Delphi consensus on stereotactic ablative radiotherapy for oligometastatic and oligoprogressive renal cell carcinoma-a European Society for Radiotherapy and Oncology study endorsed by the European Association of Urology.

The purpose of this European Society for Radiotherapy and Oncology (ESTRO) project, endorsed by the European Association of Urology, is to explore expert opinion on the management of patients with oligometastatic and oligoprogressive renal cell carcinoma by means of stereotactic ablative radiotherapy (SABR) on extracranial metastases, with the aim of developing consensus recommendations for patient selection, treatment doses, and concurrent systemic therapy. A questionnaire on SABR in oligometastatic renal cell carcinoma was prepared by a core group and reviewed by a panel of ten prominent experts in the field. The Delphi consensus methodology was applied, sending three rounds of questionnaires to clinicians identified as key opinion leaders in the field. At the end of the third round, participants were able to find consensus on eight of the 37 questions. Specifically, panellists agreed to apply no restrictions regarding age (25 [100%) of 25) and primary renal cell carcinoma histology (23 [92%] of 25) for SABR candidates, on the upper threshold of three lesions to offer ablative treatment in patients with oligoprogression, and on the concomitant administration of immune checkpoint inhibitor. SABR was indicated as the treatment modality of choice for renal cell carcinoma bone oligometatasis (20 [80%] of 25) and for adrenal oligometastases 22 (88%). No consensus or major agreement was reached regarding the appropriate schedule, but the majority of the poll (54%-58%) retained the every-other-day schedule as the optimal choice for all the investigated sites. The current ESTRO Delphi consensus might provide useful direction for the application of SABR in oligometastatic renal cell carcinoma and highlight the key areas of ongoing debate, perhaps directing future research efforts to close knowledge gaps.

A multicenter high-quality data registry for advanced proton therapy approaches: the POWER registry.

BACKGROUND: Paucity and low evidence-level data on proton therapy (PT) represent one of the main issues for the establishment of solid indications in the PT setting. Aim of the present registry, the POWER registry, is to provide a tool for systematic, prospective, harmonized, and multidimensional high-quality data collection to promote knowledge in the field of PT with a particular focus on the use of hypofractionation. METHODS: All patients with any type of oncologic disease (benign and malignant disease) eligible for PT at the European Institute of Oncology (IEO), Milan, Italy, will be included in the present registry. Three levels of data collection will be implemented: Level (1) clinical research (patients outcome and toxicity, quality of life, and cost/effectiveness analysis); Level (2) radiological and radiobiological research (radiomic and dosiomic analysis, as well as biological modeling); Level (3) biological and translational research (biological biomarkers and genomic data analysis). Endpoints and outcome measures of hypofractionation schedules will be evaluated in terms of either Treatment Efficacy (tumor response rate, time to progression/percentages of survivors/median survival, clinical, biological, and radiological biomarkers changes, identified as surrogate endpoints of cancer survival/response to treatment) and Toxicity. The study protocol has been approved by the IEO Ethical Committee (IEO 1885). Other than patients treated at IEO, additional PT facilities (equipped with Proteus®ONE or Proteus®PLUS technologies by IBA, Ion Beam Applications, Louvain-la-Neuve, Belgium) are planned to join the registry data collection. Moreover, the registry will be also fully integrated into international PT data collection networks.

Extreme-hypofractionated RT with concomitant boost to the DIL in PCa: a 5-year update on oncological and patient-reported outcomes for the phase II trial "GIVE ME FIVE".

AIM: The present work reports updated oncological results and patients-reported outcomes at 5 years of phase II trial "Short-term high precision RT for early prostate cancer with SIB to the dominant intraprostatic lesion (DIL) for patients with early-stage PCa". METHODS: Data from patients enrolled within AIRC IG-13218 (NCT01913717) trial were analyzed. Clinical and GU/GI toxicity assessment and PSA measurements were performed every 3 months for at least 2 years after RT end. QoL of enrolled patients was assessed by IPSS, EORTC QLQ-C30, EORTC QLQ-PR25, and IIEF-5. Patients' score changes were calculated at the end of RT and at 1, 12, and 60 months after RT. RESULTS: A total of 65 patients were included. At a median follow-up of 5 years, OS resulted 86%. Biochemical and clinical progression-free survival at 5 years were 95%. The median PSA at baseline was 6.07 ng/ml, while at last follow-up resulted 0.25 ng/ml. IPSS showed a statistically significant variation in urinary function from baseline (p = 0.002), with the most relevant deterioration 1 month after RT, with a recovery toward baseline at 12 months (p ≤ 0.0001). A numerical improvement in QoL according to the EORTC QLQ-C30 has been reported although not statistically significant. No change in sexual activity was recorded after RT. CONCLUSIONS: The study confirms that extreme hypofractionation with a DIL boost is safe and effective, with no severe effects on the QoL. The increasing dose to the DIL does not worsen the RT toxicity, thus opening the possibility of an even more escalated treatment.

Can we predict pathology without surgery? Weighing the added value of multiparametric MRI and whole prostate radiomics in integrative machine learning models.

OBJECTIVE: To test the ability of high-performance machine learning (ML) models employing clinical, radiological, and radiomic variables to improve non-invasive prediction of the pathological status of prostate cancer (PCa) in a large, single-institution cohort. METHODS: Patients who underwent multiparametric MRI and prostatectomy in our institution in 2015-2018 were considered; a total of 949 patients were included. Gradient-boosted decision tree models were separately trained using clinical features alone and in combination with radiological reporting and/or prostate radiomic features to predict pathological T, pathological N, ISUP score, and their change from preclinical assessment. Model behavior was analyzed in terms of performance, feature importance, Shapley additive explanation (SHAP) values, and mean absolute error (MAE). The best model was compared against a naïve model mimicking clinical workflow. RESULTS: The model including all variables was the best performing (AUC values ranging from 0.73 to 0.96 for the six endpoints). Radiomic features brought a small yet measurable boost in performance, with the SHAP values indicating that their contribution can be critical to successful prediction of endpoints for individual patients. MAEs were lower for low-risk patients, suggesting that the models find them easier to classify. The best model outperformed (p ≤ 0.0001) clinical baseline, resulting in significantly fewer false negative predictions and overall was less prone to under-staging. CONCLUSIONS: Our results highlight the potential benefit of integrative ML models for pathological status prediction in PCa. Additional studies regarding clinical integration of such models can provide valuable information for personalizing therapy offering a tool to improve non-invasive prediction of pathological status. CLINICAL RELEVANCE STATEMENT: The best machine learning model was less prone to under-staging of the disease. The improved accuracy of our pathological prediction models could constitute an asset to the clinical workflow by providing clinicians with accurate pathological predictions prior to treatment. KEY POINTS: • Currently, the most common strategies for pre-surgical stratification of prostate cancer (PCa) patients have shown to have suboptimal performances. • The addition of radiological features to the clinical features gave a considerable boost in model performance. Our best model outperforms the naïve model, avoiding under-staging and resulting in a critical advantage in the clinic. •Machine learning models incorporating clinical, radiological, and radiomics features significantly improved accuracy of pathological prediction in prostate cancer, possibly constituting an asset to the clinical workflow.

Reirradiation of head and neck squamous cell carcinomas: a pragmatic approach-part I: prognostic factors and indications to treatment.

INTRODUCTION: Reirradiation (reRT) of locally recurrent/second primary tumors of the head and neck region is a potentially curative treatment for patients not candidate to salvage surgery. Aim of the present study is to summarize available literature on both prognostic factors and indications to curative reRT in this clinical setting. MATERIALS AND METHODS: A narrative review of the literature was performed on two topics: (1) patients' selection according to prognostic factors and (2) dosimetric feasibility of reRT. Postoperative reRT and palliative intent treatments were out of the scope of this work. RESULTS: Patient-tumor and treatment-related prognostic factors were analyzed, together with dosimetric parameters concerning target volume and organs at risk. Based on available evidence, a stepwise approach has been proposed aiming to provide a useful tool to identify suitable candidates for curative reRT in clinical practice. This was then applied to two clinical cases, proposed at the end of this work. CONCLUSION: A second course of RT in head and neck recurrence/second primary tumors is a personalized approach that can be offered to selected patients only in centers with expertise and dedicated equipment following a multidisciplinary team discussion.

Multi-omics integrative modelling for stereotactic body radiotherapy in early-stage non-small cell lung cancer: clinical trial protocol of the MONDRIAN study.

BACKGROUND: Currently, main treatment strategies for early-stage non-small cell lung cancer (ES-NSCLC) disease are surgery or stereotactic body radiation therapy (SBRT), with successful local control rates for both approaches. However, regional and distant failure remain critical in SBRT, and it is paramount to identify predictive factors of response to identify high-risk patients who may benefit from more aggressive approaches. The main endpoint of the MONDRIAN trial is to identify multi-omic biomarkers of SBRT response integrating information from the individual fields of radiomics, genomics and proteomics. METHODS: MONDRIAN is a prospective observational explorative cohort clinical study, with a data-driven, bottom-up approach. It is expected to enroll 100 ES-NSCLC SBRT candidates treated at an Italian tertiary cancer center with well-recognized expertise in SBRT and thoracic surgery. To identify predictors specific to SBRT, MONDRIAN will include data from 200 patients treated with surgery, in a 1:2 ratio, with comparable clinical characteristics. The project will have an overall expected duration of 60 months, and will be structured into five main tasks: (i) Clinical Study; (ii) Imaging/ Radiomic Study, (iii) Gene Expression Study, (iv) Proteomic Study, (v) Integrative Model Building. DISCUSSION: Thanks to its multi-disciplinary nature, MONDRIAN is expected to provide the opportunity to characterize ES-NSCLC from a multi-omic perspective, with a Radiation Oncology-oriented focus. Other than contributing to a mechanistic understanding of the disease, the study will assist the identification of high-risk patients in a largely unexplored clinical setting. Ultimately, this would orient further clinical research efforts on the combination of SBRT and systemic treatments, such as immunotherapy, with the perspective of improving oncological outcomes in this subset of patients. TRIAL REGISTRATION: The study was prospectively registered at clinicaltrials.gov (NCT05974475).

Management of radiation-induced oral mucositis in head and neck cancer patients: a real-life survey among 25 Italian radiation oncology centers.

AIM: Radiation-induced oral mucositis (RIOM) is the most frequent side effect in head and neck cancer (HNC) patients treated with curative radiotherapy (RT). A standardized strategy for preventing and treating RIOM has not been defined. Aim of this study was to perform a real-life survey on RIOM management among Italian RT centers. METHODS: A 40-question survey was administered to 25 radiation oncologists working in 25 different RT centers across Italy. RESULTS: A total of 1554 HNC patients have been treated in the participating centers in 2021, the majority (median across the centers 91%) with curative intent. Median treatment time was 41 days, with a mean percentage of interruption due to toxicity of 14.5%. Eighty percent of responders provide written oral cavity hygiene recommendations. Regarding RIOM prevention, sodium bicarbonate mouthwashes, oral mucosa barrier agents, and hyaluronic acid-based mouthwashes were the most frequent topic agents used. Regarding RIOM treatment, 14 (56%) centers relied on literature evidence, while internal guidelines were available in 13 centers (44%). Grade (G)1 mucositis is mostly treated with sodium bicarbonate mouthwashes, oral mucosa barrier agents, and steroids, while hyaluronic acid-based agents, local anesthetics, and benzydamine were the most used in mucositis G2/G3. Steroids, painkillers, and anti-inflammatory drugs were the most frequent systemic agents used independently from the RIOM severity. CONCLUSION: Great variety of strategies exist among Italian centers in RIOM management for HNC patients. Whether different strategies could impact patients' compliance and overall treatment time of the radiation course is still unclear and needs further investigation.

Comparison of automated segmentation techniques for magnetic resonance images of the prostate.

BACKGROUND: Contouring of anatomical regions is a crucial step in the medical workflow and is both time-consuming and prone to intra- and inter-observer variability. This study compares different strategies for automatic segmentation of the prostate in T2-weighted MRIs. METHODS: This study included 100 patients diagnosed with prostate adenocarcinoma who had undergone multi-parametric MRI and prostatectomy. From the T2-weighted MR images, ground truth segmentation masks were established by consensus from two expert radiologists. The prostate was then automatically contoured with six different methods: (1) a multi-atlas algorithm, (2) a proprietary algorithm in the Syngo.Via medical imaging software, and four deep learning models: (3) a V-net trained from scratch, (4) a pre-trained 2D U-net, (5) a GAN extension of the 2D U-net, and (6) a segmentation-adapted EfficientDet architecture. The resulting segmentations were compared and scored against the ground truth masks with one 70/30 and one 50/50 train/test data split. We also analyzed the association between segmentation performance and clinical variables. RESULTS: The best performing method was the adapted EfficientDet (model 6), achieving a mean Dice coefficient of 0.914, a mean absolute volume difference of 5.9%, a mean surface distance (MSD) of 1.93 pixels, and a mean 95th percentile Hausdorff distance of 3.77 pixels. The deep learning models were less prone to serious errors (0.854 minimum Dice and 4.02 maximum MSD), and no significant relationship was found between segmentation performance and clinical variables. CONCLUSIONS: Deep learning-based segmentation techniques can consistently achieve Dice coefficients of 0.9 or above with as few as 50 training patients, regardless of architectural archetype. The atlas-based and Syngo.via methods found in commercial clinical software performed significantly worse (0.855[Formula: see text]0.887 Dice).

What is the best time for postoperative radiation therapy in pN1 prostate cancer?

We retrospectively compared long-term biochemical recurrence rates (BCR) in pN1 PCa patients that underwent adjuvant radiotherapy (aRT) vs. no aRT/early salvage (esRT) after robot-assisted radical prostatectomy and extended pelvic lymphadenectomy. All PCa pN1 M0 patients treated at a single high-volume center between 2010 and 2020 were analyzed. Patients with <10 LNs yield, or >10 positive LNs, or persistently detectable PSA after RARP were excluded. Kaplan-Meier (KM) plots depicted BCR rates. Multivariable Cox regression models (MCRMs) focused on predictors of BCR. The cumulative incidence plot depicted BCR rates after propensity score (PS) matching (ratio 1:1). 220 pN1 patients were enrolled, 133 (60.4%) treated with aRT and 87 (39.6%) with no-aRT/esRT. aRT patients were older, with higher rates of postoperative ISUP grade group 4-5, and higher rates of pT3b stage. The actuarial BCR was similar (aRT 39.8% vs. no-aRT/esRT 40.2%; p=1). Median time to BCR was 62 vs. 38 months in aRT vs. no-aRT/esRT patients (p=0.001). In MCRMs, patients managed with no-aRT/esRT were associated with higher rates of BCR over time (hazard ratio [HR]: 3.27, p<0.001). ISUP grade group 5 (HR: 2.18, p<0.01) was an independent predictor of BCR. In PS-matched cumulative incidence plots, the BCR rate was significantly higher in the aRT group (76.4 vs. 40.4%; p<0.01). Patients managed with no-aRT/esRT experienced BCR approximately two years before the aRT group. Despite, the important BCR benefit after aRT, this treatment strategy is underused in daily practice.

Reirradiation of head and neck squamous cell carcinomas: a pragmatic approach, part II: radiation technique and fractionations.

INTRODUCTION: Reirradiation (reRT) of local recurrent/second primary tumors of the head and neck represents a potential curative treatment for patients not candidate to a salvage surgery. Aim of the present study is to summarize literature data on modern radiation techniques and fractionations used in this setting of patients. MATERIALS AND METHODS: A narrative review of the literature was conducted on three topics: (1) target volume delineation (2) reRT dose and techniques and (3) ongoing studies. Patients treated with postoperative reRT and palliative intent were not considered for the current analysis. RESULTS: Recommendations on the target volume contouring have been reported. 3D-Conformal Radiotherapy, Intensity Modulated Radiotherapy, Stereotactic body Radiotherapy Intraoperative Radiotherapy, Brachytherapy and Charged Particles have been analyzed in terms of indication and fractionation in the field of reRT. Ongoing studies on the topic have been reported for IMRT and Charged Particles. Moreover, according to literature data a stepwise approach has been proposed aiming to provide a useful tool to select patients candidate to a curative reRT in daily clinical practice. Two clinical cases were also provided for its application. CONCLUSION: Different radiation techniques and fractionations can be used for a second course of radiotherapy in patients with recurrent/second primary tumor of head and neck region. Tumor characteristics as well as radiobiological considerations should be take into account to define the best reRT approach.

A narrative review for radiation oncologists to implement preoperative partial breast irradiation.

The strategy to anticipate radiotherapy (RT) before surgery, for breast cancer (BC) treatment, has recently generated a renewed interest. Historically, preoperative RT has remained confined either to highly selected patients, in the context of personalized therapy, or to clinical research protocols. Nevertheless, in the recent years, thanks to technological advances and increased tumor biology understanding, RT has undergone great changes that have also impacted the preoperative settings, embracing the modern approach to breast cancer. In particular, the reappraisal of preoperative RT can be viewed within the broader view of personalized and tailored medicine. In fact, preoperative accelerated partial breast irradiation (APBI) allows a more precise target delineation, with less variability in contouring among radiation oncologists, and a smaller treatment volume, possibly leading to lower toxicity and to dose escalation programs. The aim of the present review, which represents a benchmark study for the AIRC IG-23118, is to report available data on different technical aspects of preoperative RT including dosimetric studies, patient's selection and set-up, constraints, target delineation and clinical results. These data, along with the ones that will become available from ongoing studies, may inform the design of the future trials and representing a step toward a tailored APBI approach with the potential to challenge the current treatment paradigm in early-stage BC.Trial registration: The study is registered at clinicaltrials.gov (NCT04679454).

Single fraction ablative preoperative radiation treatment for early-stage breast cancer: the CRYSTAL study - a phase I/II clinical trial protocol.

BACKGROUND: Breast-conserving surgery (BCS) and whole breast radiation therapy (WBRT) are the standard of care for early-stage breast cancer (BC). Based on the observation that most local recurrences occurred near the tumor bed, accelerated partial breast irradiation (APBI), consisting of a higher dose per fraction to the tumor bed over a reduced treatment time, has been gaining ground as an attractive alternative in selected patients with low-risk BC. Although more widely delivered in postoperative setting, preoperative APBI has also been investigated in a limited, though increasing, and number of studies. The aim of this study is to test the feasibility, safety and efficacy of preoperative radiotherapy (RT) in a single fraction for selected BC patients. METHODS: This is a phase I/II, single-arm and open-label single-center clinical trial using CyberKnife. The clinical investigation is supported by a preplanning section which addresses technical and dosimetric issues. The primary endpoint for the phase I study, covering the 1st and 2nd year of the research project, is the identification of the maximum tolerated dose (MTD) which meets a specific target toxicity level (no grade 3-4 toxicity). The primary endpoint for the phase II study (3rd to 5th year) is the evaluation of treatment efficacy measured in terms of pathological complete response rate. DISCUSSION: The study will investigate the response of BC to the preoperative APBI from different perspectives. While preoperative APBI represents a form of anticipated boost, followed by WBRT, different are the implications for the scientific community. The study may help to identify good responders for whom surgery could be omitted. It is especially appealing for patients unfit for surgery due to advanced age or severe co-morbidities, in addition to or instead of systemic therapies, to ensure long-term local control. Moreover, patients with oligometastatic disease synchronous with primary BC may benefit from APBI on the intact tumor in terms of tumor progression free survival. The study of response to RT can provide useful information about BC radiobiology, immunologic reactions, genomic expression, and radiomics features, to be tested on a larger scale. TRIAL REGISTRATION: The study was prospectively registered at clinicaltrials.gov ( NCT04679454 ).

Correlation between radiological and biological features and clinical outcomes in early prostate cancer: an exploratory subgroup analysis.

PTEN deletion and Ki-67 expression are two of the most promising biomarkers in prostate cancer (PCa). In the same manner, multiparametric magnetic resonance imaging (mp-MRI) guided core biopsy is a powerful tool for PCa detection and staging. The aim of the study is to assess whether a correlation can be identified between the pathological stage defined by an mp-MRI-guided core biopsy and Ki-67 expression and PTEN deletion. Such correlation might be useful for staging and treatment personalization in PCa. This investigation was conducted in the context of phase II clinical study "Short-term radiotherapy for early prostate cancer with a concomitant boost to the dominant lesion" (AIRC IG-13218), ClinicalTrials.gov identifier: NCT01913717. Nineteen patients underwent a further in-bore MRI-targeted core biopsy (MRI-TBx) on the dominant intraprostatic lesion (DIL); on this basis, an additional Gleason Score (GS) was determined. PTEN loss and Ki-67 expression on these samples were analyzed and correlated with both risk categories modifications and oncological outcomes (overall survival, biochemical and clinical relapse). GS was upgraded in 5 cases, with 4 patients re-classified as intermediate-risk and 1 patient as high-risk. The latter experienced a clinical local relapse. No correlations between up/down-staging, PTEN deletion, and Ki-67 expression were observed in this cohort. Further investigations are needed towards the identification of a pattern in the tumor aggressiveness-response in PCa treated with ultra-hypofractionated radiotherapy. Moreover, a possible relationship between biomarker analysis and imaging textural features could be explored.

Unraveling Mitochondrial Determinants of Tumor Response to Radiation Therapy.

Radiotherapy represents a highly targeted and efficient treatment choice in many cancer types, both with curative and palliative intents. Nevertheless, radioresistance, consisting in the adaptive response of the tumor to radiation-induced damage, represents a major clinical problem. A growing body of the literature suggests that mechanisms related to mitochondrial changes and metabolic remodeling might play a major role in radioresistance development. In this work, the main contributors to the acquired cellular radioresistance and their relation with mitochondrial changes in terms of reactive oxygen species, hypoxia, and epigenetic alterations have been discussed. We focused on recent findings pointing to a major role of mitochondria in response to radiotherapy, along with their implication in the mechanisms underlying radioresistance and radiosensitivity, and briefly summarized some of the recently proposed mitochondria-targeting strategies to overcome the radioresistant phenotype in cancer.

Mastectomy alone for pT1-2 pN0-1 breast cancer patients: when postmastectomy radiotherapy is indicated.

PURPOSE: To assess outcome of breast cancer (BC) stages pT1-2 N0-1 after mastectomy alone and to identify prognostic factors calling for the need of postmastectomy radiotherapy. METHODS: Patients who were not eligible for breast conserving surgery (BCS) were operated on with mastectomy between 1998 and 2008. Locoregional (LRR), distant (DM) control and breast cancer specific survival (BCSS) were retrospectively evaluated. Cumulative incidence (CI) of events was estimated according to Kalbfleisch and Prentice while Gray's test tested difference. Kaplan-Meier method for survival and Cox proportional hazards model for univariable and multivariable analysis were used. A matched pair analysis between mastectomy alone and BCS plus whole breast irradiation (WBI), using the propensity score method, was performed. RESULTS: 1281 pT1-2 N0 and 1081 pT1-2 N1 were identified. Median follow-up was 8.2 years (9.2 years for survival). Overall, LRR rate was low for both N0 and N1 subgroups (10-year CI, 8.8% and 10.9%, respectively). Young age, lymphovascular invasion and Ki-67 ≥ 20% were proved to be statistically significant prognostic factors at multivariable analysis. The combination of ≥ 2 risk factors increased LRR rate to ≥ 15%. Risk factors combination weighed on LRR rate more than nodal status itself. DM rate doubled moving from negative to positive nodal status (10-year CI 10.5% versus 20.3%, respectively). BCSS remained high in both N0 and N1 subgroups (10-year CI 92.4% versus 84.5%, respectively). Remarkably, all the molecular subtypes except Luminal A significantly affected DM and BCSS both in the N0 and N1 subgroups. Nodes number significantly impacted on DM and BCSS but not on locoregional control. In the matched pair analysis, WBI decreased nodal recurrence rate and improved distant control, without affecting survival. CONCLUSIONS: Selected patients, namely those with at least two additional risk factors, presented high enough LRR risk to support the use of postmastectomy radiotherapy in both N0 and N1 subgroups. Moreover, the observation that radiotherapy may provide benefits that go beyond local control deserves to be further investigated.

IMRT versus 2D/3D conformal RT in oropharyngeal cancer: A review of the literature and meta-analysis.

Based on literature, intensity-modulated radiation therapy (IMRT) provides less related toxicity compared with conventional 2D/3D-RT with no impact on oncological outcomes for oropharyngeal cancer. The aim of this systematic review and meta-analysis is to assess whether IMRT might provide similar clinical outcomes with reduced related toxicity in comparison with conventional 2D/3D RT in patients treated for clinically advanced oropharyngeal cancer (OPC). Inclusion criteria for paper selection included: squamous OPC patients, treatment performed by concomitant CRT or RT alone, four treatment performed for curative intent, and presence of clinical outcome of interest, namely, overall survival (OS) and disease-free survival (DFS) and full paper available in English. Acute and late toxicities were retrieved together with OS and DFS. Crude relative risk estimates of relapse and death comparing 2D/3D-RT versus IMRT were calculated from tabular data, extracting events at 2-3 years of follow-up. Eight studies were selected. Six of them were included in the meta-analysis considering summary relative risk. Considering both acute and late toxicities, the considered studies evidenced advantages for IMRT populations, with the 2D/3D-RT population showing higher frequencies than the IMRT one. No statistical difference between IMRT and 2D/3D-RT in terms of death (SRR = 0.93, 95% CI: 0.83-1.04 with no heterogeneity I2  = 0%) and relapse (SRR = 0.92, 95% CI: 0.83-1.03, with no heterogeneity I2  = 0%) was found. Results of our study suggest the improvement in the therapeutic index with IMRT with evidenced reduced toxicity without any worsening in clinical outcome when compared to 2D/3DCRT.

Computational and Experimental Characterization of NF023, A Candidate Anticancer Compound Inhibiting cIAP2/TRAF2 Assembly.

Protein-protein interactions are the basis of many important physiological processes and are currently promising, yet difficult, targets for drug discovery. In this context, inhibitor of apoptosis proteins (IAPs)-mediated interactions are pivotal for cancer cell survival; the interaction of the BIR1 domain of cIAP2 with TRAF2 was shown to lead the recruitment of cIAPs to the TNF receptor, promoting the activation of the NF-κB survival pathway. In this work, using a combined in silico-in vitro approach, we identified a drug-like molecule, NF023, able to disrupt cIAP2 interaction with TRAF2. We demonstrated in vitro its ability to interfere with the assembly of the cIAP2-BIR1/TRAF2 complex and performed a thorough characterization of the compound's mode of action through 248 parallel unbiased molecular dynamics simulations of 300 ns (totaling almost 75 µs of all-atom sampling), which identified multiple binding modes to the BIR1 domain of cIAP2 via clustering and ensemble docking. NF023 is, thus, a promising protein-protein interaction disruptor, representing a starting point to develop modulators of NF-κB-mediated cell survival in cancer. This study represents a model procedure that shows the use of large-scale molecular dynamics methods to typify promiscuous interactors.

Muscle-invasive bladder cancer in elderly and frail people: Is hypofractionated radiotherapy a feasible approach when no other local options are available?

AIM: The study aims to report the feasibility and safety of palliative hypofractionated radiotherapy targeting macroscopic bladder tumors in a monocentric cohort of frail and elderly bladder cancer patients not eligible for curative treatments. METHODS: Patients who underwent hypofractionated radiotherapy to the gross disease or to the tumor bed after transurethral resection of bladder tumor from 2017 to 2021 at the European Institute of Oncology IRCCS, were retrospectively considered. Schedules of treatment were 30 and 25 Gy in 5 fractions (both every other day, and consecutive days). Treatment response was evaluated with radiological investigation and/or cystoscopy. Toxicity assessment was carried out according to RTOG/EORTC v2.0 criteria. RESULTS: A total of 16 patients were included in the study, of these 11 received hypofractionated radiotherapy on the macroscopic target volume and five on the tumor bed after transurethral resection of bladder tumor. No grade (G) >2 acute toxicities were described after treatment for both groups. Only one patient in the group receiving radiotherapy on the macroscopic disease reported G4 GU late toxicity. Ten patients had available follow-up status (median FU time 18 months), of them six had complete response, one had stable disease, and three had progression of disease. The overall response rate and disease control rate were 60% and 70%, respectively. CONCLUSION: Our preliminary data demonstrate that palliative hypofractionated radiotherapy for bladder cancer in a frail and elderly population is technically feasible, with an acceptable toxicity profile. These outcomes emphasize the potential of this approach in a non-radical setting and could help to provide more solid indications in this underrepresented setting of patients.

3D-printed boluses for radiotherapy: influence of geometrical and printing parameters on dosimetric characterization and air gap evaluation.

The work investigates the implementation of personalized radiotherapy boluses by means of additive manufacturing technologies. Boluses materials that are currently used need an excessive amount of human intervention which leads to reduced repeatability in terms of dosimetry. Additive manufacturing can solve this problem by eliminating the human factor in the process of fabrication. Planar boluses with fixed geometry and personalized boluses printed starting from a computed tomography scan of a radiotherapy phantom were produced. First, a dosimetric characterization study on planar bolus designs to quantify the effects of print parameters such as infill density and geometry on the radiation beam was made. Secondly, a volumetric quantification of air gap between the bolus and the skin of the patient as well as dosimetric analyses were performed. The optimization process according to the obtained dosimetric and airgap results allowed us to find a combination of parameters to have the 3D-printed bolus performing similarly to that in conventional use. These preliminary results confirm those in the relevant literature, with 3D-printed boluses showing a dosimetric performance similar to conventional boluses with the additional advantage of being perfectly conformed to the patient geometry.

Hippocampal region avoidance in whole brain radiotherapy in brain metastases: For all or for some? A real-world feasibility report.

PURPOSE: Hippocampal sparing whole-brain radiotherapy (HS-WBRT) showed significantly lower long-term side effects compared to standard WBRT. Aim of this study is to describe a HS-WBRT real-world monoinstitutional experience within a retrospective cohort. METHODS: Patients who completed HS-WBRT course, with Karnofsky Performance Status ⩾ 60 and radiological diagnosis of brain metastases (BMs) were enrolled. Treatment was performed using helical Tomotherapy scheduled in 30 Gy in 10 or 12 fractions or 25 Gy in 10 fractions. Oncological outcomes were clinically and radiologically assessed every three months. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events 4.3. RESULTS: One hundred and nineteen patients from 2016 to 2020 met inclusion criteria; after a median follow-up of 18 months, 29 patients were alive; 6- and 12-months overall survival rates were 66% and 41%, respectively. HS-WBRT response was assessed for 72 patients. Median time to any progression and intracranial failure (IF) was 4.5 and 13.7 months, respectively. The 6- and 12-month IF rates were 85% and 57%. Among 40 patients (34%) who experienced IF, 17 (42%) were oligometastatic, 23 (58%) polymetastatic and 15/40 developed IF within the hippocampi avoidance zone. No grade (G) ⩾ 2 acute toxicities were reported and one G2 (dizziness) late toxicity was described. CONCLUSIONS: HS-WBRT is well tolerated, and despite the hippocampal sparing region, the oncological control is satisfying. Further investigation is warranted to find patients who could most benefit from a HS-WBRT approach.