significant sex differences in ASCC prognoses, with females showing better survival outcomes. The prognostic value of the AJCC 9thedition staging system differs between sexes; thus, we support the inclusion of sex as aprognostic factor in staging systems.