Radiation Oncology最新文献

Background: Radiation therapy (RT) plays a significant role in the multimodal management of primary brain tumors, improving oncological outcomes. However, despite advances such as Intensity-Modulated Radiation Therapy (IMRT), photon-based RT inevitably exposes normal organs to low-dose radiation, leading to long-term functional morbidities like cognitive decline, endocrine dysfunction, auditory toxicity. These late effects are particularly concerning in patients with favorable prognoses and protracted survival. Proton beam therapy (PBT), owing to its unique physical properties, holds promise for better functional preservation, but robust clinical data in adults are lacking.

Methods: The PRIDE study is a prospective, open-label, phase 3 randomized controlled trial enrolling adults aged 18-70 years undergoing focal cranial RT with conventional fractionation for primary brain tumors with expected survival > 5 years at Tata Memorial Centre, Mumbai. Participants will be randomized 1:1 to receive either photon-IMRT (standard arm) or PBT (experimental arm), stratified by age, tumor type, proximity to the hypothalamic-pituitary axis, and radiation dose. The primary endpoint is 5-year functional survival, defined as survival without functional deterioration (neurocognitive decline, significant ototoxicity, new or worsening endocrine dysfunction, neurological impairment, severe radio-necrosis, disease progression, or death). Secondary endpoints include patient-reported quality of life and health economic analysis. Survival outcomes will be analyzed using Kaplan-Meier methods with log-rank test. Neurocognitive and quality-of-life data will be evaluated using linear mixed-effects and non-parametric tests. A total of 156 patients will be enrolled, accounting for 20% attrition, to detect a 25% absolute improvement in 5-year functional survival favoring PBT (65% vs 40%, HR 0.47, α=0.05, power=80%). An interim analysis has been planned using the O'Brien-Fleming rule after 50% of the events (n=28).

Discussion: This trial will provide level 1 evidence investigating the role of PBT in functional outcomes among adults with primary brain tumors. If study endpoint is achieved, PBT will be considered as standard of care guiding contemporary neuro-oncology practice.

Registration: The trial has been approved by the Institutional Ethics Committee of Tata Memorial Centre, Mumbai. The trial has been registered with the Clinical Trial Registry of India (CTRI/2025/03/082568) and Clinicaltrials.gov (study identifier NCT06831461).

Background: Radiation-induced senescence strongly contributes to therapy resistance in HPV-negative head and neck squamous cell carcinoma (HNSCC). In particular, the NF-[Formula: see text]B-dependent arm of the senescence-associated secretory phenotype (SASP) activates signaling pathways that are tightly associated with, and promote, resistance to irradiation. In addition to the SASP, another hallmark of senescence is the upregulation of anti-apoptotic proteins. The BH3-only mimetic ABT-263 has been shown to effectively eliminate senescent cells. In this study, we employed ABT-263 to overcome the therapy-induced resistance in HNSCC cells and uncovered a link to chemokine signaling.

Methods: The HNSCC cell lines Cal33 and UPCI:SCC040 were treated with a combination of ABT-263 and photon irradiation, followed by functional and mechanistic assays assessing viability, apoptosis, senescence, secreted proteins, clonogenic survival, and DNA repair.

Results: Functionally, ABT-263 induced apoptosis via impeding Bcl-xL and activating Bax. Senescence levels were reduced after irradiation. Mechanistically, we observed cell-line- and protein-specific changes in the SASP, including a striking difference in CXCR2 receptor expression. Cal33 cells exhibited strong downregulation of CXCR2 and were radiosensitized by ABT-263, as indicated by reduced viability and clonogenic survival. In contrast, CXCR2 expression was induced in UPCI:SCC040 cells following treatment; although viability was diminished, clonogenic survival remained unaffected. Notably, radiosensitization in UPCI:SCC040 cells could be achieved through concomitant inhibition of CXCR2. Furthermore, the radiosensitizing effect was not attributable to increased DNA damage, as evidenced by γH2AX/53BP1 co-localization.

Conclusions: These findings highlight a central role for CXCR2-mediated signaling in the development of radioresistance in HPV-negative HNSCC cells.

Clinical trial number: Not applicable.