Search Results (1,112)

Background: The integration of radiotherapy (RT) and immunotherapy (IO) is transforming oncologic paradigms by combining local tumor control with systemic immune activation. In urological cancers—prostate, bladder, and renal cell carcinoma—this strategy is supported by growing biological rationale and promising early clinical results. Methods: This narrative review synthesizes preclinical and clinical evidence on RT–IO combinations in urological malignancies. A comprehensive literature search was performed in PubMed, Embase, and ClinicalTrials.gov, focusing on mechanistic insights, clinical trials, and translational challenges related to RT–IO synergy. Results: Early-phase studies in bladder and renal cell carcinoma demonstrate feasibility, immunogenic enhancement, and manageable toxicity when RT is combined with checkpoint inhibitors. Prostate cancer remains less immunoresponsive but may benefit from RT-induced immune priming, particularly in biomarker-enriched subgroups. Innovations in precision RT, biomarkers, artificial intelligence, and novel immunotherapeutics are shaping future applications. Conclusions: RT–IO combinations represent a promising yet complex frontier in urological oncology. Future success will rely on precision-guided patient selection, optimized trial design, and equitable global implementation to ensure durable clinical benefit. Full article

Background: Chronic pelvic toxicity induced by radiotherapy and/or chemotherapy (R/CIPT) is a debilitating sequela in gynecological cancer survivors, often refractory to conventional treatments and potentially linked to gut microbiota dysbiosis. Ozone therapy (OT), particularly rectal insufflation, demonstrates anti-inflammatory and redox-modulating effects through hormetic mechanisms (Nrf2 activation/NF-κB inhibition). We hypothesize that its clinical benefit is mediated, in part, by restoring gut microbial homeostasis. Objective: This manuscript proposes a clinical study to evaluate the impact of rectal OT on the gut microbiota of patients with gynecological cancers and chronic R/CIPT. Proposed Methods: A prospective, observational study of 38 patients is outlined: 19 with CTCAE v5.0 Grade ≥2 chronic R/CIPT receiving compassionate rectal OT (~40 sessions over 4 months), and 19 matched controls without toxicity. Stool samples for 16S rRNA sequencing will be collected from the OT group pre- and post-intervention and once from controls. Primary endpoints are changes in microbiota composition/diversity and pelvic toxicity scores (CTCAE v5.0, EORTC QLQ-CX24). Secondary endpoints include quality of life (EORTC QLQ-C30, EQ-5D-5L), anxiety/depression (HADS), and serum inflammatory/oxidative stress biomarker analysis. Anticipated Results and Conclusion: This will be the first study to prospectively investigate whether rectal OT’s effect correlates with a beneficial shift in the gut microbiota, specifically an increase in commensals (e.g., short-chain fatty acids producers) and a decrease in pathobionts. If successful, OT could be assessed as a novel, microbiota-targeting intervention for R/CIPT. The findings from this pilot study will provide the necessary groundwork for a future randomized controlled trial to definitively establish causality and efficacy. Full article

Background: Locally advanced cervical cancer (LACC) represents a significant challenge in oncology, requiring accurate assessment of local extent and metastatic spread. Multiparametric magnetic resonance imaging (mpMRI) has assumed a central role in the loco-regional characterization of the tumor due to its high soft-tissue resolution and the ability to integrate functional information. Objectives: In this narrative review, we explore the use of mpMRI in the diagnosis, staging, and treatment response of LACC, comparing its performance with that of PET/CT, which remains complementary for remote staging. The potential of whole-body magnetic resonance imaging (WB-MRI) and hybrid PET/MRI techniques is also analyzed, as well as the emerging applications of radiomics and artificial intelligence. The paper also discusses technical limitations, interpretative variability, and the importance of protocol standardization. The goal is to provide an updated and translational summary of imaging in LACC, with implications for clinical practice and future research. Methods: Prospective and retrospective studies, systematic reviews, and meta-analyses on adult patients with cervical cancer were included. Results: Fifty-two studies were included. MRI demonstrated a sensitivity and specificity greater than 80% for parametrial and bladder invasion, but limited sensitivity (45–60%) for lymph node disease, lower than PET/CT. Multiparametric MRI was useful in early prediction of response to chemotherapy and radiotherapy and in distinguishing residual disease from fibrosis. The integration of MRI into Image-Guided Adaptive Brachytherapy (IGABT) resulted in improved oncological outcomes and reduced toxicity. The applications of radiomics and AI demonstrated enormous potential in predicting therapeutic response and lymph node status in the MRI study, but multicenter validation is still needed. Conclusions: MRI is the cornerstone of the local–regional staging of advanced cervical cancer; it has become an essential and crucial tool in treatment planning. Its use, combined with PET/CT for lymph node assessment and metastatic disease staging, is now the standard of care. Future prospects include the use of whole-body MRI and the development of predictive models based on radiomics and artificial intelligence. Full article

Radiotherapy (RT) remains a cornerstone of cancer treatment, offering spatially precise cytotoxicity against malignant cells. However, emerging evidence reveals that ionizing radiation (IR) exerts biological effects beyond the targeted tumor volume, manifesting as radiation bystander effects (BEs) and other non-targeted effects (NTEs). These phenomena challenge the traditional paradigm of RT as a localized intervention, highlighting systemic and long-term consequences in non-irradiated tissues. This comprehensive review synthesizes molecular, cellular, and clinical insights about BEs, elucidating the complex intercellular signaling networks gap junctions, cytokines, extracellular vesicles, and oxidative stress that propagate damage, genomic instability, and inflammation. We explore the role of mitochondrial dysfunction, epigenetic reprogramming, immune modulation, and stem cell niche disruption in shaping BEs outcomes. Clinically, BEs contribute to neurocognitive decline, cardiovascular disease, pulmonary fibrosis, gastrointestinal toxicity, and secondary malignancies, particularly in pediatric and long-term cancer survivors. The review also evaluates countermeasures including antioxidants, COX-2 inhibitors, exosome blockers, and FLASH RT, alongside emerging strategies targeting cfCh, inflammasomes, and senescence-associated secretory phenotypes. We discuss the dual nature of BEs: their potential to both harm and heal, underscoring adaptive responses and immune priming in specific contexts. By integrating mechanistic depth with translational relevance, this work posits that radiation BEs are a modifiable axis of RT biology. Recognizing and mitigating BEs is imperative for optimizing therapeutic efficacy, minimizing collateral damage, and enhancing survivorship outcomes. This review advocates for a paradigm shift in RT planning and post-treatment care, emphasizing precision, personalization, and systemic awareness in modern oncology. Full article

Background: One of the challenges in treating pancreatic ductal adenocarcinoma (PDAC) with stereotactic radiotherapy (SRT) is to manage lesions abutted to the duodenum, bowel and stomach. Simultaneous integrated protection (SIP) is one of the proposed approaches to increase plan reproducibility and quality. However, no clinical data are available regarding the dosimetric objectives impacting local control probability. Methods: This is a prospective, single-arm study. Key inclusion criteria were as follows: PDAC histology; tumor abutment with duodenum, stomach, or small bowel; and SRT schedule consisting of 45 Gy in six fractions. Delineation of the PTV overlapped with critical OARs (PTV_SIP) and PTV outside critical OARs (PTV_Dominant) was mandatory. Dose constraints were as follows: (near) maximum dose, D2cc, and D20cc to critical OARs 38 Gy, 32 Gy, and 24 Gy, respectively. This study was designed to prospectively investigate the main clinical and dosimetric parameters impacting freedom from local recurrence (FFLR). Results: From June 2019 to January 2024, 104 patients were enrolled. One-year FFLR was 91.7%. Fifteen events of local failure occurred (17.6%). Mapping of local relapses showed a relapse inside the PTV_SIP area in nine patients and outside the PTV_SIP in six cases (NS). Whole PTV > 69 cc, PTV_SIP > 4 cc, PTV-SIP/whole PTV ratio > 7%, (near) Dmin to PTV_SIP < 25 Gy, mean dose to PTV_SIP < 28 Gy, and (near) Dmin to PTV_Dominant < 29 Gy were associated with worse FFLR. Multivariable analysis showed PTV_SIP absolute volume of more than 4 cc, mean dose to PTV_SIP < 28 Gy and whole PTV > 69 cc were independently related to worse FFLR. One case of acute G4 toxicity and two cases of acute G3 toxicity occurred, with two late toxicity deaths not certainly due to treatment. Conclusions: In this prospective study, SIP planning strategy with six fractions is safe and effective in pancreatic targets with critical contact with critical OARs. Given its potential advantages, SIP planning is a potential innovative strategy that should be compared to standard SRT planning in an ad hoc trial design. Full article

Immune checkpoint inhibitors (ICIs) and thoracic radiotherapy are standard treatments for advanced non-small-cell lung cancer (NSCLC), especially in patients with high PD-L1 expression or symptoms such as superior vena cava syndrome (SVCS). Both therapies carry a risk of pulmonary toxicity, which may be exacerbated by opportunistic infections due to corticosteroid use. We report a unique case of a 65-year-old man with squamous-cell NSCLC and high PD-L1 expression (80%), who developed a rare complication: radiation recall pneumonitis (RRP), with superimposed Pneumocystis jirovecii pneumonia and severe symptomatic hyponatremia induced by trimethoprim/sulfamethoxazole (TMP-SMX). The coexistence of these three complications—radiotherapy- and immunotherapy-associated lung injury, opportunistic infection, and electrolyte imbalance—represents an exceptional clinical scenario not previously described in the literature. This report highlights the importance of differential diagnosis, early recognition of complications, and close monitoring of electrolytes in NSCLC patients undergoing complex treatment regimens. Full article

The management of large bulky tumors is very challenging. The current treatment options for effective palliation of symptoms are limited. These tumors often present a large burden at the time of diagnosis, growing along critical bony and neural structures and preventing surgical resection in most of the cases. These tumors are also known to be relatively resistant to chemotherapy, with very low response rates. In addition, conventional photon-based radiotherapy has a limited effect due to their radioresistance, the use of large treatment fields, and the impossibility of delivering high doses because of the higher risk of normal tissue toxicity. Therefore, more effective radiation treatments for palliation are needed to achieve greater local control rates. A recent approach called partial ablative radiotherapy (PART) has been shown to be potentially able to improve the effectiveness of radiotherapy. This technique is based on the ability of recent advanced delivery techniques to deliver a high “ablative” dose to the central part of the tumor, maintaining a very low and safe dose profile at the periphery to spare the surrounding organs at risk. Although this technique has been evaluated only in small studies and case reports, it showed notable treatment responses and safety profiles. The present narrative review describes the rationale for PART, the current and forthcoming state of evidence, the existing studies, and the future directions for the development of this approach, including the associated challenges. Full article

Background: A wide percentage (25–40%) of patients affected by head and neck squamous cell carcinoma (HNSCC) are over 70 years old, and they present with different characteristics if compared to younger patients. Elderly patients often receive less intensive, non-surgical, and non-multimodal treatments. Although age does not mean frailty, the elderly are at a higher risk of developing toxicity. In fact, several studies enrolling patients treated with cisplatin + radiotherapy (CISPLATIN + RT) or cetuximab + radiotherapy (Cet + RT) showed reduced efficacy over 65 years. Methods: We conducted a multicenter retrospective analysis in patients with Locally Advanced HNSCC aged over 65 years, who underwent Cet-RT, diagnosed in the period between 2017 and 2024. The primary endpoint was to describe Overall Survival (OS), the secondary endpoints were Progression Free Survival (PFS) and the percentage and type of Adverse Events (AEs). Patients received a geriatric assessment using the G8 questionnaire. Results: Data regarding Eighty-Two (82) patients were analyzed, median age was 74 years (range 65–84), most patients had oral cavity (26.8%) and laryngeal cancer (37.8%). Fifty-six point one (56.1%) of patients were smokers, and 17.1% reported alcohol consumption. All patients completed radiotherapy, and 80.5% of them developed AEs, which in 25.6% of cases were G3–4 toxicities. No relationship was found between G3–4 AEs and age (p = 0.596), G8score < 14 (p = 0.804), and smoking (p = 0.245)/drinking habits (p = 0.341). Median OS was 58 months, with a slightly non-significant positive trend in OS for patients who were non-smokers and those who did not develop G3–4 AEs (p = 0.786 and 0.799, respectively). Association between folliculitis and OS was statistically significant (p = 0.001). Conclusions: In elderly patients, Cet-RT represents a feasible, well-tolerated option, although further prospective studies are needed. Full article

Stereotactic ablative radiotherapy (SABR) has revolutionized the management of patients with oligometastatic and selected primary cancers due to its ability to deliver highly conformal, high-dose radiation in few fractions with minimal toxicity. However, the biological heterogeneity among patients treated with SABR results in variable outcomes, emphasizing the need for predictive and prognostic biomarkers to guide patient selection and post-treatment management. This narrative review discusses the current landscape of biomarker development in the context of SABR across tumor types. Key classes include circulating tumor DNA (ctDNA), extracellular vesicles (EVs), radiomic features, and immunological markers. We highlight the role of each biomarker category in refining therapeutic approaches, their integration into ongoing clinical trials, and future directions for personalized SABR paradigms. Translating these promising biomarker strategies into clinical SABR workflows will require further standardisation, validation, and regulatory alignment. Full article

Introduction: The aim of the study was to analyse the results and potential complications of local treatment with HDR (high dose-rate) brachytherapy of liver metastases from colorectal cancer, depending on the targeted therapy used and considering RAS gene mutation and chemotherapy in individual treatment lines. Material and methods: The study included 142 patients with oligoprogressive liver metastases who underwent HDR brachytherapy without changing the line of treatment, based on a retrospective analysis of 270 patients treated between 2015 and 2022. The impact of RAS gene mutations, lines of chemotherapy depending on the treatment regimens used, PFS (progression free survival), OS (overall survival), LC (local control) and the degree of radiological response were analysed. The impact of these drugs on hepatotoxicity and the risk of haemorrhagic complications was also analysed. Results: The presence of mutations in KRAS/NRAS genes (exons 2, 3, 4) had a statistically significant impact on PFS in the first, third and fourth lines of treatment, and on OS and LC in the third and fourth lines of treatment. In the third and fourth lines of treatment, patients with a mutation in the RAS gene had a poorer radiological response to treatment regardless of the chemotherapy used. PFS, OS and LC differed depending on the line of treatment and amounted to 17.5, 11, 8.5, 6 and 4 months, 27, 19, 13, 11 and 11 months, and 27, 19, 11, 6 and 6 months, respectively. The greatest benefit in terms of PFS was achieved by patients treated with first-line chemotherapy combined with epidermal growth factor receptor (EGFR) inhibitors, in the absence of RAS gene mutations. In the third line, the greatest benefit was achieved by patients treated with trifluridine/tipiracil in the absence of RAS gene mutations. The greatest percentage reduction in the volume of treated lesions and the highest percentage of control were observed in the first three lines of treatment. The toxicity of the treatment was low; only in the third and fourth lines of treatment were differences in the decrease in albumin levels found depending on the type of treatment used. Conclusions: A mutation in the RAS genes worsens the prognosis, regardless of the line of treatment and the systemic treatment used. The greatest benefit from brachytherapy is seen in patients in the first three lines of treatment without RAS mutations, treated with anti-EGFR chemotherapy in the first line and trifluridine/tipiracil in the third line. Combining brachytherapy of liver metastases with systemic treatment is safe, regardless of the systemic treatment used. Full article

Background: Integrating deep regional hyperthermia (HT) with neoadjuvant chemoradiotherapy (CRT) may enhance treatment efficacy in locally advanced rectal cancer (LARC), yet feasibility and tolerance data remain scarce for both short-course (SCRT) and long-course (LCRT) radiotherapy (RT) regimens. Methods: In this single-center prospective observational study, 67 LARC patients received neoadjuvant RT and chemotherapy (CT) combined with deep radiative HT using a phased-array system (ALBA 4D). Patients treated with SCRT (5 × 5 Gy) were prescribed two HT sessions; those treated with LCRT (25 × 2 Gy) were prescribed ten. HT planning was guided by dedicated software, and real-time thermometry ensured precise thermal delivery. Feasibility was defined as completion of ≥50% of prescribed sessions. Tolerance and toxicity were assessed with standardized clinical scales (QMHT, UMC, CTCAE v4.03). Results: HT was feasible in both groups: 100% of SCRT and 63.6% of LCRT patients completed ≥50% of prescribed sessions. In total, 243 sessions were delivered. Most symptoms were mild and transient, predominantly localized pain. No grade ≥3 HT-related toxicities occurred. All scheduled RT and surgery proceeded without delay. Median T50 was 40.3 °C (SCRT) and 40.4 °C (LCRT); the median RT-to-HT interval was 42 min in both groups. Conclusion: This first Spanish experience shows that deep radiative HT can be seamlessly integrated into both SCRT and LCRT neoadjuvant protocols for rectal cancer. High adherence, favorable tolerance, and reliable thermal control support clinical implementation. Any between-schedule observations are descriptive only; no formal comparative testing was performed. The study was not designed or powered to establish comparative effectiveness between SCRT and LCRT, and the sample size was insufficient to detect rare HT-specific adverse events. Full article

Cancer therapy is rapidly evolving from a one-size-fits-all paradigm toward highly personalized approaches. Traditional chemotherapies and radiotherapies, while broadly applied, often yield suboptimal outcomes due to tumor heterogeneity and are limited by significant toxicities. In contrast, precision oncology tailors prevention, diagnosis, and treatment to the individual patient’s genetic and molecular profile. Key advancements underscore this shift: molecularly targeted drugs (e.g., trastuzumab for HER2-positive breast cancer, EGFR and ALK inhibitors for lung cancer) have improved efficacy and reduced toxicity compared to conventional therapy. Pharmacokinetic (PK) and pharmacodynamic (PD) considerations are central to personalizing treatment, explaining variability in drug exposure and response among patients and guiding dose optimization. Modern strategies like therapeutic drug monitoring and model-informed precision dosing seek to maintain drug levels in the therapeutic range, improving outcomes. Immunotherapies, including checkpoint inhibitors and CAR-T cells, have transformed oncology, though patient selection via biomarkers (such as PD-L1 expression or tumor mutational burden) is critical to identify likely responders. Innovative drug delivery systems, notably nanomedicine, address PK challenges by enhancing tumor-specific drug accumulation and enabling novel therapeutics. Furthermore, rational combination regimens (informed by PK/PD and tumor biology) are being designed to achieve synergistic efficacy and overcome resistance. Key barriers include the high cost of biomarker testing, insufficient laboratory infrastructure, and inconsistent reimbursement policies. Operational inefficiencies such as long turnaround times or lack of clinician awareness further limit the use of precision diagnostics. Regulatory processes also remain complex, particularly around the co-development of targeted drugs and companion diagnostics, and the evidentiary requirements for rare subgroups. Addressing these barriers will require harmonized policies, investment in infrastructure, and educational initiatives to ensure that the promise of personalized medicine becomes accessible to all patients. Ensuring that advances are implemented responsibly—guided by pharmacological insights, supported by real-world evidence, and evaluated within ethical and economic frameworks—will be critical to realizing the full potential of personalized cancer medicine. Full article

Objectives: This study aimed to evaluate the efficacy and toxicity of stereotactic body radiotherapy (SBRT) for spinal metastases, focusing on pain control, local tumor control, and the incidence of vertebral compression fractures (VCF). Materials and Methods: We retrospectively analyzed 179 patients with 217 spinal metastatic lesions who underwent SBRT between July 2020 and April 2022. The prescribed doses for SBRT were 18 or 20 Gy for one fraction, ≥24 Gy for three fractions, ≥20 Gy for four fractions, and ≥25 Gy for five fractions. Patient-reported treatment response was evaluated 1–3 months after SBRT completion. Local recurrence was defined as failure within the radiotherapy field. Pain response, local progression-free survival (LPFS), and the incidence of painful VCF were assessed. Prognostic factors for LPFS and VCF risk factors were evaluated. Results: The overall pain response rate was 80.8%. LPFS rates were 90.6% at 1 year and 83.0% at 2 years. Lytic/mixed lesions and involvement of multiple segments were significant prognostic factors for reduced LPFS. The cumulative incidence of painful VCF was 8.7% at 1 year and 12.8% at 2 years. A biologically effective dose (BED₃) ≥104 Gy was the only significant risk factor for painful VCF. Conclusions: SBRT demonstrated high efficacy for pain and local tumor control in spinal metastases, with an acceptable VCF risk. Full article

Cancer continues to pose a major global health burden, with conventional therapeutic modalities such as surgical resection, chemotherapy, radiotherapy, and immunotherapy often hindered by limited tumor specificity, substantial systemic toxicity, and the emergence of multidrug resistance. The rapid advancement of nanotechnology has introduced functionalized nanomaterials as innovative tools in the realm of precision oncology. These nanoplatforms possess desirable physicochemical properties, including tunable particle size, favorable biocompatibility, and programmable surface chemistry, which collectively enable enhanced tumor targeting and reduced off-target effects. This review systematically examines recent developments in the application of nanomaterials for cancer therapy, with a focus on several representative nanocarrier systems. These include lipid-based formulations, synthetic polymeric nanoparticles, inorganic nanostructures composed of metallic or non-metallic elements, and carbon-based nanomaterials. In addition, the article outlines key strategies for functionalization, such as ligand-mediated targeting, stimulus-responsive drug release mechanisms, and biomimetic surface engineering to improve in vivo stability and immune evasion. These multifunctional nanocarriers have demonstrated significant potential across a range of therapeutic applications, including targeted drug delivery, photothermal therapy, photodynamic therapy, and cancer immunotherapy. When integrated into combinatorial treatment regimens, they have exhibited synergistic therapeutic effects, contributing to improved efficacy by overcoming tumor heterogeneity and resistance mechanisms. A growing body of preclinical evidence supports their ability to suppress tumor progression, minimize systemic toxicity, and enhance antitumor immune responses. This review further explores the design principles of multifunctional nanoplatforms and their comprehensive application in combination therapies, highlighting their preclinical efficacy. In addition, it critically examines major challenges impeding the clinical translation of nanomedicine. By identifying these obstacles, the review provides a valuable roadmap to guide future research and development. Overall, this work serves as an important reference for researchers, clinicians, and regulatory bodies aiming to advance the safe, effective, and personalized application of nanotechnology in cancer treatment. Full article

Glioblastoma (GB) is one of the most aggressive and treatment-resistant cancers affecting the central nervous system (CNS), predominantly in adults. Despite significant advancements in this field, GB treatment still relies primarily on conventional approaches, including surgical resection, radiotherapy, and chemotherapy, which, due to its complex pathological characteristics, resistance mechanisms, and restrictive nature of the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB), remain of limited efficacy. In this context, the development of innovative therapeutic strategies able to overcome these barriers, induce cancer cell death, and improve patient prognosis is crucial. Recently, nanoparticle platforms and focused ultrasounds seem to be promising approaches for cancer treatment. Nanoparticles enable targeting and controlled release, whilst focused ultrasounds enhance tissue permeation, increasing drug accumulation in a specific organ. However, nanoparticles can suffer from synthesis complexity, long-term biocompatibility and accumulation in the body with consequent toxicity, whereas focused ultrasounds require specialized equipment and can potentially cause thermal damage, hemorrhage, or cavitation injury. Cyclodextrins (CYDs) possess good properties and represent a versatile and safer alternative able to improve drug stability, solubility, and bioavailability, and depending on the type, dose, and administration route, can reduce local and systemic toxicity. Thus, CYDs emerge as promising novel excipients in GB treatment. Despite these advantages, CYD complexes suffer from receptor specificity, reducing their potential in precision medicine. By combining CYD complexes with polymeric or lipidic platforms, the advantages of CYD safety and drug solubilization together with their specific targeting can be obtained, thus enhancing selectivity and maximizing efficacy while minimizing recurrence and systemic toxicity. This review provides a comprehensive overview of GB pathology, conventional treatments, and emerging CYD-based strategies aimed at enhancing drug delivery and therapeutic efficacy. Full article