Enteric-type adenocarcinoma of the lung (lung-ETAC) is an exceptionally rare variant of lung adenocarcinoma, often presenting diagnostic challenges due to its histological resemblance to colorectal adenocarcinoma. This rarity has hindered the development of standardized treatment protocols, with most management approaches being empirical. Radiotherapy is used infrequently for lung-ETAC, predominantly reserved for palliative care in metastatic cases. Recent studies, however, suggest that lung-ETAC may have a better prognosis than other lung cancer subtypes, thus raising the need to explore alternative therapeutic strategies, including radiotherapy.

We present the case of a 73-year-old female with stage IIIA lung-ETAC who was treated with curative-intent radiotherapy (60 Gy in 30 fractions) in combination with platinum-based chemotherapy. Despite transient pulmonary complications, the patient exhibited an almost complete response to treatment after 2 months, achieving sustained clinical remission with no further antitumor therapies.

This case underscores the potential role of high-dose radiotherapy as a curative treatment for locally advanced lung-ETAC. Given the limited evidence, further research is needed to better define the role of chemoradiotherapy in the management of this rare histological subtype.

Precision medicine is an emerging field that includes tumor-targeted delivery and tumor microenvironment. This review explores the synergistic potential of combining nano-drug delivery systems with low radiation doses to achieve optimized therapeutic outcomes, particularly in the context of cancer treatment. Nanoparticle-based drug carriers offer precise and targeted delivery, enhancing the therapeutic index of anticancer agents. The use of lower radiation doses has become a focus in radiation oncology to minimize off-target effects on healthy tissues in palliation treatment with high-target volume lesions.

To conduct a bibliometric review of nanomedicine and glioblastoma (GBM), all relevant studies from the last two decades were included.

The search strategy comprised the keywords "nanomedicine "and "glioblastoma" in the title and/or abstract. All English-language documents from 1 January 2000 to 31 December 2023 were considered for the analysis. R code (version 4.2.0) with R Studio (version 2022.12.0-353) and the Bibliometrix package (version 4.0.1) were used for the analysis. A total of 680 documents were collected.

We analyzed the bibliometric features of nanomedicine in glioma. With the limitations of the research, our analysis aims to highlight the increasing interest of researchers in the precision medicine field in GBM treatment and lead us to suggest further studies focusing on the association between nanomedicine and radiotherapy.

Due to the poor prognosis associated with GBM, new therapeutic approaches are necessary. There is an increasing interest in precision medicine, which includes nanomedicine and radiotherapy, for GBM treatment. This integration enhances the efficacy of targeted treatments and provides a promising avenue for reducing adverse effects, signifying a notable advancement in precision oncology.

Background: The clinical outcome of inoperable sarcoma patients treated with LATTICE (LRT) is limited and therefore the objective of our study was to report treatment response, overall survival (OS), local-recurrence free survival (LRFS) and toxicity. Methods: This retrospective observational study includes 15 histologically proven inoperable non-extremity sarcoma patients with no treatment options or no response to systemic therapy, treated at our institution between 2020 and 2024. The patients were treated with a combination of LRT and normo- or hypo-fractionated external beam radiotherapy. Treatment response was evaluated by RECIST1.1 criteria, toxicity by CTCAE 5.0 and OS and LRFS by Kaplan-Meier curves. Results: The median follow-up (F-UP) since the beginning of the treatment was 10 months (range 4-32). Nine patients were male and six female. Their mean age was 60 years. The median gross tumor volume (GTV) was 1058 cm3 (range 142-6103 cm3). The median number of spheres was 9 (4-30). All patients with symptoms reported symptoms' relief. Based on RECIST1.1 criteria, 10 patients (67%) had stable local disease at 1-2 months F-UP on computed tomography (CT). Surgical resection was feasible in five patients. Three of them are alive without disease and two died due to metastatic progression. From 10 (67%) non operated patients, 5 patients died (50%) due to disease. The remaining five patients (50%) are alive, three with stable disease at 21, 22, and 32 months of F-UP and two with disease progression who are currently receiving palliative chemotherapy treatment. Reported G2 toxicity was as follows: gastrointestinal (2), asthenia (1). Two patients had G3 toxicity: esophagitis (1) and inguinal dermatitis (1). No acute or chronic G4-G5 toxicity was observed. Conclusions: LRT is a feasible and well-tolerated radiation technique for inoperable bulky soft-tissue sarcomas. Further studies are needed to establish protocols to determine which patients could benefit from palliative or preoperative treatment.

Spatially fractionated radiation therapy (SFRT) is an irradiation technique developed to improve large cancer response. Although preliminary studies report highly positive results, data are still limited. The aim of this retrospective monocentric study was to investigate SFRT safety and activity.

We analyzed all patients who underwent SFRT as a palliative treatment for large solid extracranial cancer (>4.5 cm) at our institution. The primary endpoint was objective response rate assessment at 3 months. Additionally, patients' antalgic response, target volume reduction, and performance status modification were measured. Toxicity data were recorded.

From November 2021 to August 2023, 20 consecutive patients (20 lesions) underwent SFRT. We prescribed a minimum dose of 20 Gy in 5 fractions to 95% of the Planning Target Volume (PTV_20) and a minimum dose of 50 Gy to 50% of the sphere volume. The median beam-on time was 5 minutes (IQR1-3, 4-7 minutes; range, 3-16 minutes). Patients' median age was 70 years (range, 18-85 years). The median lesion volume was 560.4 cm3 (IQR1-3, 297.4-931.5 cc; range, 168.3-3838.3 cm3). Of the 20 patients, 14 and 10 were alive at 3 and 6 months, respectively. The 3-month objective response rate was 79% (95% CI, 49%-95%), with a median target volume reduction of 54% (IQR1-3, 32%-69%; range, 6%-80%). At 6 months, all patients were free from local disease progression. All patients reported an antalgic response with a rapid onset. All treatment-related toxicities occurred within 1 month after SFRT and quickly recovered. No acute toxicity ≥ grade 3 and late toxicity was reported. No patient experienced a worsening in performance status.

Our results provide further evidence supporting SFRT as a safe and promising option for palliative patients affected by large neoplastic lesions.

To identify optimal therapeutic strategies for managing fungating, large or ulcerating breast tumors and highlight existing gaps in the literature.

We conducted a systematic search of Medline, Embase, APA, PsycInfo, CAB abstracts, Scopus, and Web of Science from inception to June 30, 2024, including studies on patients with fungating, large, or ulcerating breast cancers.

The search identified 7917 studies, with 79 meeting the inclusion criteria: 62 case reports, 7 case series, and 10 cohort studies. Owing to high heterogeneity, a narrative synthesis was performed, categorizing treatment by year, molecular subtype, histology, and staging. We found that treatment modalities increased, from an average of two in luminal-B cancers to three in HER2-positive cases, with over half achieving complete response. Triple-negative breast cancers averaged two modalities, with around half showing only partial response. Cohort analysis revealed a significant positive correlation between metastasis rate and radiotherapy use (Spearman's rho = 0.828, p = 0.042) and between chemotherapy and hormonal therapy use (rho = 0.69, p = 0.04). Median survival was positively correlated with surgical treatment (rho = 0.82, p = 0.046).

Local treatment is crucial for symptomatic palliation in fungating or ulcerating breast tumors, and histology should guide therapeutic choices. While local treatments remain primary, emerging systemic therapies show promise and may soon become first-line options. As the first systematic review on this topic, our study faced considerable source heterogeneity, precluding a meta-analysis. Instead, we analyzed treatment trends by demographics and tumor characteristics, providing a comprehensive overview and encouraging further research in this area.

Radiotherapy (RT) is an integral component in the multidisciplinary management of patients with head and neck squamous cell carcinoma (HNSCC). Significant advances have been made toward optimizing tumor control and toxicity profiles of RT for HNSCC in the past two decades. The development of intensity modulated radiotherapy (IMRT) and concurrent chemotherapy established the standard of care for most patients with locally advanced HNSCC around the turn of the century. More recently, selective dose escalation to the most radioresistant part of tumor and avoidance of the most critical substructures of organs at risk, often guided by functional imaging, allowed even further improvement in the therapeutic ratio of IMRT. Other highly conformal RT modalities, including intensity modulated proton therapy (IMPT) and stereotactic body radiotherapy (SBRT) are being increasingly utilized, although there are gaps in our understanding of the normal tissue complication probabilities and their relative biological effectiveness. There is renewed interest in spatially fractionated radiotherapy (SFRT), such as GRID and LATTICE radiotherapy, in both palliative and definitive settings. The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of patients with recurrent and metastatic HNSCC. Novel RT modalities, including IMPT, SBRT, and SFRT, have the potential to reduce lymphopenia and immune suppression, stimulate anti-tumor immunity, and synergize with ICIs. The next frontier in the treatment of HNSCC may lie in the exploration of combined modality treatment with new RT technologies and ICIs.

The aim of this study was to explore the feasibility and dosimetric advantage of using spot-scanning proton arc (SPArc) for lattice radiation therapy in comparison with volumetric-modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) lattice techniques.

Lattice plans were retrospectively generated for 14 large tumors across the abdomen, pelvis, lung, and head-and-neck sites using VMAT, IMPT, and SPArc techniques. Lattice geometries comprised vertices 1.5 cm in diameter that were arrayed in a body-centered cubic lattice with a 6-cm lattice constant. The prescription dose was 20 Gy (relative biological effectiveness [RBE]) in 5 fractions to the periphery of the tumor, with a simultaneous integrated boost of 66.7 Gy (RBE) as a minimum dose to the vertices. Organ-at-risk constraints per American Association of Physicists in Medicine Task Group 101were prioritized. Dose-volume histograms were extracted and used to identify maximum, minimum, and mean doses; equivalent uniform dose; D95%, D50%, D10%, D5%; V19Gy; peak-to-valley dose ratio (PVDR); and gradient index (GI). The treatment delivery time of IMPT and SPArc were simulated based on the published proton delivery sequence model.

Median tumor volume was 577 cc with a median of 4.5 high-dose vertices per plan. Low-dose coverage was maintained in all plans (median V19Gy: SPArc 96%, IMPT 96%, VMAT 92%). SPArc generated significantly greater dose gradients as measured by PVDR (SPArc 4.0, IMPT 3.6, VMAT 3.2; SPArc-IMPT P = .0001, SPArc-VMAT P < .001) and high-dose GI (SPArc 5.9, IMPT 11.7, VMAT 17.1; SPArc-IMPT P = .001, SPArc-VMAT P < .01). Organ-at-risk constraints were met in all plans. Simulated delivery time was significantly improved with SPArc compared with IMPT (510 seconds vs 637 seconds, P < .001).

SPArc therapy was able to achieve high-quality lattice plans for various sites with superior gradient metrics (PVDR and GI) when compared with VMAT and IMPT. Clinical implementation is warranted.

To evaluate the feasibility of an open-source, semi-automated, and reproducible vertex placement tool to improve the efficiency of lattice radiotherapy (LRT) planning. We used polymer gel dosimetry with a Cone Beam CT (CBCT) readout to commission this LRT technique.

We generated a volumetric modulated arc therapy (VMAT)-based LRT plan on a 2 L NIPAM polymer gel dosimeter using our Eclipse Acuros version 15.6 AcurosXB beam model, and also recalculated the plan with a pre-clinical Acuros v18.0 dose calculation algorithm with the enhanced leaf modelling (ELM). With the assistance of the MAAS-SFRThelper software, a lattice vertex diameter of 1.5 cm and center-to-center spacing of 3 cm were used to place the spheres in a hexagonal, closed packed structure. The verification plan included four gantry arcs with 15°, 345°, 75°, 105° collimator angles. The spheres were prescribed 20 Gy to 50% of their combined volume. The 6 MV Flattening Filter Free beam energy was used to deliver the verification plan. The dosimetric accuracy of the LRT delivery was evaluated with 1D dose profiles, 2D isodose maps, and a 3D global gamma analysis.

Qualitative comparisons between the 1D dose profiles of the Eclipse plan and measured gel showed good consistency at the prescription dose mark. The average diameter measured 13.3 ± 0.2 mm (gel for v15.6), 12.6 mm (v15.6 plan), 13.1 ± 0.2 mm (gel for v18.0), and 12.3 mm (v18.0 plan). 3D gamma analysis showed that all gamma pass percent were > 95% except at 1% and 2% at the 1 mm distance to agreement criteria.

This study presents a novel application of gel dosimetry in verifying the dosimetric accuracy of LRT, achieving excellent 3D gamma results. The treatment planning was facilitated by publicly available software that automatically placed the vertices for consistency and efficiency.

To evaluate the safety and efficacy of lattice radiotherapy (LRT) for large, inoperable breast cancers.

In this prospective study, patients who underwent LRT for breast tumors that were ulcerating/fungating/extensively eroding the chest wall, and were ineligible/unwilling for surgery, were enrolled from May 2021 to Nov 2023. Baseline Eastern Cooperative Oncology Group (ECOG) status, pre- and post-LRT numerical rating scale (NRS), and post-LRT changes in quality of life (QoL) were recorded. Survival outcomes were reported at 6 months and 1-year. Median rates of survival and dosimetric parameters were calculated. Kaplan-Meier curves for overall survival (OS), cancer-specific survival (CSS), and failure of local control (LC) were constructed.

Ten patients (8 females) underwent LRT. The median age was 76 years (range=57-99 years) and the median ECOG performance status was 2.5 (range=1-4). The planned schedule was completed by 9/10 patients, accounting for a 90% compliance rate. Among patients with pain (n=7), NRS rapidly reduced from 7 (range=5-10) to 3 (range=1-6). The median equivalent uniform dose was 0.71 Gy (0.09-1.59 Gy). The actuarial rates of 6-month LC, CSS, and OS were 75%, 89%, and 61%, respectively, with only LC rate changing to 50% at 1 year. Two patients had local relapse at the six-month and 1-year follow-up, respectively, after having achieved a complete response at three months, and two others died of COVID-19 infection and ischemic stroke.

LRT was found to be effective and safe in palliating symptoms among patients with large inoperable breast tumors.

Lattice radiation therapy (LRT), a form of spatially fractionated radiation therapy, holds promise for treating large tumors. Despite its introduction in clinical practice around 2010, there remains limited information on its time-related outcomes despite consistently high response rates and tolerability. We assessed the time-related outcome of our palliative LRT cohort.

We conducted an analysis of our LRT program, which involved 45 palliative patients with 56 lesions larger than 7 cm, treated between January 2022 and November 2023. Prospectively defined treatment protocols included delivering 20 to 25 Gy/5 fractions to the tumor with a stereotactic simultaneously integrated boost (SIB) of 60 to 65 Gy to lattice vertices (n = 45/56) or, mainly in preirradiated lesions, single fraction stereotaxy with 1 × 15 to 20 Gy to vertices only (n = 11/56). Follow-up (FU) intervals were determined based on clinical considerations, considering the mostly highly palliative situation of included patients. Outcome assessments focused on subjective benefit and objective radiologic FU response.

The mean/median FU was 5.5/4.0 months (0.3-21 months). A total of 25/45 (56%) patients died after a mean/median of 3.9/2.0 months (0.3-14 months). Fourteen of 56 lesions (25%) were previously irradiated, with a mean/median of 18/13 months (4-72 months) prior to LRT. The mean/median gross tumor volume (GTV) measured 797/415 cc (54-4027 cc) and 14/13 cm (7-28 cm). Subjective statements at LRT completion were available from 37 symptomatic patients: 32/37 (87%) reported fast symptom relief, and 5/37 felt no change under LRT or at LRT completion. Early tolerance was excellent (G0-1). FU imaging was available from 40/56 lesions (71%): progression in 3/40 at first exam one at 1.5 and 4 months post-LRT, and stable disease (±10%) in 5/40 assessed at 2, 3, 3, and 4 months post-LRT. First measure shrinkage of 48%/30% (10%-100%) was found in 32/40 lesions (80%) after a mean/median of 2.8/3 months (0.3-7 months). Maximum shrinkage over time based on 21 cases with at least 1 FU imaging measured a mean/median of 62%/60% after 6.2/5.5 months. The duration of radiologic response was a mean/median of 7.4/7.0 months (1-21 months).

Short-course LRT emerged as an effective and well-tolerated palliative option for very large lesions, whether treatment-naïve or previously irradiated. Nearly 90% of symptomatic patients reported significant subjective benefit, and 80% of assessed lesions demonstrated tumor shrinkage ≥10%, with a mean response duration of >6 months.

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment; yet their efficacy remains variable across patients. This review delves into the intricate interplay of tumour characteristics contributing to resistance against ICI therapy and suggests that combining with radiotherapy holds promise. Radiation, known for its ability to trigger immunogenic cell death and foster an in situ vaccination effect, may counteract these resistance mechanisms, enhancing ICI response and patient outcomes. However, particularly when delivered at high-dose, it may trigger immunosuppressive mechanism and consequent side-effects. Notably, low-dose radiotherapy (LDRT), with its capacity for tumour reprogramming and reduced side effects, offers the potential for widespread application. Preclinical and clinical studies have shown encouraging results in this regard.

Spatially fractionated radiotherapy (SFRT) includes historical grid therapy approaches but more recently encompasses the controlled introduction of one or more cold dose regions using intensity modulation delivery techniques. The driving hypothesis behind SFRT is that it may allow for an increased immune response that is otherwise suppressed by radiation effects. With both two- and three-dimensional SFRT approaches, SFRT dose distributions typically include multiple dose cold spots or valleys. Despite its unconventional methods, reported clinical experience shows that SFRT can sometimes induce marked tumor regressions, even in patients with large hypoxic tumors. Preclinical models using extreme dose distributions (i.e., half-sparing) have been shown to nevertheless result in full tumor eradications, a more robust immune response, and systemic anti-tumor immunity. SFRT takes advantage of the complementary immunomodulatory features of low- and high-dose radiotherapy to integrate the delivery of both into a single target. Clinical trials using three-dimensional SFRT (i.e., lattice-like dose distributions) have reported both promising tumor and toxicity results, and ongoing clinical trials are investigating synergy between SFRT and immunotherapies.

This study aims to investigate lattice radiotherapy (LRT) for bulky tumor in 10 patients, analyzing geometrical and dosimetrical parameters and correlations among variables.

Patients were prescribed a single-fraction of 18 Gy to 50 % of each spherical vertex (1.5 cm diameter). Vertices were arranged in equidistant planes forming a triangular pattern. Center-to-center distance (Dc-c) between vertices was varied from 4 to 5 cm. A new method for calculating the valley-to-peak dose ratio (VPDR) was proposed and compared to other two from existing literature. GTV volumes (VGTV), vertex number (Nvert), low-dose related parameters and vertex D99%, D50%, and D1% were recorded. Beam-on time and Monitor Units (MU) were also evaluated. Correlations were assessed using Spearman's coefficient, with significant differences analyzed using Mann-Whitney U test.

Tumor volumes ranged from 417 to 3615 cm3. Median vertex number was 14.5 (IQR:11.3-17.8). VPDR ranged from 0.16 to 0.28. Median D99% spanned from 10.0 to 13.7 Gy, median D50% exceeded 18.0 Gy, and median D1% surpassed 23.3 Gy. Periphery dose remained under 4.0 Gy. Plans exhibited high modulation, with median beam-on time and MU of 8.8 min (IQR:8.2-10.1) and 13,069 MU (IQR:11574-13639). Significant correlations were found between Nvert and VGTV (p < 0.01), MU (p < 0.02) and beam-on time (p < 0.01) and between Dc-c and two VPDR definitions (p < 0.02) and periphery dose (p < 0.01). Significant differences were observed among the three valley dose definitions (p < 0.01) and the three peak dose definitions (p < 0.01).

Reporting geometrical and dosimetrical parameters in LRT is crucial, alongside the need for unified definitions of valley and peak doses.

Paragangliomas (PG) are rare neoplasms of neuroendocrine origin that tend to be highly vascularized, slow-growing, and usually sporadic. To date, common treatment options are surgical resection (SR), with or without radiation therapy (RT), and a watch-and-wait approach.

To evaluate the local control and effectiveness of exclusive fractionated stereotactic RT (FSRT) treatment in unresectable PG (uPG).

We retrospectively evaluated patients with uPG (medically inoperable or refused SR) treated with FSRT with a Cyberknife System (Accuray Incorporated, Sunnyvale, California). Toxicity and initial efficacy were evaluated.

From May 2009 to January 2023, 6 patients with a median age of 68 (range 20-84) were treated with FSRT. The median delivered dose was 21 Gy (range 20-30 Gy) at a median isodose line of 75.5% (range 70%-76%) in 4 fractions (range 3-5 fractions). The median volume was 13.6 mL (range 12.4-65.24 mL). The median cumulative biological effective dose and equivalent dose in 2-Gy fractions were 70 Gy and 37.10 Gy respectively. Site of origin involved were the timpa-nojugular glomus (4/6), temporal bone, and cervical spine. In 1 of the 6 patients, the follow-up was insufficient; 5 of 6 patients showed a 5-year overall survival and 5-year progression-free survival of 100%. We observed negligible toxicities during and after RT. The majority of patients showed stable symptoms during follow-up. Only 1 patient developed spine metastases.

Our preliminary results on this small cohort of patients suggest that FSRT could be an effective and safe alternative to SR.

Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer characterized by poor prognosis. The treatment requires a multidisciplinary approach, with neoadjuvant chemotherapy, surgery, and radiation therapy (RT). Particularly, high doses of conventional RT have been historically delivered in the adjuvant setting after chemotherapy and mastectomy or as radical treatment in patients ineligible for surgery. Here, we report the case of a 49-year-old woman patient with IBC unsuitable for surgery and treated with a combination of lattice RT and fractionated external beam RT concurrent with trastuzumab, with a curative aim. One year after RT, the patient showed a complete response and tolerable toxicities. This is the first reported case of a not-operable IBC patient treated with this particular kind of RT.

Bulky tumor remains as a challenge to surgery, chemotherapy and conventional radiation therapy. Hence, in efforts to overcome this challenge, we designed a novel therapeutic paradigm via strategy of Stereotactic Central/Core Ablative Radiation Therapy (SCART).), which is based on the principles of SBRT (stereotactic body radiation therapy and spatially fractionated radiation therapy (SFRT). We intend to safely deliver an ablative dose to the core of the tumor and with a low dose at tumor edge. The purpose of the phase 1 study was to determine dose-limiting toxicities (DLT)s and the Maximum Tolerated Dose (MTD) of SCART.

We defined a SCART-plan volume inside the tumor, which is proportional to the dimension of tumor. VMAT/Cyberknife technique was adopted. In the current clinical trial; Patients with biopsy proven recurrent or metastatic bulky cancers were enrolled. The five dose levels were 15 Gy X1, 15Gy X3, 18GyX3, 21GyX3 and 24GyX3, while keeping the whole tumor GTV's border dose at 5Gy each fraction. There was no restriction on concurrent systemic chemotherapy agents.

21 patients were enrolled and underwent SCART. All 21 patients have eligible data for study follow-up. Radiotherapy was well tolerated with all treatment completed as scheduled. The dose was escalated for two patients to 24GyX3. No grade 3 or higher toxicity was observed in any of the enrolled patients. The average age of patients was 66 years (range: 14-85) and 13 (62%) patients were male. The median SCART dose was 18Gy (range: 15 - 24). Six out of the 18 patients with data for overall survival (OS) died, and the median time to death was 16.3 months (range: 1 - 25.6). The mean percent change for tumor shrinkage between first visit volumes and post-SCART volumes was 49.5% (SD: 40.89, p-value:0.009).

SCART was safely escalated to 24 GyX 3 fractions, which is the maximum Tolerated Dose (MTD) for SCART. This regimen will be used in future phase II trials.

Spatially fractionated radiation therapy (SFRT) is a therapeutic approach with the potential to disrupt the classical paradigms of conventional radiation therapy. The high spatial dose modulation in SFRT activates distinct radiobiological mechanisms which lead to a remarkable increase in normal tissue tolerances. Several decades of clinical use and numerous preclinical experiments suggest that SFRT has the potential to increase the therapeutic index, especially in bulky and radioresistant tumors. To unleash the full potential of SFRT a deeper understanding of the underlying biology and its relationship with the complex dosimetry of SFRT is needed. This review provides a critical analysis of the field, discussing not only the main clinical and preclinical findings but also analyzing the main knowledge gaps in a holistic way.

While radiotherapy has long been recognized for its ability to directly ablate cancer cells through necrosis or apoptosis, radiotherapy-induced abscopal effect suggests that its impact extends beyond local tumor destruction thanks to immune response. Cellular proliferation and necrosis have been extensively studied using mathematical models that simulate tumor growth, such as Gompertz law, and the radiation effects, such as the linear-quadratic model. However, the effectiveness of radiotherapy-induced immune responses may vary among patients due to individual differences in radiation sensitivity and other factors.

We present a novel macroscopic approach designed to quantitatively analyze the intricate dynamics governing the interactions among the immune system, radiotherapy, and tumor progression. Building upon previous research demonstrating the synergistic effects of radiotherapy and immunotherapy in cancer treatment, we provide a comprehensive mathematical framework for understanding the underlying mechanisms driving these interactions.

Our method leverages macroscopic observations and mathematical modeling to capture the overarching dynamics of this interplay, offering valuable insights for optimizing cancer treatment strategies. One shows that Gompertz law can describe therapy effects with two effective parameters. This result permits quantitative data analyses, which give useful indications for the disease progression and clinical decisions.

Through validation against diverse data sets from the literature, we demonstrate the reliability and versatility of our approach in predicting the time evolution of the disease and assessing the potential efficacy of radiotherapy-immunotherapy combinations. This further supports the promising potential of the abscopal effect, suggesting that in select cases, depending on tumor size, it may confer full efficacy to radiotherapy.

The field of precision radiation therapy has seen remarkable advancements in both experimental and computational methods. Recent literature has introduced various approaches such as Spatially Fractionated Radiation Therapy (SFRT). This unconventional treatment, demanding high-precision radiotherapy, has shown promising clinical outcomes. A comprehensive computational scheme for SFRT, extrapolated from a case report, is proposed. This framework exhibits exceptional flexibility, accommodating diverse initial conditions (shape, inhomogeneity, etc.) and enabling specific choices for sub-volume selection with administrated higher radiation doses. The approach integrates the standard linear quadratic model and, significantly, considers the activation of the immune system due to radiotherapy. This activation enhances the immune response in comparison to the untreated case. We delve into the distinct roles of the native immune system, immune activation by radiation, and post-radiotherapy immunotherapy, discussing their implications for either complete recovery or disease regrowth.

Objective. An algorithm was developed for automated positioning of lattice points within volumetric modulated arc lattice radiation therapy (VMAT LRT) planning. These points are strategically placed within the gross tumor volume (GTV) to receive high doses, adhering to specific separation rules from adjacent organs at risk (OARs). The study goals included enhancing planning safety, consistency, and efficiency while emulating human performance.Approach. A Monte Carlo-based algorithm was designed to optimize the number and arrangement of lattice points within the GTV while considering placement constraints and objectives. These constraints encompassed minimum spacing between points, distance from OARs, and longitudinal separation along thez-axis. Additionally, the algorithm included an objective to permit, at the user's discretion, solutions with more centrally placed lattice points within the GTV. To validate its effectiveness, the automated approach was compared with manually planned treatments for 24 previous patients. Prior to clinical implementation, a failure mode and effects analysis (FMEA) was conducted to identify potential shortcomings.Main results.The automated program successfully met all placement constraints with an average execution time (over 24 plans) of 0.29 ±0.07 min per lattice point. The average lattice point density (# points per 100 c.c. of GTV) was similar for automated (0.725) compared to manual placement (0.704). The dosimetric differences between the automated and manual plans were minimal, with statistically significant differences in certain metrics like minimum dose (1.9% versus 1.4%), D5% (52.8% versus 49.4%), D95% (7.1% versus 6.2%), and Body-GTV V30% (20.7 c.c. versus 19.7 c.c.).Significance.This study underscores the feasibility of employing a straightforward Monte Carlo-based algorithm to automate the creation of spherical target structures for VMAT LRT planning. The automated method yields similar dose metrics, enhances inter-planner consistency for larger targets, and requires fewer resources and less time compared to manual placement. This approach holds promise for standardizing treatment planning in prospective patient trials and facilitating its adoption across centers seeking to implement VMAT LRT techniques.

Spatially Fractionated Radiation Therapy (SFRT) is a form of radiotherapy that delivers a single large dose of radiation within the target volume in a heterogeneous pattern with regions of peak dosage and regions of under dosage. SFRT types can be defined by how the heterogeneous pattern of radiation is obtained. Immune checkpoint inhibitors (ICIs) have been approved for various malignant tumors and are widely used to treat patients with metastatic cancer. The efficacy of ICI monotherapy is limited due to the "cold" tumor microenvironment. Fractionated radiotherapy can achieve higher doses per fraction to the target tumor, and induce immune activation (immodulate tumor immunogenicity and microenvironment). Therefore, coupling ICI therapy and fractionated radiation therapy could significantly improve the outcome of metastatic cancer. This review focuses on both preclinical and clinical studies that use a combination of radiotherapy and ICI therapy in cancer.

This review aims to summarize the current preclinical and clinical evidence of nontargeted immune effects of spatially fractionated radiation therapy (SFRT). We then highlight strategies to augment the immunomodulatory potential of SFRT in combination with immunotherapy (IT).

The response of cancer to IT is limited by primary and acquired immune resistance, and strategies are needed to prime the immune system to increase the efficacy of IT. Radiation therapy can induce immunologic effects and can potentially be used to synergize the effects of IT, although the optimal combination of radiation and IT is largely unknown. SFRT is a novel radiation technique that limits ablative doses to tumor subvolumes, and this highly heterogeneous dose deposition may increase the immune-rich infiltrate within the targeted tumor with enhanced antigen presentation and activated T cells in nonirradiated tumors. The understanding of nontargeted effects of SFRT can contribute to future translational strategies to combine SFRT and IT. Integration of SFRT and IT is an innovative approach to address immune resistance to IT with the overall goal of improving the therapeutic ratio of radiation therapy and increasing the efficacy of IT.

Clinical attempts to find benefit from specifically targeting and boosting resistant hypoxic tumor subvolumes have been promising but inconclusive. While a first preclinical murine tumor type showed significant improved control with hypoxic tumor boosts, a more thorough investigation of efficacy from boosting hypoxic subvolumes defined by electron paramagnetic resonance oxygen imaging (EPROI) is necessary. The present study confirms improved hypoxic tumor control results in three different tumor types using a clonogenic assay and explores potential confounding experimental conditions.

Three murine tumor models were used for multi-modal imaging and radiotherapy: MCa-4 mammary adenocarcinomas, SCC7 squamous cell carcinomas, and FSa fibrosarcomas. Registered T2-weighted MRI tumor boundaries, hypoxia defined by EPROI as pO2 ≤ 10 mmHg, and X-RAD 225Cx CT boost boundaries were obtained for all animals. 13 Gy boosts were directed to hypoxic or equal-integral-volume oxygenated tumor regions and monitored for regrowth. Kaplan-Meier survival analysis was used to assess local tumor control probability (LTCP). The Cox proportional hazards model was used to assess the hazard ratio of tumor progression of Hypoxic Boost vs. Oxygenated Boost for each tumor type controlling for experimental confounding variables such as EPROI radiofrequency, tumor volume, hypoxic fraction, and delay between imaging and radiation treatment.

An overall significant increase in LTCP from Hypoxia Boost vs. Oxygenated Boost treatments was observed in the full group of three tumor types (p < 0.0001). The effects of tumor volume and hypoxic fraction on LTCP were dependent on tumor type. The delay between imaging and boost treatments did not have a significant effect on LTCP for all tumor types.

This study confirms that EPROI locates resistant tumor hypoxic regions for radiation boost, increasing clonogenic LTCP, with potential enhanced therapeutic index in three tumor types. Preclinical absolute EPROI may provide correction for clinical hypoxia images using additional clinical physiologic MRI.

Tumor behavior is determined by its interaction with the tumor microenvironment (TME). Chimeric antigen receptor (CART) cell therapy represents a new form of cellular immunotherapy (IT). Immune cells present a different sensitivity to radiation therapy (RT). RT can affect tumor cells both modifying the TME and inducing DNA damage, with different effects depending on the low and high doses delivered, and can favor the expression of CART cells. CART cells are patients' T cells genetically engineered to recognize surface structure and to eradicate cancer cells. High-dose radiation therapy (HDRT, >10-20 Gy/fractions) converts immunologically "cold" tumors into "hot" ones by inducing necrosis and massive inflammation and death. LDRT (low-dose radiation therapy, >5-10 Gy/fractions) increases the expansion of CART cells and leads to non-immunogenetic death. An innovative approach, defined as the LATTICE technique, combines a high dose in higher FDG- uptake areas and a low dose to the tumor periphery. The association of RT and immune checkpoint inhibitors increases tumor immunogenicity and immune response both in irradiated and non-irradiated sites. The aim of this narrative review is to clarify the knowledge, to date, on CART cell therapy and its possible association with radiation therapy in solid tumors.

To provide clinical guidance for centers wishing to implement photon spatially fractionated radiation therapy (SFRT) treatments using either a brass grid or volumetric modulated arc therapy (VMAT) lattice approach.

We describe in detail processes which have been developed over the course of a 3-year period during which our institution treated over 240 SFRT cases. The importance of patient selection, along with aspects of simulation, treatment planning, quality assurance, and treatment delivery are discussed. Illustrative examples involving clinical cases are shown, and we discuss safety implications relevant to the heterogeneous dose distributions.

SFRT can be an effective modality for tumors which are otherwise challenging to manage with conventional radiation therapy techniques or for patients who have limited treatment options. However, SFRT has several aspects which differ drastically from conventional radiation therapy treatments. Therefore, the successful implementation of an SFRT treatment program requires the multidisciplinary expertise and collaboration of physicians, physicists, dosimetrists, and radiation therapists.

We have described methods for patient selection, simulation, treatment planning, quality assurance and delivery of clinical SFRT treatments which were built upon our experience treating a large patient population with both a brass grid and VMAT lattice approach. Preclinical research and patient trials aimed at understanding the mechanism of action are needed to elucidate which patients may benefit most from SFRT, and ultimately expand its use.

To evaluate the role of stereotactic body radiation therapy (SBRT) delivered after external-beam fractionated irradiation in non-small-cell lung cancer (NSCLC) patients with clinical stage III A, B.

All patients received three-dimensional conformal radiotherapy (3D-CRT) or intensity modulated radiation therapy (IMRT) (60-66 Gy/30-33 fractions of 2 Gy/5 days a week) with or without concomitant chemotherapy. Within 60 days from the end of irradiation, a SBRT boost (12-22 Gy in 1-3 fractions) was delivered on the residual disease.

Here we report the mature results of 23 patients homogeneously treated and followed up for a median time of 5.35 years (range 4.16-10.16). The rate of overall clinical response after external beam and stereotactic boost was 100%. No treatment-related mortality was recorded. Radiation-related acute toxicities with a grade ≥ 2 were observed in 6/23 patients (26.1%): 4/23 (17.4%) had esophagitis with mild esophageal pain (G2); in 2/23 (8.7%) clinical radiation pneumonitis G2 was observed. Lung fibrosis (20/23 patients, 86.95%) represented a typical late tissue damage, which was symptomatic in one patient. Median disease-free survival (DFS) and overall survival (OS) were 27.8 (95% CI, 4.2-51.3) and 56.7 months (95% CI, 34.9-78.5), respectively. Median local progression-free survival (PFS) was 17 months (range 11.6-22.4), with a median distant PFS of 18 months (range 9.6-26.4). The 5-year actuarial DFS and OS rates were 28.7% and 35.2%, respectively.

We confirm that a stereotactic boost after radical irradiation is feasible in stage III NSCLC patients. All fit patients who have no indication to adjuvant immunotherapy and presenting residual disease after curative irradiation could benefit from stereotactic boost because outcomes seem to be better than might be historically assumed.

Lattice radiation therapy (LRT) is an innovative type of spatially fractionated radiation therapy. It aims to increase large tumors control probability by administering ablative doses without an increased toxicity. Considering the rising number of positive clinical experiences, the objective of this work is to evaluate LRT safety and efficacy.

Reports about LRT clinical experience were identified with a systematic review conducted on four different databases (namely, Medline, Embase, Scopus, and Cochrane Library) through the August 2022. Only LRT clinical reports published in English and with the access to the full manuscript text were considered as eligible. The 2020 update version PRISMA statement was followed.

Data extraction was performed from 12 eligible records encompassing 7 case reports, 1 case series, and 4 clinical studies. 81 patients (84 lesions) with a large lesion ranging from 63.2 cc to 3713.5 cc were subjected to exclusive, hybrid, and metabolism guided LRT. Excluding two very severe toxicity with a questionable relation with LRT, available clinical experience seem to confirm LRT safety. When a complete response was not achieved 3-6 months after LRT, a median lesion reduction approximately ≥50 % was registered.

This systematic review appear to suggest LRT safety, especially for exclusive LRT. The very low level of evidence and the studies heterogeneity preclude drawing definitive conclusions on LRT efficacy, even though an interesting trend in terms of lesions reduction has been described.

The safe use of radiotherapy (RT) requires compliance with dose/volume constraints (DVCs) for organs at risk (OaRs). However, the available recommendations are sometimes conflicting and scattered across a number of different documents. Therefore, the aim of this work is to provide, in a single document, practical indications on DVCs for OaRs in external beam RT available in the literature.

A multidisciplinary team collected bibliographic information on the anatomical definition of OaRs, on the imaging methods needed for their definition, and on DVCs in general and in specific settings (curative RT of Hodgkin's lymphomas, postoperative RT of breast tumors, curative RT of pediatric cancers, stereotactic ablative RT of ventricular arrythmia). The information provided in terms of DVCs was graded based on levels of evidence.

Over 650 papers/documents/websites were examined. The search results, together with the levels of evidence, are presented in tabular form.

A working tool, based on collected guidelines on DVCs in different settings, is provided to help in daily clinical practice of RT departments. This could be a first step for further optimizations.