Alessio Giuseppe Morganti

Background: Tumor hypoxia is a major determinant of radioresistance, limiting oxygen-mediated fixation of radiation-induced DNA damage and promoting metabolic adaptation, tumor aggressiveness, and treatment failure. Nitroimidazole derivatives and related hypoxia-targeting compounds have been investigated as radiosensitizers because of their oxygen-mimetic properties and selective activation under low-oxygen conditions. Methods: A structured narrative review was conducted to evaluate recent evidence on hypoxia-targeting strategies and nitroimidazole-based radiosensitizers combined with radiotherapy. PubMed and Scopus were searched in March 2026 using terms related to radiotherapy and nitroimidazoles. Studies published within the last five years were included if they investigated hypoxia-targeting compounds, radiosensitization strategies, or dose–response relationships relevant to radiotherapy. Preclinical, computational, and clinical studies were considered. Results: Sixteen studies were included, comprising preclinical, computational, and clinical investigations. Most studies were preclinical and evaluated in vitro cell lines, murine tumor models, or xenografts across multiple tumor types, including head and neck cancer, glioblastoma, breast cancer, colorectal cancer, cervical cancer, renal carcinoma, pancreatic cancer, and ovarian-related models. Nitroimidazole-based and related hypoxia-targeting strategies generally enhanced radiation response under hypoxic conditions, with sensitizer enhancement ratio values ranging from approximately 1.09 to 1.65. In vivo studies reported reductions in tumor growth or tumor volume when radiosensitizers were combined with radiotherapy. Clinical evidence, mainly in head and neck squamous cell carcinoma, showed variable effects on locoregional outcomes. Conclusions: Current evidence supports the biological relevance of hypoxia-targeting strategies for improving radiotherapy response. Nitroimidazole-based compounds show consistent radiosensitizing effects in preclinical models, but clinical translation remains heterogeneous. Future studies should integrate hypoxia imaging, standardized endpoints, advanced drug delivery systems, and clinically relevant radiotherapy models to better define their role in modern radiation oncology.

Objective: This study aimed to explore the association between magnetic resonance imaging (MRI)-derived volumetric parameters and oncological outcomes, and to develop an exploratory predictive model based on these variables in patients treated with radio-chemotherapy followed by interventional radiotherapy (modern brachytherapy). Methods: Between 2021 and 2024, 300 patients with cervical cancer were included. Treatment was pelvic external beam radiotherapy with platinum-based chemotherapy followed by interventional radiotherapy boost. Volumetric MRI variables for each patient were collected. Time-to-event analyses were performed using Cox proportional hazards regression models. Model performance was assessed using Harrell’s concordance index (C-index). Internal validation was performed using bootstrap resampling. Based on the final multivariable Cox models, an interactive web-based nomogram was developed as an exploratory tool to visualize model-derived associations. Results: Median tumor volume decreased from 69.4 cm³ at diagnosis to 2.2 cm³ at the time of pre-interventional radiotherapy MRI, with a median reduction rate of 96.5%. Tumor volume at diagnosis, pre-interventional radiotherapy residual tumor volume, and tumor volume reduction rate were significantly associated with loco-regional relapse and distant metastases in Cox regression analyses. These findings were consistent across univariate and multivariable models. Internal validation confirmed the stability of the model estimates. Conclusions: MRI-derived volumetric parameters are associated with oncological outcomes in patients with locally advanced cervical cancer and may contribute to early risk stratification. The proposed model should be considered exploratory and hypothesis-generating and requires external validation before any potential clinical application.

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.

Palliative radiotherapy (PRT) is central to symptom control in advanced cancer, yet referrals are often late, and patients and clinicians frequently hold misconceptions about intent, benefits, and logistics. Patient education may address these gaps, but the PRT-specific evidence base has not been consolidated. We conducted a narrative review following SANRA guidance. We searched PubMed, Scopus, and the Cochrane Library for English-language studies from 1 January 2000 to 18 July 2025. Eligible articles evaluated structured patient-education interventions or characterized education or communication content, information needs, or decision processes among adults referred to or receiving PRT. Two reviewers independently screened and extracted data. Owing to heterogeneity of designs and endpoints, we performed a narrative synthesis without meta-analysis. Six studies met criteria: two randomized controlled trials, two prospective pre–post studies, one qualitative interview study, and one observational communication study, conducted in the Netherlands, the United States, Canada, and Hong Kong. Education at referral or consultation improved knowledge, reduced decisional uncertainty, and increased readiness to proceed with PRT. Education integrated with treatment improved symptom outcomes, including higher rates of pain control at 12 weeks and faster time to pain control when a nurse-led pain-education program accompanied PRT for painful bone metastases, and improvements in dyspnea, fatigue, anxiety, and function in advanced lung cancer. Observational and qualitative work showed low patient question-asking and persistent curative expectations; overall quality of life generally did not change. Although the evidence is limited and heterogeneous, targeted, standardized education appears to improve decision quality and selected symptoms in PRT pathways. Pragmatic multi-site trials and implementation studies are needed to define content, timing, personnel, and delivery models that are scalable in routine care.

Background: Previous studies have often reported a link between advanced age and inadequate cancer pain management. Given Italy’s demographic profile as the country with the oldest population in Europe, it offers an ideal setting to explore whether this association remains valid today. Aim: This study aimed primarily to assess the influence of advanced age on the adequacy of pain management among patients receiving treatment in Italian radiotherapy (RT) departments, and secondarily, to identify age-specific determinants of analgesic undertreatment. Methods: In this prospective, multicenter study, we enrolled 2104 consecutive patients attending 13 RT centers between October and November 2019. Pain intensity was evaluated using the numeric rating scale (NRS), and patients reporting scores ≥ 1 (n = 1353) were included in the analysis. Pain management adequacy was assessed using the Pain Management Index (PMI), with negative values indicating undertreatment. A two-step statistical approach was employed: variable selection via Least Absolute Shrinkage and Selection Operator regression, followed by Classification and Regression Tree analysis to identify key predictors. Separate analyses were performed for the overall population, older adults (≥65 years), and younger adults (18–64 years). Results: Overall, 42% of patients were undertreated (PMI < 0), without significant differences between older (41.0%) and younger patients (43.1%). However, factors contributing to undertreatment varied according to age. For the entire cohort, non-cancer pain was associated with substantially higher rates of undertreatment (74.3%) compared to cancer-related pain (34.2%). Among cancer patients, those receiving curative RT had poorer pain control (49.4%) than those receiving palliative RT (28.8%). In older patients, geographic location strongly influenced pain management, with higher rates of undertreatment in central and southern Italy compared to the north (e.g., palliative RT: 64.0% vs. 15.4%, respectively). Conversely, younger patients showed no geographical differences; instead, timing of assessment (beginning vs. end of RT) influenced outcomes, with improved PMI values towards the end of treatment. Conclusions: Unlike previous studies, advanced age itself was not associated with inadequate analgesia. However, the determinants of inadequate pain management differed significantly by age: geographic disparities were predominant among older patients, while assessment timing influenced outcomes for younger patients. Further longitudinal research and targeted interventions are needed to address these age-dependent challenges.

In a recent multicenter analysis of 454 patients undergoing post-prostatectomy salvage radiotherapy, the open surgical approach, as opposed to minimally invasive surgery, emerged, unexpectedly, as the strongest predictor of acute gastrointestinal and genitourinary toxicity. Patients treated with laparoscopic or robotic prostatectomy experienced significantly lower rates of ≥grade 2 toxicity compared to those who had undergone open retropubic surgery, irrespective of total dose, treatment margins, or radiation delivery platform. This finding, which to our knowledge has not been previously reported, raises the hypothesis that surgical technique leaves a lasting biological imprint on irradiated tissues. Drawing on current knowledge in radiobiology, cytokine signaling, wound healing, and pelvic dosimetry, we explore potential mechanisms by which open surgery may create a more hypoxic, inflamed, and fibrotic microenvironment, thereby amplifying radiation damage. We further discuss how target volume margins may biologically interact with this tissue state to increase normal tissue exposure. This Perspective aims to provide a conceptual framework for understanding this unexpected association, highlighting its clinical relevance for individualizing margins, counselling high-risk patients, and designing future studies at the interface of surgery and radiation oncology. This paper does not introduce additional patients or statistical models; instead, it offers an in-depth clinical and mechanistic interpretation of previously published ICAROS findings.

Background/Objectives: Effective palliative care relies on accurate identification and management of symptoms, especially in patients referred for palliative radiotherapy (PRT). This study aimed to identify symptom clusters (SCs)—defined as ≥2 interrelated symptoms—in patients evaluated at a multidisciplinary Radiotherapy and Palliative Care (RaP) outpatient clinic, using the Edmonton Symptom Assessment System (ESAS). Methods: We retrospectively analyzed data from patients referred to the RaP clinic between February 2017 and April 2020. Demographic and clinical characteristics, including ESAS scores at first visit, were collected. Principal component analysis (PCA) and unsupervised K-means clustering (KMC) were used to identify SCs. Associations with ECOG performance status (PS), primary tumor site, metastases site and PRT administration were analyzed. Exploratory survival analyses were performed.Results: Among 215 patients (median age 71 years; 53% male), the mean total ESAS score was 24.03 ± 15.28. PCA identified four SCs: SCPCA1 (tiredness, drowsiness, dyspnea, malaise), SCPCA2 (depression, anxiety), SCPCA3 (nausea, loss of appetite) and SCPCA4 (pain). KMC revealed three SCs: SCKMC1 (pain, tiredness, drowsiness, malaise), SCKMC2 (nausea, loss of appetite, dyspnea), SCKMC3 (depression, anxiety). Worse ECOG PS correlated significantly with physical SCs (p < 0.05). A trend linked SCKMC1 with greater PRT use. Psychological SCs (SCPCA2, SCKMC3) were significantly associated with a lower likelihood of receiving PRT. A trend toward shorter survival was observed among patients belonging to SCKMC2. Conclusions: SC analysis could improve clinical decision-making in the PRT setting. SC profiles reflect patient complexity and may guide personalized symptom management and treatment selection in advanced cancer.

Background: This study aimed to develop a predictive model for acute gastrointestinal (GI) and genitourinary (GU) toxicity in prostate cancer patients treated with salvage radiotherapy (SRT) post-prostatectomy, using machine learning techniques to identify key prognostic factors. Methods: A multicenter retrospective study analyzed 454 patients treated with SRT from three Italian radiotherapy centers. Acute toxicity was assessed using Radiation Therapy Oncology Group criteria. Predictors of grade ≥ 2 toxicity were identified through Least Absolute Shrinkage and Selection Operator (LASSO) regression and Classification and Regression Tree (CART) modeling. The analyzed variables included surgical technique, clinical target volume (CTV) to planning target volume (PTV) margins, extent of lymphadenectomy, radiotherapy technique, and androgen-deprivation therapy (ADT). Results: No patients experienced grade ≥ 4 toxicity, and grade 3 toxicity was below 1% for both GI and GU events. The primary determinant of acute toxicity was the surgical technique. Open prostatectomy was associated with significantly higher grade ≥ 2 GI (41.8%) and GU (35.9%) toxicity compared to laparoscopic/robotic approaches (18.9% and 12.2%, respectively). A CTV-to-PTV margin ≥ 10 mm further increased toxicity, particularly when combined with extensive lymphadenectomy. SRT technique and ADT were additional predictors in some subgroups. Conclusions: SRT demonstrated excellent tolerability. Surgical technique, CTV-to-PTV margin, and treatment parameters were key predictors of toxicity. These findings emphasize the need for personalized treatment strategies integrating surgical and radiotherapy factors to minimize toxicity and optimize outcomes in prostate cancer patients.