Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.

Carcinoma of the rectum is a heterogeneous disease. The clinical spectrum identifies a subset of patients with locally advanced tumours that are close to or involve adjoining structures, such as the sacrum, pelvic sidewalls, prostate or bladder. Within this group of patients categorized as ''locally advanced", there is also variability in the extent of disease with no uniform definition of resectability. A practice-oriented definition of a locally advanced tumour is a tumour that cannot be resected without leaving microscopic or gross residual disease at the resection site. Since these patients do poorly with surgery alone, irradiation and chemotherapy have been added to improve the outcome. Intraoperative irradiation (IORT) is a component of local treatment intensification with favourable results in this subgroup of patients. International guidelines (National Comprehensive Cancer Network (NCCN) guidelines) currently recommend the use of IORT for rectal cancer resectable with very close or positive margins, especially for T4 and recurrent cancers. We report the ESTRO-ACROP (European Society for Radiotherapy and Oncology-Advisory Committee on Radiation Oncology Practice) recommendations for performing IORT in primary locally advanced rectal cancer.

Approximately 20% patients with non-small cell lung cancer (NSCLC) present with CNS spread at the time of diagnosis and 25–50% are found to have brain metastases (BMs) during the course of the disease. The improvement in the diagnostic tools and screening, as well as the use of new systemic therapies have contributed to a more precise diagnosis and prolonged survival of lung cancer patients with more time for BMs development. In the past, most of the systemic therapies failed intracranially because of the inability to effectively cross the blood brain barrier. Some of the new targeted therapies, especially the group of tyrosine kinase inhibitors (TKIs) have shown durable CNS response. However, the use of ionizing radiation remains vital in the management of metastatic brain disease. Although a decrease in CNS-related deaths has been achieved over the past decade, many challenges arise from the need of multiple and repeated brain radiation treatments, which carry along not insignificant risks and toxicity. The combination of stereotactic radiotherapy and systemic treatments in terms of effectiveness and adverse effects, such as radionecrosis, remains a subject of ongoing investigation. This review discusses the challenges of the use of radiation therapy in NSCLC BMs in view of different systemic treatments such as chemotherapy, TKIs and immunotherapy. It also outlines the future perspectives and strategies for personalized BMs management.

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