Nunziata D’Abbiero

Unresectable locally advanced non-small cell lung cancer (LA-NSCLC) remains a therapeutic challenge, despite the paradigm shift established by the PACIFIC trial (concurrent chemoradiation followed by Durvalumab consolidation). A substantial number of patients still experience disease progression and significant toxicity. This narrative review explores innovative radiation therapy (RT) strategies and their integration with systemic therapy. Key innovations analyzed include: 1. Systemic Therapy Intensification: Induction chemo-immunotherapy or novel multi-agent consolidation regimens show promise, but managing increased toxicity remains critical. The integration of DNA damage response inhibitors with RT is also being actively explored to maximize radiosensitization. 2. RT Dose and Volume Modulation: Recent data suggests that dose escalation via highly conformal hypofractionation or stereotactic ablative body radiotherapy (SABR) may enhance efficacy, particularly when combined with immunotherapy. Conversely, risk-adapted de-escalation of dose or volumes is studied to reduce immunosuppression and treatment-related toxicity, allowing more patients, including the elderly and frail, to complete consolidation. 3. Organ-at-Risk (OAR) Sparing: Advanced techniques like intensity-modulated radiation therapy (IMRT), adaptive RT (ART), and proton beam therapy (PBT) are crucial for minimizing dose to OARs and new substructures, such as specific cardiac subregions and lymphoid tissues. This OAR sparing is strongly correlated with improved OS and reduced immunosuppression. In conclusion, this narrative review focuses on the future of LA-NSCLC treatment, which is moving toward personalized, precision RT, embracing both intensification and thoughtful de-escalation, supported by synergistic systemic agents, to maximize curative potential and minimize toxicity.

Background: Stereotactic body radiotherapy (SBRT) has gained increasing interest in the treatment of locally advanced pancreatic cancer (LAPC), although its effectiveness has not been defined in randomized trials. This systematic review and meta-analysis aimed to compare clinical outcomes and treatment-related toxicity between SBRT and CFRT in LAPC. Methods: This analysis was performed in accordance with PRISMA guidelines (PROSPERO: CRD420251128943). MEDLINE and Scopus were searched for comparative studies published between January 2015 and July 2025. Five retrospective studies comprising 768 patients fulfilled the eligibility criteria. Pooled hazard ratios (HRs) were calculated for overall survival (OS) and progression-free survival (PFS), while risk ratios (RRs) were estimated for severe (grade ≥ 3) acute toxicity using random-effects models. Study quality was evaluated using the ROBINS-I tool. Results: No significant OS or PFS differences were observed between SBRT and CFRT. SBRT was associated with a lower incidence of severe acute toxicity. The overall risk of bias across studies was moderate. Conclusions: SBRT appears to achieve survival outcomes comparable to CFRT with a favorable acute toxicity profile in patients with LAPC. Nevertheless, the current evidence is limited by retrospective designs and heterogeneity, highlighting the need for prospective randomized trials to define the role of SBRT in this setting.

Locally advanced pancreatic cancer (LAPC) represents a major urgency in oncology. Due to the massive involvement of the peripancreatic vessels, a curative-intent surgery is generally precluded. Historically, LAPC has been an indication for palliative systemic therapy. In recent years, with the introduction of intensive multi-agent chemotherapy regimens and aggressive surgical approaches, the survival of LAPC patients has significantly improved. In this complex and rapidly evolving scenario, the role of radiotherapy is still debated. The use of standard-dose conventional fractionated radiotherapy in LAPC has led to unsatisfactory oncological outcomes. However, technological advances in radiation therapy over recent years have definitively changed this paradigm. The use of ablative doses of radiotherapy, in association with image-guidance, respiratory organ-motion management, and adaptive protocols, has led to unprecedented results in terms of local control and survival. In this overview, principles, clinical applications, and current pitfalls of ablative radiotherapy (ART) as an emerging treatment option for LAPC are discussed.