High-dose Radiotherapy Research Articles

High and low dose radiotherapy combined with ICIs for MSS colorectal cancer patients with liver metastases: a phase I study (HaRyPOT)

IntroductionMicrosatellite stable (MSS) colorectal cancer with liver metastases (CLRM) responds poorly to immunotherapy, and various approaches to break immune tolerance have been tried. Radiotherapy in combination with immune checkpoint inhibitors is one of promising therapies, and the choice of radiotherapy and immunotherapy modalities is also a hot issue.MethodsHere, we report on a Phase I trial treating nine patients with MSS CLRM using a combination of high and low dose radiotherapy and immune checkpoint inhibitors (ICIs).ResultsThe primary endpoint of the trial was the safety and tolerability of this combination treatment modality. Secondary endpoints included the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). The study results showed that at three dose levels—single doses of 6Gy (n=3), 8Gy (n=3), and 10Gy (n=3)—the most common treatment-related adverse events (TRAEs) were nausea, vomiting, fatigue, and abnormal liver function. At the first condition assessment, four patients were observed to have stable disease (SD) and one patient achieved partial response (PR). In exploratory endpoint analyses, tissue biopsies and paired hematologic samples from patients showed M2 macrophage reduction. Plasma cytokines IL-10, IL-17, and INF-α increased after treatment with both drugs.DiscussionIn summary, this is the first clinical trial demonstrating the safety and immunogenic activity of combined high and low dose radiotherapy with ICIs in MSS colorectal cancer liver metastases (CRLMs). The combination therapy stimulated the immune response and altered the tumour microenvironment, warranting further exploration in the future.

Skull base osteoradionecrosis: from pathogenesis to treatment.

This review aims to provide a comprehensive analysis of skull base osteoradionecrosis (ORN), a severe and rare complication of radiotherapy for head and neck malignancies. It explores pathogenesis, clinical presentation, diagnostic strategies, and management approaches, emphasizing the importance of multidisciplinary care in addressing this challenging condition. Skull base ORN results from radiotherapy-induced tissue damage, characterized by hypovascularity, hypoxia, and necrosis, often compounded by secondary infections. Advances in radiotherapy techniques, such as intensity-modulated radiotherapy and heavy particles, have reduced ORN incidence, though cases persist, particularly in high-dose radiotherapy fields. Emerging treatments, including hyperbaric oxygen therapy and the pentoxifylline-tocopherol protocol, show promise but lack robust evidence for standardized use. Surgical interventions, especially those incorporating vascularized tissue reconstruction, have demonstrated favorable outcomes in refractory cases. Recent studies underscore the utility of multimodal imaging techniques, including MRI and PET/CT, for distinguishing ORN from tumor recurrence. Skull base ORN represents a complex and potentially life-threatening condition requiring tailored, multidisciplinary management. Although advancements in diagnostics and therapeutics have improved outcomes, significant challenges remain, particularly in developing standardized protocols. Further research is needed to refine treatment strategies and improve evidence-based practices for this entity.

CyberKnife in Pediatric Oncology: A Narrative Review of Treatment Approaches and Outcomes

Pediatric cancers, while rare, pose unique challenges due to the heightened sensitivity of developing tissues and the increased risk of long-term radiation-induced effects. Radiotherapy (RT) is a cornerstone in pediatric oncology, but its application is limited by concerns about toxicity, particularly secondary malignancies, growth abnormalities, and cognitive deficits. CyberKnife (CK), an advanced robotic radiosurgery system, has emerged as a promising alternative due to its precision, non-invasiveness, and ability to deliver hypofractionated, high-dose RT while sparing healthy tissues. This narrative review explores the existing evidence on CK application in pediatric patients, synthesizing data from case reports, small series, and larger cohort studies. All the studies analyzed reported cases of tumors located in the skull or in the head and neck region. Findings suggest CK’s potential for effective tumor control with favorable toxicity profiles, especially for complex or inoperable tumors. However, the evidence remains limited, with the majority of studies involving small sample sizes and short follow-up periods. Moreover, concerns about the “dose-bath” effect and limited long-term data on stochastic risks warrant cautious adoption. Compared to Linac-based RT and proton therapy, CK offers unique advantages in reducing session numbers and enhancing patient comfort, while its real-time tracking provides superior accuracy. Despite these advantages, CK is associated with significant limitations, including a higher potential for low-dose scatter (often referred to as the “dose-bath” effect), extended treatment times in some protocols, and high costs requiring specialized expertise for operation. Emerging modalities like π radiotherapy further underscore the need for comparative studies to identify the optimal technique for specific pediatric cases. Notably, proton therapy remains the benchmark for minimizing long-term toxicity, but its cost and availability limit its accessibility. This review emphasizes the need for balanced evaluations of CK and highlights the importance of planning prospective studies and long-term follow-ups to refine its role in pediatric oncology. A recent German initiative to establish a CK registry for pediatric CNS lesions holds significant promise for advancing evidence-based applications and optimizing treatment strategies in this vulnerable population.

B7-H3 CAR-T cell therapy combined with irradiation is effective in targeting bulk and radiation-resistant chordoma cancer cells

BackgroundChordoma is a slow-growing, primary malignant bone tumor that arises from notochordal tissue in the midline of the axial skeleton. Surgical excision with negative margins is the mainstay of treatment,...

Dose-Escalated SBRT for Borderline and Locally Advanced Pancreatic Cancer: Resectability Rate and Pathological Results of a Multicenter Prospective Study.

We demonstrated for the first time the safety and feasibility of escalating up to 55 Gy/11 Gy/fr/5fr in borderline (BRPC)/unresectable locally advanced pancreatic cancer (LAPC), using the standard LINAC platform. The aim of the present study is to assess for the first time the impact of this high-dose neoadjuvant stereotactic ablative radiotherapy (SABRT) protocol on tumor resectability and pathological responses. From June 2017 to December 2022, patients with BRPC/LAPC were treated with neoadjuvant chemotherapy (ChT) and SABRT-escalated doses of SIB at 45 Gy, 50 Gy, and up to 55 Gy (BED ≥ 100). Radiological evaluation was conducted with a CT scan 6-8 weeks post-treatment to determine resectability status based on established criteria (SAR/APA2014). Surgical decisions were made by the multidisciplinary tumor board of the participating institutions. Pathological assessments post-surgery used criteria from the College of American Pathologists (CAP), categorizing resection status as R0 (negative margins), R1 (microscopic tumor margins), and R2 (macroscopic tumor margins). Tumor response was evaluated with the Tumor Response Scoring (TRS) system, as G0 (no viable cancer cells), G1 (single cells or rare small groups), G2 (residual cancer with evident regression), and G3 (extensive residual cancer). Thirty-three patients (p) were included: 39.4% (13p) BRPC/60.6% (20p) LAPC. After ChT-SABRT, 45.5% (15p) were considered resectable, with 11/13 (84.6%) BRPC and 4/20 (20%) LAPC (p < 0.0001). One patient refused surgery and other patient died of COVID sepsis. Two more patients had disseminated disease at surgery. Among the 11 patients who underwent full surgery, all patients achieved either clean margins R0: 72.7% (8p) or microscopic affected margins R1: 27.3% (3p). TRS scores were G1: 27.3% (3p), G2: 54.5% (6p), and G3: 18.2% (2p). The present follow-up (FUP) was closed on 1 November 2024 (23.55 months, range: 6-71 months). The mean freedom from local progression as the first cause of disease failure was 43.30 ± 3.09 (37.23-49.38), and the median was not reached. The actuarial 1- and 2-year rates for freedom from local relapse as a first cause of disease failure were 92.3% (87.7-93.3%) and 79.7% (79.7-87.7%), respectively. Neoadjuvant ChT-SABRT in LAPC improves resectability rates and induces relevant tumor regression. These promising findings should be validated by larger sample sizes and extended follow-up.

Insufficiency fractures in patients with sacral chordoma treated with high-dose radiation therapy with and without resection.

Determine the incidence, location, and features of insufficiency fractures (IFs) in sacral chordoma patients treated with high-dose radiation therapy (HDR) with(out) resection, relative to radiation therapy type and irradiation plans. Clinical data, including details of all surgical procedures and radiotherapies of patients histologically diagnosed with sacral chordoma between 2008 and 2023 available at our database, were retrospectively reviewed. Inclusion criteria were as follows: availability of diagnostic, treatment planning and follow-up magnetic resonance and/or computed tomography scans, and completed treatment. Scans were re-evaluated for the presence and location of IF defined as linear abnormalities with(out) bone marrow oedema (BME)-like changes. From 48 included patients (29 male, median age 66, range 27-85), 22 were diagnosed with 56 IF (45.8%). IF occurred 3-266 months following the treatment. All sacral and iliac bone IF had vertical components parallel to the SI joint. Twenty patients had bilateral and 16 unilateral IF. BME-like changes were visible in 46 IF (82.1%, 0.80, P ≤ .001). In 13/56 IF (23.2%), BME-like changes were seen prior to IF diagnosis; in only 1 patient, BME-like changes did not develop into an IF. Thirty-nine IF (84.7%) occurred within low-dose volume and 7 (15.3%) outside of irradiated volume in 16/44 irradiated patients. Six IF occurred in 1 patient treated with surgery only. Pelvic IFs are common in sacral chordoma patients treated with definitive or (neo)adjuvant HDR, occurring months to years following treatment. Not all IF occur in the irradiated volume. When present, BME-like changes indicate risk of IF developing. IF do not heal over time.

Zinc-based radioenhancers to activate tumor radioimmunotherapy by PD-L1 and cGAS-STING pathway

Radiotherapy and immunotherapy have already become the primary form of treatment for non-small-cell lung cancer (NSCLC), but are limited by high radiotherapy dose and low immune response rate. Herein, a multi-pronged strategy using a radio-immuno-enhancer (ZnO–Au@mSiO2) is developed by inducing tumor cells apoptosis and reprograming the immunosuppressive tumor microenvironment (TME). The radio-immuno-enhancer employed Au as a radiosensitizer, transition Zn ions as immune activators, which not only tremendously enhances the anti-proliferative activity of radiotherapy toward cancer cells, but also activates the immune response with multi-targets to let “exhausted” T cells “back to life” by triggering immunogenic cell death (ICD), immune checkpoint blockade (ICB) that target PD-1/PD-L1 and cGAS-STING under X-ray irradiation with a low dosage. The in vivo results demonstrate desirable antitumor and immunogenic effects of radio-immuno-enhancer-mediated immune activation by increasing the ratio of cytotoxic T cells (CTLs) and helper T cells. This work provides a feasible approach for future development of effective transition metal ion-activated radio-immunotherapeutic agents.Graphic

Enhancing Chordoma Radiotherapy: Ta@PVP Nanoparticles as Potent Radiosensitizers.

Surgical resection and high-dose radiotherapy constitute the standard therapeutic approaches for chordoma. However, the efficacy of radiotherapy is often compromised by the tumor microenvironment's hypoxic conditions, which confer radiation resistance, and by the potential damage to adjacent spinal cord and neural structures from elevated radiation doses. To address these challenges, we employed high biocompatible poly(vinylpyrrolidone)-modified tantalum nanoparticles (Ta@PVP NPs) as a potent radiosensitizer to augment the radiotherapy sensitivity of chordoma. Upon exposure to X-ray irradiation, Ta@PVP NPs demonstrated the capability to efficiently deposit X-ray radiation energy within the tumor microenvironment, subsequently generating reactive oxygen species (ROS) that induce oxidative stress in the tumor. Both in vitro and in vivo experiments revealed that Ta@PVP NPs significantly enhanced the cytotoxic effects of X-ray, thereby markedly inhibiting the proliferation of chordoma cells and impeding tumor growth. This study explored the radiosensitization potential of Ta@PVP NPs in the context of chordoma, highlighting the application of radiosensitizers as a promising strategy to augment the efficacy of chordoma radiotherapy.

Neoadjuvant Chemotherapy and Transoral Robotic Surgery for Human Papillomavirus–Related Oropharyngeal Cancer

Distant metastasis (DM) remains the leading cause of death in patients treated for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). An effective treatment strategy needs to address DM while reducing treatment-related toxic effects. To assess DM-free survival in patients with HPV-OPSCC treated with neoadjuvant chemotherapy followed by transoral robotic surgery (NECTORS) and neck dissection compared with standard of care, concurrent chemoradiation (CCRT). This multicenter retrospective cohort study compares prospective data from the NECTORS treatment group with a historical cohort of patients treated with CCRT. Patients with American Joint Committee on Cancer seventh edition stage III and IVa HPV-OPSCC treated with NECTORS and CCRT between February 2010 and September 2021 were included. Data were analyzed in September 2024. Patients in the NECTORS arm were treated with 3 cycles of neoadjuvant docetaxel and cisplatin followed by TORS and neck dissection. Patients in the radiation therapy arm were treated with concurrent high-dose cisplatin and radiotherapy. DM-free survival was analyzed with Kaplan-Meier and Cox regression after adjusting for age, sex, tobacco and alcohol use, site, and cancer stage. Of 342 included patients, 282 (82.5%) were male, and the mean (SD) age was 61.4 (9.4) years. A total of 232 patients were treated with CCRT and 110 patients were treated with NECTORS. Within the CCRT arm, 11 patients (4.7%) had locoregional recurrence (LRR), 5 (2.2%) had LRR and DM, and 28 (12.1%) developed distant-only metastasis. For patients treated with NECTORS, 5 (4.5%) developed LRR, 1 (0.9%) developed LRR plus DM, and no patients developed distant-only metastasis. With pseudorandomization matching for T and N stages, 209 patients were matched between the 2 treatment groups for further analysis (105 in the CCRT treatment arm and 104 in the NECTORS arm). The median (range) follow-up period for the CCRT and NECTORS groups were 5.8 (3.8-7.5) years and 5.1 (4.0-5.9) years, respectively. The hazard ratio of developing distant recurrence in the CCRT group was 10.77 (95% CI, 1.40-82.90) in univariate analysis and 9.98 (95% CI, 1.29-77.29) in multivariable analysis. In Kaplan-Meier survival analysis, the risk of developing DM was higher in the CCRT group. The hazard ratio for failure anywhere in the CCRT group was 3.32 (95% CI, 1.23-8.97) in univariate analysis and 3.21 (95% CI, 1.18-8.72) in multivariable analysis. In this study, neoadjuvant chemotherapy followed by transoral robotic surgery and neck dissection was an effective treatment option for patients with stage III and IVa HPV-OPSCC. Findings from our study suggest lower rates of DM with NECTORS worthy of further investigation in prospective randomized trials.

Outcomes With Radiation Therapy as Primary Treatment for Unresectable Cutaneous Head and Neck Squamous Cell Carcinoma.

Unresectable cutaneous squamous cell cancer of the head and neck (HNcSCC) poses treatment challenges in elderly and comorbid patients. Radiation therapy (RT) is often employed for locoregional control. This study aimed to determine progression-free survival (PFS) and overall survival (OS) outcomes achieved with upfront RT in unresectable HNcSCC. It also aimed to determine the impact of varying RT dose regimes on disease outcomes. A retrospective cohort study was conducted of patients with unresectable HNcSCC treated with first-line RT at a tertiary teaching hospital in Sydney, Australia between 2015-2024. Patient, disease, treatment and follow-up data were extracted from the electronic records. Of 36 patients, 67% were male, median age was 81 years, and median Charlson Comorbidity Index was 6.5. Median follow-up was 21 months. 83% of RT courses were delivered via intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). Objective response rate was 97%. Patients were grouped into low-dose RT receiving biologically equivalent dose (BED) <60Gy (n = 18) or high-dose RT (BED ≥ 60Gy, n = 18). Infield progression-free survival (PFS) at 6 months was 56% and 78%, respectively. Overall survival at 6 months was 83% and 89%, and by 24 months 31% and 65%, respectively. RT is an efficacious treatment that can be tailored to individual patient contexts with unresectable HNcSCC. It has a high response rate overall, with higher doses producing longer disease control. Some patients with poorer functional status receiving low-dose RT can still achieve a sustained response. Future comparisons of outcomes and cost-effectiveness with emerging treatments such as immunotherapy will be important in guiding management for frail patients with unresectable disease.

Identification of a Suitable Subgroup for Radiation Dose Escalation in Definitive Concurrent Chemoradiation Therapy for Nonmetastatic Esophageal Squamous Cell Carcinoma.

Dose escalation may only be suitable for some patients with esophageal cancer (EC) undergoing concurrent chemoradiotherapy (CCRT). This study aimed to identify specific subgroups of patients for whom dose escalation was most beneficial. Between January 2008 and December 2022, 187 patients with EC underwent CCRT; 94 patients received high-dose (HD) radiotherapy (RT; >64.8 Gy), and 93 patients received low-dose (LD) RT. We developed a model on the basis of clinical and radiomic features to compare the predicted survival probabilities of patients with EC receiving HD- and LD-RT. Patients suitable for HD-RT could be identified. We validated our findings of a suitable HD subgroup by evaluating the actual overall survival (OS) across different subgroups in the testing set. Our model comprised HD and LD submodels, each predicting patient survival under their respective RT doses. The HD and LD submodels achieved concordance indexes of 0.78 and 0.75 in their respective testing sets. The average areas under the receiver operating characteristic curve over years 1-3 were 0.890 and 0.807 in the HD and LD testing sets, respectively. By comparing patients' predicted survival under HD- and LD-RT in the model, we classified the patients in the testing set into the HD-suitable (HDS) subgroup and the HD-unsuitable subgroup. In the subgroup analysis, HD-RT led to a better OS benefit for the identified HDS subgroup compared with LD-RT (P = .014). Among the HD-treated patients, the HDS subgroup showed better OS than did patients identified as unsuitable (P < .001). We identified a suitable subgroup of patients with EC who might benefit from HD-RT. This model could aid clinicians in prescribing RT doses.

Jaw exercise in head and neck cancer patients for prevention of temporomandibular disorders: a randomized controlled trial.

To prospectively evaluate the effect of a preventive jaw-training intervention program on the development of temporomandibular disorders (TMD) in patients treated for head and neck cancer (HNC). We randomized 58 consecutive patients with squamous cell carcinoma in the head and neck area into two groups before initiation of a curatively intended oncologic treatment: training with a jaw mobilizer once a day or a control group without active exercise. A comprehensive examination according to diagnostic criteria for temporomandibular disorders (DC/TMD) was conducted at baseline (before oncologic treatment) 6 and 12months after completed radiation therapy (RT). The patients recorded training frequency in a diary. There were significant differences in the changes of maximal incisal opening (MIO) between the intervention and control groups at 6 and 12months compared to baseline (p = 0.010 and p = 0.012, respectively) with more deterioration in the control group. The control group had a higher prevalence of TMD diagnosis at the 6-month follow-up (p = 0.010) and a close to significant level at the 12-month follow-up (p = 0.055). This unique study, which evaluates the effect of a preventive jaw-training program for prevention of TMD in patients with HNC undergoing high dose RT, found that the preventive jaw-training program could prevent the deterioration of MIO and development of TMD. This preventive exercise program could prevent the deterioration in MIO and the development of TMD in HNC patients, leading to less pain and better jaw function.

Stereotactic arrhythmia radioablation - A systematic review and meta-analysis of the prospective clinical studies

Abstract Background Stereotactic arrhythmia radioablation (STAR) is increasingly being evaluated in prospective studies as a new promising treatment option for patients with therapy-refractory ventricular tachycardia (VT). In STAR, the VT substrate is noninvasively treated with a high dose of radiotherapy. Recently, several single-arm prospective studies evaluating the clinical outcomes of STAR were published. Considering that the evidence base consists mainly of retrospective case series, we conducted a systematic review and meta-analysis to synthesize the prospective data on outcomes of STAR. Purpose To perform a systematic review and meta-analysis of prospective studies evaluating clinical outcomes of STAR for VT. Methods This study was registered in PROSPERO and adhered to the PRISMA reporting guidelines. Full-text studies describing prospective studies evaluating the safety and efficacy of STAR for VT were included in this study. Records published until August 2023 were retrieved from OVID MEDLINE, OVID Embase, Web of Science Core Collection, the Cochrane Central Register of Controlled Trials, and Google Scholar search engine (top 200 hits), deduplicated, and screened for eligibility. Abstract screening, full-text screening, data extraction and quality assessment were performed by two reviewers independently. Endpoints were defined as treatment related CTCAE grade ≥3 adverse events within 90 days after treatment, overall survival (OS), time to VT recurrence, and recurrence-free survival. Rates of patients achieving pre-defined 50%, 75% and 95% VT burden reduction thresholds were summarised. Random-effects generalized linear mixed-effects models and inverse variance models were used for the meta-analysis. Results 1861 records were identified, 987 were screened, and 10 full-text manuscripts published between 2019 and 2023 describing the results of STAR in 82 patients were included in this study. The majority were male (n=72; 88%), between 45 and 85 years old, and suffered from ischaemic cardiomyopathy (n=51; 62%). Median left ventricular ejection fraction ranged from 21 to 38% between studies. 20 patients did not undergo a prior catheter ablation for VT. All patients were treated with a single dose of 25 Gy and median planned target volume ranged from 45 to 198 cc between studies. Pooled 12-month OS rate was 0.73, and the proportion of patients experiencing grade ≥3 adverse events within 90 days after STAR was 0.11 (Figure 1). Reduction in VT burden is shown in Table 1. Although these were not pooled because of large heterogeneity in VT reduction time frame definitions, it can be appreciated that most of the patients experienced a reduction in VT burden. Conclusion The increasing evidence from prospective studies on STAR shows acceptable 12-month OS in a population of patients with advanced heart failure and refractory VT. Moreover, there is a modest rate of high-grade adverse events and most patients experience a reduction in VT burden.

The value of a multimodal approach combining radical surgery and intraoperative radiotherapy in the recurrence treatment of gynecological malignancies - analysis of a large patient cohort in a tertiary care center

BackgroundRecurrent and locally advanced gynecological malignancies have a poor prognosis. In particularly, pelvic local recurrence after previous radiotherapy and/or positive resection margins during surgical treatment for recurrent disease result in low survival rates. Consequently, locoregional control is of utmost importance in this cohort of patients. The aim of this study was to analyze treatment outcomes and determine prognostic factors for patients treated with surgery and intraoperative radiotherapy (IORT) for recurrent and locally advanced gynecological malignancies.Methods40 patients who underwent surgical treatment and IORT between 2010 and 2022 were eligible for inclusion. The median follow-up time was 22 months. The outcomes measured were locoregional control (LRC), overall survival (OS), and survival without distant metastases (DMFS). The Cox proportional hazards model was used for univariate and multivariate analysis to assess the impact of patient variables and treatment factors on the endpoints mentioned. The following variables were analyzed: age at surgical treatment and IORT and initial diagnosis (< 65 vs. ≥65 years, each), disease-free interval (DFI) between initial diagnosis and first recurrence, DFI to surgical treatment and IORT, grading, histology, IORT dose (≤ 13 vs. >13 Gy) and technique (high dose radiotherapy (HDR) vs. IORT using electrons, (IOERT)). Survival curves were generated using the Kaplan-Meier method.ResultsThe mean IORT dose was 13.8 Gy (range 10–18 Gy). Cervical carcinoma was most frequently found in 27.5% of patients followed by endometrial carcinoma and vulvar carcinoma in 25% respectively. The final histopathologic results after surgery with IORT showed no residual tumour in 24 patients (60%), microscopic residual disease in 5 patients (12.5%), resection status could not be evaluated in three patients (7.5%) and the resection status was unknown in eight patients (20%). Subsequently, 27.5% of patients also received adjuvant radiotherapy of the local recurrence bed. However, after IORT, 65% of the women suffered a recurrence. Of these, the recurrences were localized: in-field 32.5%, out-of-field 22.5% and margin-of-field 12.5%. The 3- and 5-year OS was 69% and 55% respectively. The 3- and 5-year LRC was 56% respectively. The 3- and 5-year DMFS was 66% and 49%. Whereas the comparison between groups by IORT dose level (≤ 13 vs. >13 Gy) showed a non-significant trend in favor of the higher dose only for OS (p = 0.094), but not in LRC and DMFS (p > 0.05). OS and DMFS, but not LRC, differed significantly between the HDR-IORT and IOERT groups (p = 0.06 and p = 0.03,) in favor of the HDR-IORT technique. For HDR-IORT technique a trend towards superior OS and LRC was observed in the univariate analysis: HR 3.76, CI 95%: 0.95–14.881, p = 0.059 and HR 2.165 CI 95%: 0.916–5.114, p = 0.078ConclusionsThe survival rate for pelvic recurrence in gynecological malignancies remains poor and comparable with historical data from the last two decades. Particularly HDR-IORT, appears to provide a long-term oncological benefit in carefully selected patients.

Advantages of single high-dose radiation therapy compared with conventional fractionated radiation therapy in overcoming radioresistance

Background Radioresistance is a major clinical challenge in cancer treatment, as it reduces the effectiveness of radiation therapy (RT). While advances in radiation delivery have enabled the clinical use of high-dose hypofractionated RT, its impact on radioresistant tumors remains unclear. This study aimed to compare the effects of single high-dose RT with conventional fractionated RT on radioresistant breast cancer cells and explore the underlying mechanisms. Methods Radioresistant cell lines were previously established by exposing SK-BR-3 and MCF-7 cells to 48 Gy and 70 Gy of radiation, respectively, in multiple fractions. We compared the effects of 2 Gy × 5 and 7 Gy × 1 fractions on these cells using clonogenic survival assays and western blot analysis. In vivo antitumor effects were assessed in SR tumor-bearing BALB/c mice irradiated with either 2 Gy × 5 or 7 Gy × 1 fractions. Results 7 Gy x1 was more efficient at killing radioresistant breast cancer cells than 2 Gy x5. Furthermore, the 7 Gy x1 fraction produced higher levels of reactive oxygen species (ROS) and decreased the expression of radioresistance factors such as p-STAT3, ACSL4, FOXM1, RAD51, Bcl-xL, and survivin. Consistent with the in vitro studies, the 7 Gy × 1 fraction also showed superior antitumor effects in SR tumor-bearing BALB/c mice. Conclusions Single high-dose RT offers superior advantages over conventional fractionated RT in regard to overcoming radioresistance, supporting its potential as a promising treatment for recurrent tumors.

Non-homogenous intratumor ionizing radiation doses synergize with PD1 and CXCR2 blockade

The efficacy and side effects of radiotherapy (RT) depend on parameters like dose and the volume of irradiated tissue. RT induces modulations of the tumor immune microenvironment (TIME) that are dependent on the dose. Low dose RT (LDRT, i.e., single doses of 0.5–2 Gy) has been shown to promote immune infiltration into the tumor. Here we hypothesize that partial tumor irradiation combining the immunostimulatory/non-lethal properties of LDRT with cell killing/shrinkage properties of high dose RT (HDRT) within the same tumor mass could enhance anti-tumor responses when combined with immunomodulators. In models of colorectal and breast cancer in immunocompetent female mice, partial irradiation (PI) with millimetric precision to deliver LDRT (2 Gy) and HDRT (16 Gy) within the same tumor induces substantial tumor control when combined with anti-PD1. Using flow cytometry, cytokine profiling and single-cell RNA sequencing, we identify a crosstalk between the TIME of the differentially irradiated tumor volumes. PI reshapes tumor-infiltrating CD8+ T cells into more cytotoxic and interferon-activated phenotypes but also increases the infiltration of pro-tumor neutrophils driven by CXCR2. The combination of the CXCR2 antagonist SB225002 with PD1 blockade and PI improves tumor control and mouse survival. Our results suggest a strategy to reduce RT toxicity and improve the therapeutic index of RT and immune checkpoint combinations.

Involved-field high-dose chemoradiotherapy with respiratory motion management for esophageal squamous cell carcinoma.

We investigated the clinical outcomes of involved-field high-dose (≥66 Gy) chemoradiotherapy (CRT) combined with respiratory motion management for esophageal squamous cell carcinoma (ESCC). Patients who underwent definitive CRT for histologically confirmed ESCC in our department between 2012 and 2018 were retrospectively analyzed. Respiratory motion management strategies included breath-holding (63%) and mask immobilization (29%) based on individual measurements of respiratory tumor motion using radiographic fluoroscopy with endoscopically placed clip markers as landmarks. We evaluated patient characteristics, treatment efficacy, failure patterns, and toxicities. We enrolled 35 patients with a prescribed dose of 66-70 Gy in 33-35 fractions. The overall response rate within 6 months post-CRT was 94.3%; the median follow-up period for survivors was 43 months. The 2-year overall survival (OS), progression-free survival, and locoregional failure-free survival rates were 51.4%, 42.9%, and 42.9%, respectively. A significant difference in OS was observed between patients with and without esophageal fistulas after CRT (p = 0.002, log-rank test). Disease failure occurred in 16 patients (45.7%), including one (2.9%) with out-of-field regional nodal failure. Major grade 3 or higher toxicities included decreased white blood cell count (48.6%), neutrophil count (34.3%), and esophageal stenosis (31.4%). No grade 3 or higher cardiopulmonary toxicities were observed. Bronchial/tracheal tumor compression and a higher radiotherapy dose (70 Gy) were significantly correlated with esophageal fistulas. Involved-field high-dose CRT with respiratory motion management may be a feasible treatment option for ESCC. However, a comprehensive assessment of esophageal fistula risk is required to identify suitable candidates.

6955 A Rare Case of Rapidly Enlarging High Grade Follicular-Derived Carcinoma in a Young Patient - Formerly Known as Insular Thyroid Carcinoma with good response to Radioactive iodine ablation- A New Name, Same Aggressive Features

Abstract Disclosure: R. Abdelmasih: None. N. Prasad: None. N. Shah: None. Introduction: Follicular-derived thyroid carcinomas, formerly known as insular thyroid carcinomas, are an albeit rare but highly lethal thyroid carcinoma subtype with an incidence of 1-10% worldwide. It is known for its aggressive nature and comprises the majority of deaths from non-anaplastic follicular thyroid cancers. Case Presentation: A 30-year-old male presented with 2-year history of progressively enlarging painless right neck mass. Physical exam revealed 6x3 cm right well-circumscribed mobile mass not displacing the trachea. Head and neck CT showed 6.5 cm right thyroid mass with level 2A lymph node. Neck Ultrasound showed a 6.4 cm right thyroid nodule. Fine needle aspiration of the mass showed atypia of undetermined significance. Patient returned to clinic 1 year later with progressively enlarging right neck mass, now associated with dysphagia measuring 10 cm in physical exam deviating the trachea to the left. Repeat CT H&amp;N showed 10 cm right thyroid mass with moderate tracheal deviation and US showed 11 cm right heterogenous thyroid mass with regular margins and negative LNs. Patient underwent right thyroid lobectomy with surgical pathology showed 11.4 cm tumor with vascular invasion and no extrathyroidal extension. Pathology showed high grade follicular-derived Thyroid Carcinoma. Patient underwent completion thyroidectomy with benign pathology followed by radioactive iodine ablation 107.8 mCi I131 with successful targeting of residual thyroid tissue and no evidence of iodine avid distant metastasis. Patient has been followed closely for 2 years now with regular US, thyroglobulin level with recurrence. Discussion: Insular thyroid carcinomas are aggressive malignancies predominantly seen in females within the age of 55-65 though cases of young patients and children have been reported. Patients often present with enlarging goiter, dysphagia, and dyspnea however, metastatic disease to lymph nodes, lung and bone has also been reported as primary presentation in 20% of cases. Per literature review, recurrence and mortality rates have very wide range of 36-83% and 9-75% respectively which could be explained by a variety of prognostic factors including Patient age, tumor size, Macroscopic evident extrathyroidal extension, distant metastasis, or tumor necrosis. Often times insular thyroid carcinomas are mistaken for anaplastic carcinoma and thus fine needle aspiration is a helpful diagnostic tool to differentiate insular carcinoma. Pathology typically demonstrates well-defined insulae of thyroglobulin-filled follicles, necrotic foci, and high random mitotic activity. Treatment includes total thyroidectomy followed by high-dose radiotherapy. We Present this case to shed light on such a rare aggressive entity that requires early detection, belligerent management, and close follow-up for promising outcomes. Presentation: 6/3/2024

Long-Term Outcome of a Multicenter Prospective Study on Efficacy and Safety of High-Dose Stereotactic Body Radiation Therapy ≥48-h Interfraction Interval for ≤5 cm Hepatocellular Carcinoma

Introduction: The goal of this study was to evaluate the efficacy and safety of high-dose stereotactic body radiation therapy (SBRT) with an extended (48 h or more) interfraction interval for hepatocellular carcinoma (HCC) ≤5 cm in size after incomplete response to transarterial chemoembolization (TACE). Methods: This multicenter prospective study included 54 patients with inoperable HCC of ≤5 cm size between July 2012 and June 2015. A total SBRT dose of 60 Gy in 3 fractions was administered within 14 days with ≥48-h interfraction interval to patients who showed an incomplete response after 1–5 sessions of TACE. Treatment responses were defined according to the modified Response Evaluation Criteria for Solid Tumors. Toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Results: Forty-eight patients were evaluated with a median follow-up period of 66 months (range, 2–126 months). The median tumor size was 2.0 cm (range, 1.0–4.5 cm), and most patients (87.5%) had a single lesion. The 1-, 2-, and 5-year local control (LC) rates were 100%, 94.8%, and 90.7%, respectively. The 1-, 2-, and 5-year progression-free survival (PFS) rates were 63.4%, 56.9%, and 24.9%, respectively. The 1-, 2-, and 5-year overall survival (OS) rates were 95.6%, 90.9%, and 76.5%, respectively. None of the patients experienced grade 3+ gastrointestinal toxicity, while 1 patient developed non-classic radiation-induced liver disease 2 months after SBRT. Conclusion: High-dose SBRT with a ≥48-h interfraction interval after incomplete response to TACE is effective for HCC ≤5 cm in size as evidenced by the high rates of LC and OS and acceptable treatment-related toxicity.

EP.13C.02 High-Dose Radiation Therapy for Limited-Stage Small-Cell Lung Cancer: Real-World Experience from Two Tertiary Centers

EP.13C.02 High-Dose Radiation Therapy for Limited-Stage Small-Cell Lung Cancer: Real-World Experience from Two Tertiary Centers