Clinical Insights and Future Prospects: A Comprehensive Narrative Review on Immunomodulation Induced by Electrochemotherapy.

Electrochemotherapy (ECT) is an emerging therapeutic approach gaining growing interest for its potential immunomodulatory effects in cancer treatment. This narrative review systematically examines the current state of knowledge regarding the interplay between ECT and the immune system. Through an analysis of preclinical and clinical studies, the review highlights ECT capacity to induce immunogenic cell death, activate dendritic cells, release tumor antigens, trigger inflammatory responses, and occasionally manifest systemic effects-the abscopal phenomenon. These mechanisms collectively suggest the ECT potential to influence both local tumor control and immune responses. While implications for clinical practice appear promising, warranting the consideration of ECT as a complementary treatment to immunotherapy, the evidence remains preliminary. Consequently, further research is needed to elucidate the underlying mechanisms, optimize treatment protocols, explore potential synergies, and decipher the parameters influencing the abscopal effect. As the field advances, the integration of ECT's potential immunomodulatory aspects into clinical practice will need careful evaluation and collaboration among clinical practitioners, researchers, and policymakers.

Automated single-isocenter stereotactic body radiotherapy for multiple metastases from breast cancer: A case study.

Oligometastatic breast cancer patients can today could benefit from a multimodal approach, combining systemic therapy with metastasis-directed treatment using stereotactic body radiotherapy (SBRT). However, the possibility to synchronously treat multiple lesions is still challenging, needing the ability to generate complex dose distributions with steep dose gradients outside the lesions and major sparing of surrounding organs at risk and accurately track and reproduce the patient's position before and during radiation therapy. We report the case of an oligometastatic patient from left breast cancer, which occurred after a full course of whole breast radiotherapy, treated using the potential of modern technology including single-isocenter setup, plan automation, breath-hold technique and surface guided tracking and reproducibility of patient's position before and during radiation therapy. A 44-year-old female patient with a history of left breast cancer, specifically a luminal-B-like invasive ductal carcinoma with Her2 overexpression, was admitted to our department. The patient previously underwent a left mastectomy (pT2N0M0), 4 cycles of adjuvant chemotherapy, adjuvant radiotherapy on the chest wall and lymph nodes drainage, and 5 years of hormonal therapy. A chest wall ultrasound and positron emission tomography revealed the presence of new lesions in the area of the surgical scar from the previous mastectomy, internal mammary, axillary and retropectoral levels. The 3 lesions were simultaneously treated with a mono-isocentric VMAT plan using SBRT technique with a total dose of 30 Gy delivered in 5 fractions. Due to the technical challenges, this treatment was supported by the use of planning automation, breath-hold technique and surface-guided radiation therapy to improve the accuracy of the dose delivery. Two different plans were generated and compared to pursue the best dosimetric result, including a summed plan obtained from 3 individual SBRT plans for each lesion with a separate isocenter placed in each of them (MIP), and a single-isocenter SBRT plan able to treat multiple lesions synchronously (SIP). Because of the advantages in terms of dosimetry and dose delivery efficiency, the patient was successfully treated with the SIP plan. The treatment time was reduced to about 4.5 minutes, allowing the comfortably use of breath-hold technique. After treatment, the condition of the patient was normal, and no toxicities have been observed in follow-up. SBRT with mono isocentric VMAT planning represents the recommended approach to simultaneously treat multiple lesions in close proximity in the thoracic district.

Personalizing Prophylactic Radiotherapy for Hip Heterotopic Ossification: An AMSTAR-2 Compliant Review of Meta-analyses.

BACKGROUND/AIM: Heterotopic ossification (HO) is a common complication following total hip arthroplasty. Various prophylactic treatments have been proposed, including radiotherapy (RT). This review summarizes the evidence from meta-analyses on the efficacy of RT in preventing hip HO. MATERIALS AND METHODS: A literature search was conducted on PubMed. The quality of the meta-analyses was assessed using the AMSTAR-2 tool. RESULTS: Seven meta-analyses were included. One meta-analysis reported a significant reduction in HO occurrence after RT compared to the control group. Comparing RT and non-steroidal anti-inflammatory drugs, one and two meta-analyses showed significantly greater efficacy of RT in preventing severe HO and better outcomes in patients receiving drugs, respectively. Regarding RT settings, the postoperative and preoperative RT were each supported by one meta-analysis. Furthermore, two meta-analyses showed an advantage of multi-fractionated RT over single fraction RT. The overall confidence rate of the meta-analyses was moderate, low, and critically low in one, three, and three meta-analyses, respectively. CONCLUSION: RT is a confirmed prophylactic intervention for HO. However, the precise optimization of timing, dosage, and fractionation requires elucidation. Future research should focus on the development of predictive models through large-scale data collection and advanced analytics to refine individualized treatment strategies and assess RT comparative effectiveness with drugs.

Assessing the effectiveness of palliative radiotherapy for painful bone metastases in low- and middle-income countries: A systematic review.

Palliative radiotherapy (RT) effectively relieves pain in patients with bone metastases (BMs). Furthermore, several clinical trials, in most cases conducted in high-income countries (HICs), proved that single-fraction RT is equally effective compared to multi-fractionated RT. However, the evidence is scarce regarding low/middle-income countries (LMICs), where the diagnosis of BMs could be later and RT techniques less advanced. Therefore, we conducted a systematic literature review to evaluate the efficacy of palliative RT of BMs in the LMIC setting. A literature search was performed independently by two authors on the PubMed, Cochrane and Scopus databases. Overall, 333 records were screened and after the selection process, 11 papers were included in the analysis. Complete pain response rates ranged from 11.5% to 37.1% (median: 22%) for single-fraction RT and from 0% to 35.1% (median: 19%) for multi-fractionated RT. Partial pain response rates ranged from 23.1% to 76.9% (median: 53.8%) for single fraction RT and from 23.8% to 84.6% (median: 65%) for multi-fractionated RT. Four randomized trials compared single-fraction RT with multiple-fraction RT and none of them showed significant differences in terms of pain relief. Our analysis showed that pain response rates after palliative RT recorded in LMIC are like those reported in studies performed in HIC. Even in this setting, RT in single fraction shows comparable pain response rates to multifractional RT.

Further Clarification of Pain Management Complexity in Radiotherapy: Insights from Modern Statistical Approaches.

BACKGROUND: The primary objective of this study was to assess the adequacy of analgesic care in radiotherapy (RT) patients, with a secondary objective to identify predictive variables associated with pain management adequacy using a modern statistical approach, integrating the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm and the Classification and Regression Tree (CART) analysis. METHODS: This observational, multicenter cohort study involved 1387 patients reporting pain or taking analgesic drugs from 13 RT departments in Italy. The Pain Management Index (PMI) served as the measure for pain control adequacy, with a PMI score < 0 indicating suboptimal management. Patient demographics, clinical status, and treatment-related factors were examined to discern the predictors of pain management adequacy. RESULTS: Among the analyzed cohort, 46.1% reported inadequately managed pain. Non-cancer pain origin, breast cancer diagnosis, higher ECOG Performance Status scores, younger patient age, early assessment phase, and curative treatment intent emerged as significant determinants of negative PMI from the LASSO analysis. Notably, pain management was observed to improve as RT progressed, with a greater discrepancy between cancer (33.2% with PMI < 0) and non-cancer pain (73.1% with PMI < 0). Breast cancer patients under 70 years of age with non-cancer pain had the highest rate of negative PMI at 86.5%, highlighting a potential deficiency in managing benign pain in younger patients. CONCLUSIONS: The study underscores the dynamic nature of pain management during RT, suggesting improvements over the treatment course yet revealing specific challenges in non-cancer pain management, particularly among younger breast cancer patients. The use of advanced statistical techniques for analysis stresses the importance of a multifaceted approach to pain management, one that incorporates both cancer and non-cancer pain considerations to ensure a holistic and improved quality of oncological care.

The role of training simulators in interventional radiation therapy (brachytherapy) training: A narrative review.

Simulators have revolutionized medical education and training across various disciplines, offering unique advantages in skill acquisition and performance improvement. In the context of interventional radiation therapy (IRT), simulators have emerged as valuable tools for training healthcare professionals in these complex procedures. This narrative review summarized the available evidence on the use of simulators in IRT training, highlighting their impact on proficiency, engagement, and self-confidence as well as their benefits for medical physicists and radiation therapists. A systematic search was conducted in PubMed, resulting in inclusion of 10 papers published since 2009, with 5 of them published since 2020. Publications originated from centers in USA, Ireland, Switzerland, Canada, and Japan, covering a range of IRT settings, including general, prostate, and cervical IRT. The review demonstrated that simulators provide a controlled and realistic environment for skill acquisition, allowing healthcare professionals to practice procedures, optimize image quality, and enhance technical proficiency. The use of simulators addressed the barriers associated with limited caseload and procedural complexity, ultimately contributing to improved education and IRT training. While cost considerations may exist, simulators offer long-term cost-effective solutions, balancing the potential benefits in improving educational outcomes and patient care. Overall, simulators play a crucial role in IRT training, enhancing the skills and competence of healthcare providers and improving access to quality IRT care worldwide. Future research should focus on evaluating the long-term impact of simulation-based training on clinical outcomes and patient satisfaction, exploring different simulation models and training approaches, and addressing region-specific barriers to optimize the utilization of IRT.

Stereotactic Arrhythmia Radioablation (STAR): A Multidisciplinary Narrative Minireview of Preclinical Studies.

The aim of this narrative review of the literature was to collect and analyze the results of the published preclinical studies on stereotactic arrhythmia radioablation (STAR) in the treatment of refractory cardiac arrhythmias. A literature search was conducted on PubMed using the following terms: ("stereotactic" OR "SBRT" OR "SABR" OR "radioablation" OR "radiosurgery") AND ("arrhythmia" OR "tachycardia"). Preclinical and pathological reports published in English without time limit, comprising studies of STAR in animal models and histological analyzes of explanted animal and human hearts were included. The analyzed studies confirm that doses lower than 25 Gy seem to produce sub-optimal therapeutic results whereas doses >35 Gy are less safe in terms of radiation-induced toxicity. However, long-term results (>1 year) are still missing and reporting outcomes based on low dose irradiation (≤15 Gy). Finally, STAR proved to be an effective therapy in the analyzed studies despite the irradiation of rather different cardiac targets. Therefore, additional studies are needed to: 1) compare the outcomes of STAR at doses of 25 Gy versus 30 Gy; 2) evaluate the long-term results (>1 year) in animal models irradiated at doses similar to those used in the clinic; 3) define the optimal target.

How smart is artificial intelligence in organs delineation? Testing a CE and FDA-approved Deep-Learning tool using multiple expert contours delineated on planning CT images.

Background: A CE- and FDA-approved cloud-based Deep learning (DL)-tool for automatic organs at risk (OARs) and clinical target volumes segmentation on computer tomography images is available. Before its implementation in the clinical practice, an independent external validation was conducted. Methods: At least a senior and two in training Radiation Oncologists (ROs) manually contoured the volumes of interest (VOIs) for 6 tumoral sites. The auto-segmented contours were retrieved from the DL-tool and, if needed, manually corrected by ROs. The level of ROs satisfaction and the duration of contouring were registered. Relative volume differences, similarity indices, satisfactory grades, and time saved were analyzed using a semi-automatic tool. Results: Seven thousand seven hundred sixty-five VOIs were delineated on the CT images of 111 representative patients. The median (range) time for manual VOIs delineation, DL-based segmentation, and subsequent manual corrections were 25.0 (8.0-115.0), 2.3 (1.2-8) and 10.0 minutes (0.3-46.3), respectively. The overall time for VOIs retrieving and modification was statistically significantly lower than for manual contouring (p<0.001). The DL-tool was generally appreciated by ROs, with 44% of vote 4 (well done) and 43% of vote 5 (very well done), correlated with the saved time (p<0.001). The relative volume differences and similarity indexes suggested a better inter-agreement of manually adjusted DL-based VOIs than manually segmented ones. Conclusions: The application of the DL-tool resulted satisfactory, especially in complex delineation cases, improving the ROs inter-agreement of delineated VOIs and saving time.

Adaptive Individualized high-dose preoperAtive (AIDA) chemoradiation in high-risk rectal cancer: a phase II trial.

PURPOSE: To evaluate the pathological complete response (pCR) rate of locally advanced rectal cancer (LARC) after adaptive high-dose neoadjuvant chemoradiation (CRT) based on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG-PET/CT). METHODS: The primary endpoint was the pCR rate. Secondary endpoints were the predictive value of 18 F-FDG-PET/CT on pathological response and acute and late toxicity. All patients performed 18 F-FDG-PET/CT at baseline (PET0) and after 2 weeks during CRT (PET1). The metabolic PET parameters were calculated both at the PET0 and PET1. The total CRT dose was 45 Gy to the pelvic lymph nodes and 50 Gy to the primary tumor, corresponding mesorectum, and to metastatic lymph nodes. Furthermore, a sequential boost was delivered to a biological target volume defined by PET1 with an additional dose of 5 Gy in 2 fractions. Capecitabine (825 mg/m2 twice daily orally) was prescribed for the entire treatment duration. RESULTS: Eighteen patients (13 males, 5 females; median age 55 years [range, 41-77 years]) were enrolled in the trial. Patients underwent surgical resection at 8-9 weeks after the end of neoadjuvant CRT. No patient showed grade > 1 acute radiation-induced toxicity. Seven patients (38.8%) had TRG = 0 (complete regression), 5 (27.0%) showed TRG = 2, and 6 (33.0%) had TRG = 3. Based on the TRG results, patients were classified in two groups: TRG = 0 (pCR) and TRG = 1, 2, 3 (non pCR). Accepting p < 0.05 as the level of significance, at the Kruskal-Wallis test, the medians of baseline-MTV, interim-SUVmax, interim-SUVmean, interim-MTV, interim-TLG, and the MTV reduction were significantly different between the two groups. 18 F-FDG-PET/CT was able to predict the pCR in 77.8% of cases through compared evaluation of both baseline PET/CT and interim PET/CT. CONCLUSIONS: Our results showed that a dose escalation on a reduced target in the final phase of CRT is well tolerated and able to provide a high pCR rate.

Stereotactic radiotherapy of nodal oligometastases from prostate cancer: a prisma-compliant systematic review.

Androgen deprivation therapy (ADT) is the standard treatment of metastatic prostate cancer (PCa). However, metastases-directed therapies can delay the initiation or switch of systemic treatments and allow local control (LC) and prolonged progression-free survival (PFS), particularly in patients with lymph nodes (LN) oligometastases. We performed a systematic review on stereotactic body radiotherapy (SBRT) in this setting. Papers reporting LC and/or PFS were selected. Data on ADT-free survival, overall survival, and toxicity were also collected from the selected studies. Fifteen studies were eligible (414 patients), 14 of them were retrospective analyses. A high heterogeneity was observed in terms of patient selection and treatment. In one study SBRT was delivered as a single 20 Gy fraction, while in the others the median total dose ranged between 24 and 40 Gy delivered in 3-6 fractions. LC and PFS were reported in 15 and 12 papers, respectively. LC was reported as a crude percentage in 13 studies, with 100% rate in seven and 63.2-98.0% in six reports. Five studies reported actuarial LC (2-year LC: 70.0-100%). PFS was reported as a crude rate in 11 studies (range 27.3-68.8%). Actuarial 2-year PFS was reported in four studies (range 30.0-50.0%). SBRT tolerability was excellent, with only two patients with grade 3 acute toxicity and two patients with grade 3 late toxicity. SBRT for LN oligorecurrences from PCa in safe and provides optimal LC. However, the long-term effect on PFS and OS is still unclear as well as which patients are the best candidate for this approach.

Memantine in the Prevention of Radiation-Induced Brain Damage: A Narrative Review.

Preserving cognitive functions is a priority for most patients with brain metastases. Knowing the mechanisms of hyperglutamatergic neurotoxicity and the role of some hippocampal areas in cognitive decline (CD) led to testing both the antiglutamatergic pharmacological prophylaxis and hippocampal-sparing whole-brain radiotherapy (WBRT) techniques. These studies showed a relative reduction in CD four to six months after WBRT. However, the failure to achieve statistical significance in one study that tested memantine alone (RTOG 0614) led to widespread skepticism about this drug in the WBRT setting. Moreover, interest grew in the reasons for the strong patient dropout rates in the first few months after WBRT and for early CD onset. In fact, the latter can only partially be explained by subclinical tumor progression. An emerging interpretation of the (not only) cognitive impairment during and immediately after WBRT is the dysfunction of the limbic and hypothalamic system with its immune and hormonal consequences. This new understanding of WBRT-induced toxicity may represent the basis for further innovative trials. These studies should aim to: (i) evaluate in greater detail the cognitive effects and, more generally, the quality of life impairment during and immediately after WBRT; (ii) study the mechanisms producing these early effects; (iii) test in clinical studies, the modern and advanced WBRT techniques based on both hippocampal-sparing and hypothalamic-pituitary-sparing, currently evaluated only in planning studies; (iv) test new timings of antiglutamatergic drugs administration aimed at preventing not only late toxicity but also acute effects.

Pain Relief after Stereotactic Radiotherapy of Pancreatic Adenocarcinoma: An Updated Systematic Review.

Severe pain is frequent in patients with locally advanced pancreatic ductal adenocarcinoma (PDCA). Stereotactic body radiotherapy (SBRT) provides high local control rates in these patients. The aim of this review was to systematically analyze the available evidence on pain relief in patients with PDCA. We updated our previous systematic review through a search on PubMed of papers published from 1 January 2018 to 30 June 2021. Studies with full available text, published in English, and reporting pain relief after SBRT on PDCA were included in this analysis. Statistical analysis was carried out using the MEDCALC statistical software. All tests were two-sided. The I2 statistic was used to quantify statistical heterogeneity (high heterogeneity level: >50%). Nineteen papers were included in this updated literature review. None of them specifically aimed at assessing pain and/or quality of life. The rate of analgesics reduction or suspension ranged between 40.0 and 100.0% (median: 60.3%) in six studies. The pooled rate was 71.5% (95% CI, 61.6−80.0%), with high heterogeneity between studies (Q2 test: p < 0.0001; I2 = 83.8%). The rate of complete response of pain after SBRT ranged between 30.0 and 81.3% (median: 48.4%) in three studies. The pooled rate was 51.9% (95% CI, 39.3−64.3%), with high heterogeneity (Q2 test: p < 0.008; I2 = 79.1%). The rate of partial plus complete pain response ranged between 44.4 and 100% (median: 78.6%) in nine studies. The pooled rate was 78.3% (95% CI, 71.0−84.5%), with high heterogeneity (Q2 test: p < 0.0001; I2 = 79.4%). A linear regression with sensitivity analysis showed significantly improved overall pain response as the EQD2α/ß:10 increases (p: 0.005). Eight papers did not report any side effect during and after SBRT. In three studies only transient acute effects were recorded. The results of the included studies showed high heterogeneity. However, SBRT of PDCA resulted reasonably effective in producing pain relief in these patients. Further studies are needed to assess the impact of SBRT in this setting based on Patient-Reported Outcomes.

Prophylactic Radiotherapy of Hip Heterotopic Ossification: A Narrative Mini Review.

Evidence on prophylactic radiotherapy (RT) in hip heterotopic ossification (HO) is sparse and conflicting. The aim of this literature review was to collect and summarize the available data on RT efficacy in preventing hip HO. The results of this review show that RT is effective in the prevention of hip HO, albeit with large variability across series. Effective prophylactic RT requires optimal treatment fields and time intervals with surgery. On the contrary, there is no clear evidence on the optimal timing (post-operative versus pre-operative RT). Comparisons between prophylactic RT and use of non-steroidal anti-inflammatory drugs showed conflicting results, although most were in favor of RT. In conclusion, RT is an established prophylactic treatment for hip HO. However, optimal dose, technique and timing remain unclear, as does the usefulness of combining RT with drugs.

An Intensive Educational Intervention Significantly Improves the Adoption of Single Fractionation Radiotherapy in Uncomplicated Bone Metastases.

INTRODUCTION: An education strategy was employed in our department to increase the rate of patients with uncomplicated painful bone metastases undergoing single fractionation radiotherapy (SFRT). The purpose of this report is to analyze the results of this strategy over a 5 year period. MATERIALS AND METHODS: In January 2015, two meetings were organized in our department. In the first, data from an audit on the current SFRT rate were shown. In the second, evidence of SFRT efficacy in the relief of pain from uncomplicated bone metastases was presented. In addition, during the weekly discussion of clinical cases, the opportunity to use the SFRT was systematically recalled. Using our institutional database, all patients treated with radiotherapy for uncomplicated painful bone metastases in the period between 2014 (year considered as a reference) and 2019 were retrieved. Data regarding treatment date (year), radiotherapy fractionation, and tumor, patients, and radiation oncologists characteristics were collected. RESULTS: A total of 627 patients were included in the analysis. The rate of patients undergoing SFRT increased from 4.0% in 2014 to 63.5% in 2019 (p < 0.001). At multivariable analysis, the delivery of SFRT was significantly correlated with older patients age (>80 years), lung cancer as the primary tumor, treatment prescribed by a radiation oncologist dedicated to palliative treatments, and treatment date (2014 vs 2015-2019). CONCLUSIONS: This retrospective single-center analysis showed that a simple but intensive and prolonged departmental education strategy can increase the rate of patients treated with SFRT by nearly 16 times.