OBJECTIVE:To evaluate the prognostic significance of tumor p16(INK4a) expression in predicting treatment response and survival in patients with locally advanced squamous cell vulvar cancer (LAVC) undergoing chemoradiotherapy (CRT). METHODS:Retrospective data were collected from patients with stage II-IVB disease managed with definitive or neoadjuvant CRT between January 2016 and March 2024. Clinical response to CRT and survival outcomes according to tumor p16 expression were evaluated. RESULTS:Among 61 patients, 39 (63.9%) had p16-negative (p16-) tumors, 22 (36.1%) had p16-positive (p16+) tumors. p16 positivity was linked to higher complete clinical response (cCR) rates (odds ratio [OR]=9.8; p<0.001) and, after adjusting for tumor size, lymph node status and radiation dose, was the only independent predictor of cCR (OR=7.0; p=0.003). The 3-year progression-free survival (PFS), locoregional control (LRC), and overall survival (OS) rates were 12.6%, 17.3%, and 19.5% for p16- tumors, 60.4% (p<0.001), 80.4% (p<0.001), and 64.9% (p<0.001) for p16+ tumors. Among patients who achieved a cCR, the 3-year PFS, LRC and OS were 14.3%, 14.3%, and 33.3% for p16- tumors, 69.6% (p=0.001), 85.7% (p<0.001), and 80.2% (p=0.008) for p16+ tumors. p16 positivity was independently associated with improved PFS (hazard ratio [HR]=0.15, p<0.001), LRC (HR=0.09, p<0.001), and OS (HR=0.16, p<0.001). Larger tumor size adversely affected all outcomes, while age, lymph node status, and RT dose were not significant predictors. CONCLUSION:p16(INK4a) expression predicts treatment response, locoregional disease control and survival in LAVC undergoing upfront CRT. These findings highlight the importance of integrating p16 expression into treatment protocols and future clinical trials.

BACKGROUND AND PURPOSE:Despite recent advances in the management of vulvar cancer (VC), adjuvant radiotherapy (RT) remains an area characterized by limited evidence, permissive recommendations, and substantial clinical variability. The 2023 ESGO guidelines aimed to standardize practice, yet their real-world implementation has not been systematically explored. MATERIALS AND METHODS:An international cross-sectional survey was conducted among radiation oncologists with recognized expertise in gynecologic malignancies to assess adherence to ESGO 2023 recommendations and identify grey zones. A 23-item questionnaire covering five thematic domains was distributed to 75 specialists worldwide. RESULTS:A total of 54 of 75 radiation oncologists completed the survey; non-response was attributable to limited availability rather than explicit refusal. Respondents included 21 centers from Italy and 33 international centers across Europe, North America, South America, Asia, and Australia. Vulvar bed irradiation for local risk factors and/or nodal metastases was recommended by 31/54 respondents (57.4%). Groin irradiation strictly according to guideline criteria was reported by 27/54 centers (50%), while the remainder considered treatment for a single positive node or whenever the vulvar bed was irradiated. Inclusion of the ipsilateral external iliac region regardless of inguinal tumor burden was reported by 30/54 centers (55.6%). Concurrent chemotherapy was delivered according to guidelines by 21/54 respondents (38.9%) but was also used in sentinel node micrometastasis settings by 28/54 (51.9%) despite limited evidence; weekly cisplatin was selected by 47/54 (87.1%). Elective nodal doses aligned with recommendations in 43/54 centers (79.7%), whereas boost indications remained inconsistent, with only 27/54 (50%) delivering a boost for macrometastatic disease or extracapsular extension. Prophylactic RT was omitted by 36/54 centers (66.8%) when lymph node staging was not performed. CONCLUSIONS:This survey reveals marked variability and critical evidence gaps in adjuvant RT practice for VC. While prospective trials are needed, the findings highlight the urgency of multidisciplinary expert consensus to guide clinical decision-making in key grey zones.

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.

Background/Objectives: To evaluate clinical and dosimetric predictors of vaginal toxicity in patients treated with vaginal-cuff brachytherapy (VCB), with or without external beam radiotherapy (EBRT), and assess the impact of different prescription and optimization strategies on dose-volume parameters. Methods: We retrospectively analyzed 217 patients treated with EBRT combined with VCB (n = 120) or VCB alone (n = 97). In VCB three prescription and optimization strategies (volume-based, graphical optimization, and 5 mm distance-based prescription) were compared to determine differences in dose-volume parameters. In patients who developed late vaginal side effects, the dosimetric parameters were evaluated using descriptive statistics and Cox regression modeling. Kaplan-Meier analysis was performed to assess time to toxicity. Results: In the EBRT+VCB cohort, 34/120 patients (28.3%) developed grade 1-2 vaginal toxicity compared to 35/97 (36%) in the VCB alone cohort. In the EBRT+VCB group, patients with toxicity received a higher D90 per fraction and higher vaginal D2cc. In multivariable analysis, vaginal D2cc (HR = 1.60, 95% CI = 1.01-2.54, p = 0.045) and CTV-DVH (HR = 0.77, 95% CI = 0.61-0.97, p = 0.027) were independently associated with toxicity. No significant dose-toxicity associations were observed in the VCB-alone cohort. Most events occurred within 48 months in both groups. Comparison of prescription strategies showed systematic differences in target and organ-at-risk dose-volume parameters, including vaginal D2cc. The 5 mm distance-based prescription consistently resulted in higher D90, D100, EQD2, and vaginal D2cc values. Conclusions: In patients receiving EBRT combined with VCB, both vaginal D2cc and target dose distribution were associated with vaginal toxicity. The prescription and optimization strategy significantly influenced dose-volume parameters. Planning methodology and dosimetric aspects should be considered when interpreting dose-toxicity relationships in vaginal brachytherapy.

Background: The abscopal effect refers to the clinical response of non-irradiated tumor lesions following localized radiotherapy (RT). Once regarded as a rare phenomenon, it has gained renewed interest in the era of immunotherapy, as RT may promote systemic anti-tumor immune responses. This narrative review summarizes current biological, radiobiological, and clinical evidence on the abscopal effect and highlights translational gaps limiting its reproducibility. Methods: Preclinical, translational, and clinical evidence was qualitatively analyzed across seven domains: RT, immunology, and clinical oncology. A structured qualitative gap analysis was used to identify disconnections between biological mechanisms, RT parameters, biomarkers, and clinical outcomes. Results: Current evidence supports the biological plausibility of the abscopal effect through immunogenic cell death, antigen and damage-associated molecular patterns (DAMP) release, activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, dendritic-cell priming, and T-cell-mediated responses. However, clinical results remain heterogeneous. Dose, fractionation, irradiated volume, timing, lymphocyte preservation, and interventional RT (modern brachytherapy, IRT) may influence systemic immune activation. Emerging biomarkers, particularly extracellular vesicles (EVs), may help connect radiation-induced biological stress with immune modulation and clinical response. Conclusions: The main barrier to clinical translation is the fragmentation of evidence across RT, immunology, and clinical oncology. Integrated translational frameworks combining dosimetry, immune monitoring, EVs-based biomarkers, imaging, and clinical endpoints may improve the interpretation and reproducibility of abscopal responses in immuno-RT.

Introduction Contact interventional radiotherapy (cIRT) is an effective technique for treating non-melanoma skin cancers (NMSC). The use of curved applicators may enhance dose distribution and optimize therapeutic outcomes. This study analyzes the impact of applicator curvature on dose distribution, introducing the concept of the “Nautilus Effect.” Materials and methods In silico simulations were performed on twelve different curvature configurations, in particular 12 ROIs were contoured in Oncentra Brachy treatment planning system (®Elekta) in the form of three-dimensional circular crowns with a uniform thickness t of 5 mm. Key dosimetric parameters were measured, including the therapeutic window (TW), defined as the distance between the 100% and 150% isodoses. Results and discussion Results show a strong correlation between applicator curvature and dose distribution: as curvature increases, the concave TW decreases while the convex TW increases. The “Nautilus Effect” highlights the advantages of curved applicators in optimizing dose coverage in complex anatomical regions. Conclusions Future works are needed to focus on clinical validation and creation of a personalized curvature applicator for complex anatomical regions to improve the treatment outcomes.

This study aimed to evaluate clinical outcomes in patients with vaginal recurrences treated with radiotherapy with or without chemotherapy, followed by image-guided interventional radiotherapy (IG-IRT). We retrospectively analyzed patients with vaginal recurrences treated with external beam radiotherapy (EBRT) ± chemotherapy followed by endovaginal high dose rate IG-IRT. The EBRT total dose was 45 Gy. The interventional radiotherapy boost delivered 28 Gy in four high-dose-rate fractions, achieving 85–95 Gy EQD2 (α/β 10) to the high-risk clinical target volume and 60 Gy EQD2 (α/β 10) to the intermediate-risk clinical target volume. The primary endpoint was local control. Secondary endpoints included metastasis-free survival, overall survival, cancer-specific survival, and acute and late toxicities. Thirty-two patients (median age, 54 years) were included. Two-year actuarial local control, metastasis-free survival, overall survival, and cancer-specific survival rates were 100

The aim of this study was to investigate the correlation between clinical and dosimetric factors and the incidence of pelvic insufficiency fractures (PIFs) in patients with cervical cancer treated with radical radiotherapy (RT), with or without chemotherapy, and to identify dose constraints that may reduce this risk. We reviewed data from cervical cancer patients treated with pelvic external-beam RT at our institution between 2020 and 2023. For each patient, pelvic bone marrow (BM) was contoured and divided into three subsites: lumbosacral spine (LSBM), ilium (IBM), and lower pelvis (LPBM). Data on the volume of each region receiving 10, 20, 30, and 40 Gy (V10, V20, V30, and V40, respectively) and Dmean were collected. A total of 202 patients were retrospectively analyzed. Of these, 36 patients (17.8

Vulvar and vaginal cancers represent rare malignancies for which high-quality evidence remains scarce, largely due to their low incidence and biological heterogeneity. Therefore, the clinical management of these tumors poses significant challenges for multidisciplinary teams. To address this unmet need, an interdisciplinary expert panel developed the present position paper based on the best available evidence regarding surgical, locoregional and systemic treatment strategies. In addition, considerations relevant to the care of transgender and gender-diverse individuals are incorporated. This document aims to support multidisciplinary clinical decision-making in vulvar and vaginal cancers by synthesising current evidence, identifying areas of uncertainty, and outlining available resources to promote the implementation of structured, evidence-informed, and patient-centered treatment approaches.

Extracellular vesicles (EVs) play a key role in radiation-induced biological responses and intercellular signaling. While extensively studied in external beam radiotherapy, their interaction with interventional radiotherapy (IRT, modern brachytherapy), characterized by steep and localized dose gradients, remains poorly explored. A qualitative literature-based gap analysis was conducted using PubMed and Scopus to identify studies investigating EVs in clinical or experimental settings involving IRT. Eligible publications included any form of EV analysis in patients or models treated with IRT alone or in combination with other therapies. Studies were qualitatively categorized according to treatment modality, EV characterization strategy, biological samples, and study endpoints. Only a limited number of original studies were identified. When IRT was delivered as a standalone treatment, localized irradiation was sufficient to induce measurable modulation of EV populations and cargo. In combined treatment settings, EVs were more commonly investigated as systemic biomarkers of treatment response or immune modulation, without isolating the specific biological contribution of IRT. Across studies, EV characterization approaches and clinical contexts were highly heterogeneous, and spatial dose–response relationships intrinsic to IRT were rarely addressed. Despite its intrinsic physical advantages, IRT remains underutilized as a platform for investigating EV-mediated radiation responses. The available evidence suggests that IRT can induce distinct EV modulation, but its biological potential is largely unexplored. Integrating EV analysis with IRT-specific dosimetry and spatial dose gradients represents a relevant translational opportunity for future radiobiological research.

Background: High-dose-rate interventional radiotherapy (HDR IRT) relies on accurate dose calculations to ensure safe and effective treatment. The AAPM TG-43 formalism, based on homogeneous water assumptions, has long been the clinical standard, but the growing use of patient-specific applicators and heterogeneous materials challenges its accuracy. Materials and Methods: A literature narrative review was performed using PubMed and Scopus to identify studies comparing TG-43 and model-based dose calculation algorithms (MBDCAs), including deterministic methods (ACE, Acuros BV) and Monte Carlo simulations. Thirty-five studies were selected and qualitatively analyzed. Results: TG-43 yielded higher dose compared with MBDCAs, particularly in the presence of tissue heterogeneities, air gaps, shielding materials, and limited scatter conditions. Differences ranged from 2 to 5% in relatively homogeneous settings to more than 10–20% in complex geometries such as superficial mould treatments and head-and-neck IRT. Model-based approaches showed better agreement with Monte Carlo simulations and experimental measurements, especially in contact HDR IRT and applications involving 3D-printed applicators. Conclusion: While TG-43 remains clinically established and widely used, its limitations are increasingly evident in modern personalized HDR IRT. Model-based dose calculation algorithms provide greater dosimetric accuracy and should be progressively integrated into clinical practice, particularly in treatments involving significant heterogeneities.

The goal is to investigate the best time point for assessing radiological complete response after exclusive chemoradiation in locally advanced cervical cancer (LACC). This is a retrospective single-center study. Seventy-nine patients with LACC, stage IB3-IVA FIGO 2018 treated between January and December 2020 were retrospectively analyzed. All patients received external beam radiotherapy (45 Gy in 25 daily fractions ± simultaneous boost to lymph nodes), and interventional radiotherapy (IRT, 28 Gy/twice/weekly) with concurrent chemotherapy. The radiological complete response evaluation was examined using magnetic resonance imaging (MRI) at three timepoints: (i) before IRT, at the end of external beam radiotherapy, (ii) 3 months following the completion of IRT and (iii) 6 months after IRT. Seventy-nine patients were included. At the three timepoints, the complete response rate increased with 21, 53, and 59 patients reporting a complete response at MRI scan, respectively. Seven patients with partial response at the second assessment had complete response 6 months after treatment completion, overall resulting in 80

Background/Objectives: Liver metastases are common among patients with breast cancer and have a poor prognosis if left untreated. The aim of this systematic review is to evaluate and compare chemoembolization (TACE) versus radioembolization (TARE) treatments in patients with breast cancer liver-dominant metastases in terms of overall survival (OS), local tumor control (LC), and toxicity. Methods: The S.P.I.D.E.R framework was used to address the clinical question. A systematic literature search using PubMed and Scopus was performed to identify full articles evaluating the efficacy of TACE and TARE in patients with liver metastases from breast cancer. Results: The literature search resulted in 10 articles for TACE, 13 articles for TARE and 1 for combined TACE/TARE, totaling 462 patients for the TACE group and 627 for the TARE group. The median LC was 68.7% for TACE and 78.9% for TARE. The median OS was 15.3 months for TACE and 11.9 for TARE. Progression at three months was 32.5% for TACE and 20.6% for TARE. Conclusions: The included studies were heterogeneous, varying widely in design, patient selection, and therapeutic protocols. Nonetheless, this systematic review suggests that locoregional therapies are effective in the treatment of liver metastases in patients with breast cancer and may improve tumor burden, alleviate symptoms and extend overall survival. The median LC of the liver metastases at three months was higher in the TARE group compared to TACE. However, the TARE group showed lower OS rates after treatment.

Introduction: Interventional radiotherapy (brachytherapy, IRT, BT) has evolved with technological advancements, improving dose precision while minimizing exposure to healthy tissues. The integration of 3D-printing technology in IRT has enabled the development of patient-specific devices, optimizing treatment personalization and dosimetric accuracy. Methods: A systematic literature search was conducted in PubMed, Scopus, and Google Scholar to identify studies published between 2020 and 2024 on 3D-printing applications in IRT. The selection process resulted in 74 peer-reviewed articles categorized by radioactive source, brachytherapy technique, endpoint of the 3D-printed product, and study type. Results: The analysis highlights the growing implementation of 3D-printed devices in brachytherapy, particularly in gynecological, prostate, and skin cancers. Most studies focus on technique, including intracavitary, interstitial, and contact applications, with custom applicators and templates emerging as predominant endpoints. The majority of studies involved in vivo clinical applications, followed by in silico computational modeling and in vitro experiments. Conclusions: The upward trend in scientific publications underscores the growing attention on 3D printing for enhancing personalized brachytherapy. The increasing use of 3D-printed templates and applicators highlights their role in optimizing dose delivery and expanding personalized treatment strategies. The current research trend is shifting toward real-world data and in vivo studies to assess clinical applications, ensuring these innovations translate effectively into routine practice. The integration of 3D printing represents a major advancement in radiation oncology, with the potential to enhance treatment efficacy and patient outcomes. Future research should focus on standardizing manufacturing processes and expanding clinical validation to facilitate broader adoption.

Aim: To identify dosimetric parameters associated with acute hematologic toxicity (HT) in endometrial cancer treated with volumetric modulated arc therapy (VMAT-RT). Methods: Patients with uterine adenocarcinoma treated in our Institution from March 2019 to November 2022 were retrospectively enrolled in this study. All patients underwent adjuvant external beam radiotherapy with Volumetric modulated arc therapy (VMAT) strategy plus a brachytherapy boost on vaginal cuff. When indicated, adjuvant platin-based chemotherapy was administered after surgery in upfront or sandwich setting. Pelvic bone marrow was contoured for each patient and divided into three subsites: lumbosacral spine (LSBM), ilium (IBM) and lower pelvis (LPBM). The volume of each region receiving 10,20,30 and 40 Gy (V10, V20, V30, V40, respectively) and mean dose (Dmean) was collected. Hematological toxicity during radiotherapy treatment was graded according to the CTCAE V 5.0. Linear logistic regression models were used to test associations between dosimetric parameters and HT. Results: Data from 99 patients were retrospectively analyzed. Adjuvant external beam radiotherapy was delivered to the pelvis with Volumetric modulated arc therapy (VAMT) strategy for a total dose of 45 Gy, 1.8 Gy/fraction plus a brachytherapy boost on vaginal cuff for a total dose of 10 Gy in 2 fractions weekly. Thirty-one patients developed during radiotherapy treatment an HT ≥ grade 2.With a sensitivity of 83.3 % and specificity of 61.5 %, V20 Gy LSBM < 64 % is associated to a maximum 20 % risk of Grade 2 or worse HT in patients with < 60 years old; for patients older than 70, the risk of toxicity is below 20 % independently by the percentage volume of V20Gy LSBM (95 % CI 0.60–0.87; p = 0.03).No association between hematological toxicity and V10-20–30-40 or Dmean of IBM and LPBM were observed.Dosimetric parameters involving the lower pelvis had stronger association with hematological toxicity than those involving the ilium, even if not significant. Conclusions: In this experience a dose constraint age-dependent was proposed, to reduce the risk of HT.The volume of lombo-sacral pelvis receiving low-dose radiation (V20 LSBM > 64 %) seems to be associated with HT in younger patients; instead in older than 70 patients the percentage of V20Gy LSBM seems not correlate with risk of toxicity. Future investigations should seek to confirm these findings through the inclusion of these parameters in the planning process.