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Highlights • The main aim of MBM treatment is to palliate neurological symptoms and to maintain an adequate QoL. • SRT could be the “new standard” over WBI in the management of MBM patients. • Neurocognitive functions could deteriorate more after WBI than after SRT., Aims To evaluate neurocognitive performance, daily activity and quality of life (QoL), other than usual oncologic outcomes, among patients with brain metastasis ≥5 (MBM) from solid tumors treated with Stereotactic Brain Irradiation (SBI) or Whole Brain Irradiation (WBI). Methods This multicentric randomized controlled trial will involve the enrollment of 100 patients (50 for each arm) with MBM ≥ 5, age ≥ 18 years, Karnofsky Performance Status (KPS) ≥ 70, life expectancy > 3 months, known primary tumor, with controlled or controllable extracranial disease, baseline Montreal Cognitive Assessment (MoCA) score ≥ 20/30, Barthel Activities of Daily Living score ≥ 90/100, to be submitted to SBI by LINAC with monoisocentric technique and non-coplanar arcs (experimental arm) or to WBI (control arm). The primary endpoints are neurocognitive performance, QoL and autonomy in daily-life activities variations, the first one assessed by MoCa Score and Hopkins Verbal Learning Test-Revised, the second one through the EORTC QLQ-C15-PAL and QLQ-BN-20 questionnaires, the third one through the Barthel Index, respectively. The secondary endpoints are time to intracranial failure, overall survival, retreatment rate, acute and late toxicities, changing of KPS. It will be considered significant a statistical difference of at least 30% between the two arms (statistical power of 80% with a significance level of 95%). Discussion Several studies debate what is the decisive factor accountable for the development of neurocognitive decay among patients undergoing brain irradiation for MBM: radiation effect on clinically healthy brain tissue or intracranial tumor burden? The answer to this question may come from the recent technological advancement that allows, in a context of a significant time saving, improved patient comfort and minimizing radiation dose to off-target brain, a selective treatment of MBM simultaneously, otherwise attackable only by WBI. The achievement of a local control rate comparable to that obtained with WBI remains the fundamental prerequisite. Trial registration NCT number: NCT04891471.

Purpose: To evaluate feasibility, toxicities, and clinical response in Stage IV patients treated with palliative “metabolism-guided” lattice technique. Patients and Methods: From June 2020 to December 2021, 30 consecutive clinical stage IV patients with 31 bulky lesions were included in this study. All patients received palliative irradiation consisting of a spatially fractionated high radiation dose delivered in spherical deposits (vertices, Vs) within the bulky disease. The Vs were placed at the edges of tumor areas with different metabolisms at the PET exam following a non-geometric arrangement. Precisely, the Vs overlapped the interfaces between the tumor areas of higher 18F-FDG uptake (>75% SUV max) and areas with lower 18F-FDG uptake. A median dose of 15 Gy/1 fraction (range 10–27 Gy in 1/3 fractions) was delivered to the Vs. Within 7 days after the Vs boost, all the gross tumor volume (GTV) was homogeneously treated with hypo-fractionated radiation therapy (RT). Results: The rate of symptomatic response was 100%, and it was observed immediately after lattice RT delivery in 3/30 patients, while 27/30 patients had a symptomatic response within 8 days from the end of GTV irradiation. Radiation-related acute grade ≥1 toxicities were observed in 6/30 (20%) patients. The rate of overall clinical response was 89%, including 23% of complete remission. The 1-year overall survival rate was 86.4%. Conclusions: “Metabolism-guided” lattice radiotherapy is feasible and well-tolerated, being able to yield very impressive results both in terms of symptom relief and overall clinical response rate in stage IV bulky disease patients. These preliminary results seem to indicate that this kind of therapy could emerge as the best therapeutic option for this patient setting.

Bulky gynecological tumors are a rare entity of large primary tumors, for which only a limited range of therapeutic options is available. Among these, when surgical approach is deemed unsuitable based on comorbidities and/or technical feasibility, radiotherapy is administered at low doses with palliative intent only. Aggressive treatment of such large primary tumors might significantly prolong patient survival and improve their quality of life by effectively delaying tumor progression to extra-pelvic sites. Lattice radiotherapy is a type of Spatially Fractionated Radiation Therapy, specifically devoted to treat and debulk large tumor masses, which are not candidates for normofractionated homogeneous high-dose radiotherapy schedules due to potential harmful dose-volume effects. The aim of this case study was to report on the feasibility of a Magnetic Resonance Imaging-based Lattice approach.Herein we report a case of a patient with a locally advanced uterine serous papillary carcinoma submitted to radical surgery and rapidly experiencing a painful large pelvic recurrence eroding the sacrum. The patient was submitted to Magnetic Resonance Imaging-based Lattice radiotherapy consisting of an Apparent Diffusion Coefficient Map-Based boost followed by a normofractionated radiotherapy course. The patient impressively developed an almost complete clinical response with a long-lasting symptom relief. Subsequently, the disease course was burdened by limited extra- and in-field recurrences amenable of re-irradiation as long as the cumulative radiation dose did not seriously threaten the tolerance of neighboring organs at risk (especially the bowel). The patient is still alive 20 months after Lattice radiotherapy delivery with no radiation-related toxicities.Magnetic resonance imaging (MRI)-based Lattice radiotherapy might be safe and effective for the treatment of inoperable bulky gynecological tumors.

Several recent studies are providing increasing insights into reliable markers to improve the diagnostic and prognostic assessment of meningioma patients. The evidence of brain invasion (BI) signs and its associated variables has been focused on, and currently, scientific research is investing in the study of key aspects, different methods, and approaches to recognize and evaluate BI. This paradigm shift may have significant repercussions for the diagnostic, prognostic, and therapeutic approach to higher-grade meningioma, as long as the evidence of BI may influence patients’ prognosis and inclusion in clinical trials and indirectly impact adjuvant therapy. We intended to review the current knowledge about the impact of BI in meningioma in the most updated literature and explore the most recent implications on both clinical practice and trials and future directions. According to the PRISMA guidelines, systematic research in the most updated platform was performed in order to provide a complete overview of characteristics, preoperative applications, and potential implications of BI in meningiomas. Nineteen articles were included in the present paper and analyzed according to specific research areas. The detection of brain invasion could represent a crucial factor in meningioma patients’ management, and research is flourishing and promising.

Background/aim This study aimed to analyze the dosimetric gain of the deep-inspiration-breath-hold (DIBH) technique over the free-breathing (FB) one in left breast cancer (LBC) 3D-conformal-radiotherapy (3D-CRT), and simultaneously investigate the anatomical parameters related to heart RT-exposure. Patients and methods Treatment plans were generated in both DIBH and FB scenarios for 116 LBC patients monitored by the Varian RPM™ respiratory gating system for delivery of conventional or moderately hypofractionated schedules (±sequential boost). For comparison, we considered cardiac and ipsilateral lung doses and volumes. Results A significant reduction of cardiac and pulmonary doses using DIBH technique was achieved compared to FB plans. Larger clinical target volumes generally need longer distance between medial and lateral entrances of tangent fields at body surface, thus conditioning a worse heart RT-exposure. Conclusion The DIBH technique reduces cardiac and pulmonary doses for LBC patients. Through easily detectable anatomical parameters, it is possible to predict which patients benefit most from DIBH-RT.

Radiation therapy (RT) is an effective therapeutic option for small localized cutaneous squamous cell carcinoma (cSCC) among patients who are not eligible for or refuse surgery. RT also has a defined role as an adjuvant treatment in cases of adverse features that predispose to tumor recurrence after local excision. Since the development of cSCC is often a late consequence of chronic sun exposure, its occurrence is more common among elderly patients whose comorbidities may contraindicate surgical procedures. These could be impeded not only by frail medical conditions but also by technical issues. Indeed, an aggressive locoregional behavior of cSCC may culminate in unresectability due to widespread invasion of neighboring tissues. Moreover, cSCC could develop distant metastases. Both locally advanced and metastatic cSCCs carry a poor prognosis. In these scenarios, recent discoveries of tumor molecular targets are promoting the use of promising systemic therapies, especially immunotherapy, over RT. However, the results from using immunotherapy and, even more so, of chemotherapy are still not optimal. By contrast, advances in radiation delivery equipment can safely treat even large and complex-shaped cSCC targets in challenging body sites. In addition, RT could also have a role in metastatic cSCC settings by enhancing the effectiveness of concomitant immunotherapy. The aim of this review is to summarize and comment on the body of literature about the use of radiotherapy for operable and inoperable locally advanced cSCCs and for metastatic ones in an attempt to define its current and future role.

IntroductionMetastatic cutaneous squamous cell carcinoma (cSCC) is a very rare condition. The lack of definition of an oligometastatic subgroup means that there is no consensus for its treatment, unlike the mucosal head and neck counterpart. Like the latter, the cutaneous form is able to develop bulky tumor masses. When this happens, the classic care approach is just for palliative intent due to a likely unfavorable benefit–risk balance typical of aggressive treatments. Here we proposed a novel radiotherapy (RT) technique to treat bulky metastases from cSCC in the context of an overall limited tumor burden and tried to explain its clinical outcome by the currently available mathematical radiobiological and ad hoc developed models.MethodsWe treated a case of facial cSCC with three metastases: two of them by classic stereotactic RT and the other by lattice RT supported by metabolic imaging (18F-FDG PET) due to its excessively large dimensions. For the latter lesion, we compared four treatment plans with different RT techniques in order to define the best approach in terms of normal tissue complication probability (NTCP) and tumor control probability (TCP). Moreover, we developed an ad hoc mathematical radiobiological model that could fit better with the characteristics of heterogeneity of this bulky metastasis for which, indeed, a segmentation of normoxic, hypoxic, and necrotic subvolumes might have been assumed.ResultsWe observed a clinical complete response in all three disease sites; the bulky metastasis actually regressed more rapidly than the other two treated by stereotactic RT. For the large lesion, NTCP predictions were good for all four different plans but even significantly better for the lattice RT plan. Neither the classic TCP nor the ad hoc developed radiobiological models could be totally adequate to explain the reported outcome. This finding might support a key role of the host immune system.ConclusionsPET-guided lattice RT might be safe and effective for the treatment of bulky lesions from cSCC. There might be some need for complex mathematical radiobiological models that are able to take into account any immune system’s role in order to explain the possible mechanisms of the tumor response to radiation and the relevant key points to enhance it.

Radiotherapy represents an essential part of the therapeutic algorithm for breast cancer patients after conservative surgery. The treatment of left-sided tumors has been associated with a non-negligible risk of developing late-onset cardiovascular disease. The cardiac risk perception has especially increased over the last years due to the prolongation of patients’ survival owing to the advent of new drugs and an ever earlier cancer detection through screening programs. Improvements in radiation delivery techniques could reduce the treatment-related heart toxicity. The deep-inspiration-breath-hold (DIBH) irradiation is one of the most advanced treatment approaches, which requires specific technical equipment and uses inspiration to displace the heart from the tangential radiation fields. However, not all patients benefit from its use. Moreover, DIBH irradiation needs patient compliance and accurate training. Therefore, such a technique may be unjustifiably cumbersome and time-consuming as well as unnecessarily expensive from a mere healthcare cost point of view. Hence the need to early select only the true beneficiaries while tailoring more effective heart-sparing techniques for the others and streamlining the workflow, especially in high-volume radiation oncology departments. In this literature overview, we collected some possible predictors of cardiac dose sparing in DIBH irradiation for left breast treatment in an effort to provide an easy-to-consult summary of simple instruments to insiders for identifying patients actually benefitting from this technique. We critically reviewed the reliability and weaknesses of each retrieved finding, aiming to inspire new insights and discussions on this much-debated topic.

Simple Summary Oxygen-guided radiotherapy is a new modality for cancer irradiation. Spatially Fractionated Radiation Therapy allows the treatment of hypoxic tumor areas with high radiation doses. Radiotherapy enhances immunotherapy effectiveness. Abscopal and bystander effects are important radiobiological issues. The aim of this paper was to analyze the recent development of a particular kind of radiation therapy that is based on high-dose delivery in small areas within large tumor masses. We performed a narrative review of the radiobiological rationale behind a potential benefit by using these techniques combined with immunotherapy and employing personalized target definition according to hypoxic areas. Abstract Palliative radiotherapy has a great role in the treatment of large tumor masses. However, treating a bulky disease could be difficult, especially in critical anatomical areas. In daily clinical practice, short course hypofractionated radiotherapy is delivered in order to control the symptomatic disease. Radiation fields generally encompass the entire tumor mass, which is homogeneously irradiated. Recent technological advances enable delivering a higher radiation dose in small areas within a large mass. This goal, previously achieved thanks to the GRID approach, is now achievable using the newest concept of LATTICE radiotherapy (LT-RT). This kind of treatment allows exploiting various radiation effects, such as bystander and abscopal effects. These events may be enhanced by the concomitant use of immunotherapy, with the latter being ever more successfully delivered in cancer patients. Moreover, a critical issue in the treatment of large masses is the inhomogeneous intratumoral distribution of well-oxygenated and hypo-oxygenated areas. It is well known that hypoxic areas are more resistant to the killing effect of radiation, hence the need to target them with higher aggressive doses. This concept introduces the “oxygen-guided radiation therapy” (OGRT), which means looking for suitable hypoxic markers to implement in PET/CT and Magnetic Resonance Imaging. Future treatment strategies are likely to involve combinations of LT-RT, OGRT, and immunotherapy. In this paper, we review the radiobiological rationale behind a potential benefit of LT-RT and OGRT, and we summarize the results reported in the few clinical trials published so far regarding these issues. Lastly, we suggest what future perspectives may emerge by combining immunotherapy with LT-RT/OGRT.

Background/aim To evaluate if topical support therapy during static-intensity modulated radiotherapy (sIMRT) course is able to equal the characteristic minimum risk for radiation proctitis of Image-guided volumetric modulated arc therapy (IG-VMAT) treatment among localized prostate cancer patients. Patients and methods Rectal toxicity data of the above patients were retrospectively collected throughout three different clinical periods at our Radiotherapy Deparment: from October 2011 to December 2012, prostate cancer patients were treated with sIMRT and in advance supported by means of daily topical corticosteroids; from January 2013 to November 2016, topical corticosteroids were replaced by daily hyaluronic acid enemas; from December 2016 to May 2018 eligible patients were treated with newly introduced IG-VMAT supported by only on-demand topical corticosteroids. Results Among 359 eligible patients, IG-VMAT was proven generally more effective than sIMRT supported by topical medications in terms of proctitis reduction, although without clinical and practical relevance. Conclusion Topical medications might have a role in radiation proctitis prevention.

Purpose or objective: To evaluate toxicity and outcomes of moderately hypofractionated helical tomotherapy for the curative treatment of a cohort of patients aged ≥ 75years with localized prostate cancer (PC). Materials and methods: From January 2013 to February 2017, 95 patients with median age 77years (range 75–88) were treated for PC. 39% were low risk, 33% intermediate risk (IR), 28% high risk (HR). Median iPSA was 9.42ng/ml (1.6–107). Androgen deprivation was prescribed according to NCCN recommendations. All patients received 70Gy in 28 fractions to theprostate; 61.6Gy were delivered to the seminal vesicles for IR; whole pelvis irradiation with a total dose of 50.4Gy was added in the HR group.Toxicity evaluation was based on CTCAE V4.0 criteria, biochemical failure was defined following Phoenix criteria. Quality of Life was assessed with the EPIC-26 index. Overall survival and biochemical failure-free survival were analysed with Kaplan–Meier method. Results: With a median follow-up of 36months (range 24–73), acute and late toxicity were acceptable. No correlation between toxicity patterns and clinical or dosimetric parameter was registered. EPIC-26 showed a negligible difference in urinary and bowel function post-treatment that did not reach statistical significance. The 2- and 3-years OS were 93% and 87% with cancer specific survival of 97.9% and 96.2%. Conclusion: Moderate hypofractionated RT reported excellent outcomes in our cohort of older patients. Shorter schedules may be proposed regardless of chronological age facilitating the treatment compliance in the older population.

Background/aim Pineoblastoma of the adult age is an uncommon tumor with only 200 cases reported. A standardized approach for an optimal adjuvant strategy is currently lacking. The case presented herein also deals with the issue of central nervous system tumors in pregnancy. Case report A 21-year-old pregnant woman presented with massive hydrocephalus due to a mass in the pineal region detected with MRI. After positioning an urgent ventricular derivation, a cesarean section was performed. During a third ventriculocisternostomy, a biopsy revealed a pineoblastoma. After a maximal safe resection, postoperative craniospinal irradiation for a total dose of 36 Gy plus a sequential boost to the tumor bed to 54 Gy, and adjuvant chemotherapy with CDDP plus CCNU plus vincristine were performed. After one year, the patient is alive with no evidence of disease. Conclusion The use of adjuvant radio-chemotherapy provided excellent outcomes in our case. The advanced gestational age facilitated the choice of the therapeutic strategy.

Francesco Cuccia,1,2 Gianluca Mortellaro,2 Vincenzo Serretta,3 Vito Valenti,1,2 Antonella Tripoli,1,2 Marina Gueci,1,2 Nicoletta Luca,1,2 Antonio Lo Casto,4 Giuseppe Ferrera2 1Radiation Oncology School, University of Palermo, Palermo, Italy; 2Radiation Oncology, ARNAS-Civico Hospital, Palermo, Italy;3Section of Urology, Department of Surgical Oncological and Oral Science, University of Palermo, Palermo, Italy; 4Radiation Oncology School, Section of Radiological Sciences, DIBIMED, Università degli Studi di Palermo, Palermo, Italy Purpose: This is a mono-institutional study of acute and late toxicities and early biochemical control of a retrospective series of 75 prostate cancer patients treated with moderate postoperative hypofractionation delivered by helical tomotherapy (HT). Patients and methods: From April 2013 to June 2017, 75 patients received adjuvant (n=37) or salvage (n=38) treatment, delivering to prostate bed a total dose of 63.8 Gy (equivalent dose in 2-Gy fractions=67.4 Gy) using 2.2 Gy fractions. Whole-pelvis irradiation was performed in 63% of cases (median dose, 49.3 Gy; range, 48–55.1 Gy). Concurrent hormonal therapy was administered in 46% of cases. Common Terminology Criteria for Adverse Events (version 4.0) was adopted for acute and lategenitourinary (GU) and gastrointestinal (GI) toxicity evaluations. Biochemical progression was defined as PSA level increase of ≥0.2 or more above the postoperative radiotherapy (RT) nadir. Results: Acute GU toxicities were as follows: G1 in 46% and G2 in 4%, detecting no G≥3 events. For GI toxicity, we recorded G1 in 36% and G2 in 18%. With a median follow-up of 30 months (range, 12–58 months), we found late toxicity G2 GI in 6.6% and G≥2 GU in 5.3%, including two patients who underwent surgical incontinence correction. Acute GI≥2 toxicity and diabetes were found to be predictive of late GI≥2 toxicity (P=0.04 and P=0.0019). Actuarial 2- and 3-year biochemical recurrence-free survivals were 88% and 73%, respectively, for the entire population. Conclusion: In our experience, moderate hypofractionated postoperative RT with HT was feasible and safe, with reports of low incidence of toxicity and promising biochemical control rates. Keywords: prostate neoplasm, radiotherapy, hypofractionation, adjuvant, salvage