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Aim: In this study, a not yet commercially available fully-automated lexicographic optimization (LO) planning algorithm, called mCycle (Elekta AB, Stockholm, Sweden), was validated for cervical cancer., Material and Methods: Twenty-four mono-institutional consecutive treatment plans (50 Gy/25 fx) delivered between November 2019 and April 2022 were retrospectively selected. The automatic re-planning was performed by mCycle, implemented in the Monaco TPS research version (v5.59.13), in which the LO and Multicriterial Optimization (MCO) are coupled with Monte Carlo calculation. mCycle optimization follows an a priori assigned priority list, the so-called Wish List (WL), representing a dialogue between the radiation oncologist and the planner, setting hard constraints and following objectives. The WL was tuned on a patient subset according to the institution's clinical protocol to obtain an optimal plan in a single optimization. This robust WL was then used to automatically re-plan the remaining patients. Manual plans (MP) and mCycle plans (mCP) were compared in terms of dose distributions, complexity (modulation complexity score, MCS), and delivery accuracy (perpendicular diode matrices, gamma analysis-passing ratio, PR). Their clinical acceptability was assessed through the blind choice of two radiation oncologists. Finally, a global quality score index (SI) was defined to gather into a single number the plan evaluation process., Results: The WL tuning requested four patients. The 20 automated re-planning tasks took three working days. The median optimization and calculation time can be estimated at 4 h and just over 1 h per MP and mCP, respectively. The dose comparison showed a comparable organ-at-risk spare. The planning target volume coverage increased (V 95% : MP 98.0% [95.6-99.3]; mCP 99.2%[89.7-99.9], p >0.05). A significant increase has been registered in MCS (MP 0.29 [0.24-0.34]; mCP 0.26 [0.23-0.30], p <0.05) without affecting delivery accuracy (PR (3%/3mm): MP 97.0% [92.7-99.2]; mCP 97.1% [95.0-98.6], p >0.05). In the blind choice, all mCP results were clinically acceptable and chosen over MP in more than 75% of cases. The median SI score was 0.69 [0.41-0.84] and 0.73 [0.51-0.82] for MP and mCP, respectively (p >0.05)., Conclusions: mCycle plans were comparable to clinical manual plans, more complex but accurately deliverable and registering a similar SI. Automated plans outperformed manual plans in blinded clinical choice., Competing Interests: RP serves as Director of Clinical Science at Elekta AB. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Trivellato, Caricato, Pellegrini, Montanari, Daniotti, Bordigoni, Faccenda, Panizza, Meregalli, Bonetto, Arcangeli and De Ponti.)

In Europe, Cytauxzoon spp. infection was documented in domestic and wild felids. Cats often develop a subclinical infection, while fatal disease is rare. Currently, information on the epidemiology, risk factors and clinicopathological findings of Cytauxzoon spp. infection remains limited and obtained by a single subject or small groups of cats. The objective of this case-control study was to evaluate clinicopathological findings and to describe risk factors associated with Cytauxzoon spp. infection in domestic cats. Infected cats ( n = 39) and non-infected ( n = 190) cats were selected from the database of the referral San Marco Veterinary Laboratory between 2008 and 2021. Demographic information, a preset questionnaire considering lifestyle, environment, and clinical status, and a CBC performed contextually with the PCR analysis were recorded for all cats. Data on the biochemical profile and serum protein electrophoresis were also evaluated when available. Compared to the control group, infection was more likely to occur in stray cats (24/39, 61.5%, P < 0.001), living totally/partially outdoors (36/39, 92.3%, P < 0.001), in an urban context (37/39, 94.9%, P = 0.002), taken or recently adopted from colonies (34/35, 97.1, P < 0.001), with irregular or absent parasite preventive treatments (39/39, 100%, p = 0.005), without fleas (28/35, 80%, P = 0.047) and without clinical signs (22/39, 56.4%, p = 0.026) at the time of medical evaluation. Anemia was not associated with infection, but in cats without clinical signs, the percentage of anemic-infected cats (7/22, 31.8%, P = 0.009) was higher compared to non-infected cats (5/65, 7.7%). Furthermore, a decrease in total iron serum concentration approximating the lowest reference interval [median values (IQR): 79 μg/dL (52.25) vs. 50.5 μg/dL (34), P = 0.007] was likely in infected cats. No other laboratory findings were associated with infection. Interestingly, a partial/total outdoor lifestyle was a risk factor for infection (OR: 8.58, 95% CI: 2.90-37.0, P < 0.001). In conclusion, the present study revealed that Cytauxzoon spp. infection manifests itself prevalently as a subclinical infection, based on physical examination and laboratory findings, in domestic European cats. However, subclinical infected cats were more likely to be anemic compared to non-infected., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Carli, Solano-Gallego, De Arcangeli, Ventura, Ligorio and Furlanello.)

Purpose of Review: Determining the risk for progression or survival after standard androgen deprivation treatment (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC) is essential for stratifying patients according to expected outcomes in future studies of treatment combination. This systematic review and meta-analysis aims to estimate the progression-free survival (PFS) and overall survival (OS) probabilities in the control group of randomized controlled trials (RCTs) of different regimens of standard androgen deprivation treatment (ADT) in mHSPC and to identify possible predictors of outcomes., Recent Findings: Studies reporting time-dependent outcomes (progression or death) after standard ADT treatment of mHSPC were searched in MEDLINE, CANCERLIT, the Cochrane Controlled Trials Register, and the Cochrane Library from inception through June 2021. Data on patient populations and outcomes were extracted from each study by three independent observers and combined using a distribution-free summary survival curve. Primary outcomes were actuarial probabilities of disease progression and survival. Fifteen studies met the inclusion criteria. The pooled estimate of the actuarial PFS rate was 35.2% at two years. The pooled actuarial OS rate was 62.5% at three years. Heterogeneity among studies was highly significant for all outcomes. By univariate meta-regression analyses, high-volume disease and the presence of visceral metastases were associated with shorter survival. Our findings show that PFS and OS are highly variable in patients with mHSPC treated with ADT, providing a helpful benchmark for indirect comparisons of the benefits of the combination of chemotherapy and second-generation hormonotherapy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Since the first definition by Hellman and Weichselbaum in 1995, the concept of OligoMetastatic Disease (OMD) is a growing oncology field. It was hypothesized that OMD is a clinical temporal window between localized primary tumor and widespread metastases deserving of potentially curative treatment. In real-world clinical practice, OMD is a "spectrum of disease" that includes a highly heterogeneous population of patients with different prognosis. Metastasis directed therapy with local ablative treatment have proved to be a valid alternative to surgical approach. Stereotactic body radiation therapy demonstrated high local control rate and increased survival outcomes in this setting with a low rate of toxicity. However, there is a lack of consensus regarding many clinical, therapeutic, and prognostic aspects of this disease entity. In this review, we try to summarize the major critical features that could drive radiation oncologists toward a better selection of patients, treatments, and study endpoints. With the help of a set of practical questions, we aim to integrate the literature discussion., (© 2022. The Author(s).)

Objectives: We aimed to analyze the impact of a 3-week schedule of HypoFractionated (HF) radiotherapy (RT) after axillary dissection and breast surgery, in terms of safety and efficacy in patients with locally advanced breast cancer (BC)., Methods: Eligible patients were females with Stage IIA - IIIC BC who underwent axillary dissection and breast surgery, either quadrantectomy or mastectomy. HF RT was delivered in 15 or 16 fractions for a total dose of 40.05 Gy or 42.56 Gy, respectively, to the clavicular nodal region along with the whole breast (HF WBRT) or the chest wall (HF PMRT), according to the type of surgery. Locoregional recurrence (LRR), distant metastases-free survival (DMFS), overall survival (OS) and acute and late treatment-related toxicities were estimated., Results: 57 patients with a median age of 60 years (32-85) were retrospectively analyzed. 34 (60%) of patients underwent breast conservative surgery in the form of quadrantectomy and 23 (40%) were offered radical mastectomy. All patients underwent hypofractionated regional nodal irradiation (HF RNI). 34 (60%) of them underwent HF WBRT, while 23 (40%) received HF PMRT.At a median follow-up of 80 months (30-113), the 7-year LRR-free survival was 93% (95% CI, 74%-95%). The same features for DMFS and OS were 76% (95% CI, 52%-78%) and 67% (95% CI, 50%-80%), respectively. Only one (2%) patient experienced G3 acute skin toxicity. No grade ≥2 late toxicity was observed., Conclusion: Our study shows that HF RNI with HF RT to the whole breast or the chest wall after breast surgery is safe and effective in patients with locally advanced BC. Longer follow-up is needed to strengthen further analyses on late toxicity and clinical outcomes., Advances in Knowledge: This paper adds to the evidence that post-operative RNI with WBRT or PMRT can be safely and effectively delivered with 3-week HF regimen. Locally advanced BC patients can be offered HF RT to the regional nodes and the breast or the chest wall regardless the type of surgery.

This paper focuses on stereotactic radiotherapy (SRT ) interactions with targeted therapies and immune system modulating agents because SRT inevitably interacts with them in the treatment of oligometastatic patients. Radiation oncologists need to be aware of the advantages and risks of these interactions which can, on one hand, enhance the effect of therapy or, on the other, potentiate reciprocal toxicities. To date, few prospective studies have evaluated the interactions of SRT with new-generation drugs and data are mainly based on retrospective experiences, which are often related to small sample sizes., Competing Interests: Conflicts of interest The authors have no conflict of interest to declare., (© 2022 Greater Poland Cancer Centre.)

Introduction: Stage III non-small cell lung cancer (NSCLC) is a variable entity, encompassing bulky primary tumors, nodal involvement, or both. Multidisciplinary evaluation is essential to discuss multiple treatment options, to outline optimal management, and to examine the main debated topics and critical issues not addressed by current trials and guidelines that influence daily clinical practice., Areas Covered: From March to 5 May 2021 ,meetings were scheduled in a webinar format titled 'Radio Talk' due to the COVID-19 pandemic; the faculty was composed of 6 radiation oncologists from 6 different Institutions of Italy, all of them were the referring radiation oncologist for lung cancer treatment at their respective departments and were or had been members of AIRO (Italian Association of Radiation Oncology) Thoracic Oncology Study Group. The topics covered included: pulmonary toxicity, cardiac toxicity, radiotherapy dose, fractionation and volumes, unfit/elderly patients, multidisciplinary management., Expert Opinion: The debate was focused on the unmet needs triggered by case reports, personal experiences and questions; the answers were often not univocal; however, the exchange of opinion and the contribution of different centers confirmed the role of multidisciplinary management and the necessity that the most critical issues should be investigated in clinical trials.

Purpose: Our study investigated the association between treatment-related lymphopenia and overall survival (OS) in a series of glioblastoma (GBM) patients. We also explored clinical and dosimetric predictors of lymphocytes depletion., Methods: Between 2015 and 2019, 64 patients were treated at the same institution with postoperative chemoradiotherapy. Peripheral lymphocyte count (PLC) data and dose-volume histogram parameters were collected. Radiotherapy (RT) schedule consisted in standard total dose of 60 Gy in 30 daily fractions, with concomitant and adjuvant temozolomide (TMZ). Posttreatment acute absolute lymphopenia (nadir AAL) was calculated as a PLC lower than 1.0 × 10 3 /mm 3 . Acute relative lymphopenia (ARL) was expressed by the nadir-PLC/baseline-PLC ratio < 0.5. Nadir-PLC was the lowest PLC registered between the end of RT and the first month of follow-up. Survival rates were estimated with Kaplan-Meier curves. Clinical and dosimetric variables related to AAL/ARL and OS were identified by univariate and multivariate analyses., Results: A total of 57 patients were eligible and included in the analyses. The median PLC was significantly decreased following chemoradiotherapy (2180/mm 3 vs 900/mm 3 ). Median OS was 16 months (range 5-55 months), with no significant difference between patients who developed nadir AAL and those who did not (16 months vs 16.5 months; p = 0.304). When considering ARL vs non-ARL, median OS was 14 months vs 26 months (p = 0.013), respectively. In multivariate Cox regression only age, sex, extent of surgery, access to adjuvant chemotherapy and brain D98% were independently associated with OS., Conclusion: Although iatrogenic immunosuppression could be associated with inferior clinical outcomes, our data show that treatment-related lymphopenia does not adversely affect GBM survival. Prospective studies are required to confirm these findings., (© 2021. The Author(s).)

Background: Extreme hypofractionation requires tight planning margins, high dose gradients, and strict adherence to planning criteria in terms of patient positioning and organ motion mitigation. This study reports the first clinical experience worldwide using a novel electromagnetic (EM) tracking device for intrafraction prostate motion management during dose-escalated linac-based stereotactic body radiation therapy (SBRT)., Methods: Thirteen patients with organ-confined prostate cancer underwent dose-escalated SBRT using flattening filter-free (FFF) volumetric modulated arc therapy (VMAT). The EM tracking device consisted of an integrated Foley catheter with a transmitter. Patients were simulated and treated with a filled bladder and an empty rectum. Setup accuracy was achieved by ConeBeam-CT (CBCT) matching, and motion was tracked during all the procedure. Treatment was interrupted when the signals exceeded a 2 mm threshold in any of the three spatial directions and, unless the offset was transient, target position was re-defined by repeating CBCT. Moreover, the displacements that would have occurred without any intrafraction organ motion management (i.e. no interruptions and repositionings) were simulated., Results: In 31 out of 56 monitored fractions (55%), no intervention was required to correct the target position. In 25 (45%) a correction was mandated, but only in 10 (18%), the beam delivery was interrupted. Total treatment time lasted on average 10.2 minutes, 6.7 minutes for setup, and 3.5 minutes for beam delivery. Without any intrafraction motion management, the overall mean treatment time and the mean delivery time would have been 6.9 minutes and 3.2 minutes, respectively. The prostate would have been found outside the tolerance in 8% of the total session time, in 4% of the time during the setup, and in 14% during the beam-on phase. Predominant motion pattern was posterior and its probability increased with time, with a mean motion ≤ 2 mm occurring within 10 minutes., Conclusions: EM real-time tracking was successfully implemented for intrafraction motion management during dose-escalated prostate SBRT. Results showed that most of the observed displacements were < 2 mm in any direction; however, there were a non-insignificant number of fractions with motion exceeding the predefined threshold, which would have otherwise gone undetected without intrafraction motion management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Panizza, Faccenda, Lucchini, Daniotti, Trivellato, Caricato, Pisoni, De Ponti and Arcangeli.)

The liver is the first metastatic site in 15-25% of colorectal cancer patients and one of the first metastatic sites for lung and breast cancer patients. A computed tomography (CT ) scan with contrast medium is a standard procedure for assessing liver lesions but magnetic resonance imaging (MRI) characterizes small lesions better thanks to its high soft-tissue contrast. Positron emission tomography with computed tomography (PET-CT ) plays a complementary role in the diagnosis of liver metastases. Triphasic (arterial, venous and time-delayed) acquisition of contrast-medium CT images is the first step in treatment planning. Since the liver exhibits a relatively wide mobility due to respiratory movements and bowel filling, appropriate techniques are needed for target identification and motion management. Contouring requires precise recognition of target lesion edges. Information from contrast MRI and/or PET-CT is crucial as they best visualize metastatic disease in the parenchyma. Even though different fractionation schedules were reported, doses and fractionation schedules for liver stereotactic radiotherapy (SRT ) have not yet been established. The best local control rates were obtained with BED 10 values over 100 Gy. Local control rates from most retrospective studies, which were limited by short follow-ups and included different primary tumors with intrinsic heterogeneity, ranged from 60% to 90% at 1 and 2 years. The most common SRT-related toxicities are increases in liver enzymes, hyperbilirubinemia and hypoalbuminemia. Overall, late toxicity is mild even in long-term follow-ups., Competing Interests: Conflicts of interest The authors have no conflict of interest to declare., (© 2022 Greater Poland Cancer Centre.)

Although systemic therapy represents the standard of care for polymetastatic kidney cancer, stereotactic body radiation therapy (SBRT) may play a relevant role in the oligometastatic setting. We conducted a multicenter study including oligometastatic kidney cancer treated with SBRT. We retrospectively analyzed 207 patients who underwent 245 SBRT treatments on 385 lesions, including 165 (42.9%) oligorecurrent (OR) and 220 (57.1%) oligoprogressive (OP) lesions. Most common sites were lung (30.9%) for OR group, and bone (32.7%) for OP group. Among 78 (31.8%) patients receiving concomitant systemic therapy, sunitinib (61.5%) and pazopanib (15.4%) were the most common for OR patients, while sunitinib (49.2%) and nivolumab (20.0%) for OP patients. End points were local control (LC), progression free survival (PFS), overall survival (OS), time to next systemic therapy (TTNS) and toxicity. Median follow-up was 18.6 months. 1, 2 and 3-year LC rates were 89.4%, 80.1% and 76.6% in OR patients, and 82.7%, 76.9% and 64.3% in those with OP, respectively. LC for OP group was influenced by clear cell histology (p = 0.000), total number of lesions (p = 0.004), systemic therapy during SBRT (p = 0.012), and SBRT dose (p = 0.012). Median PFS was 37.9 months. 1, 2- and 3-year OS was 92.7%, 86.4% and 81.8%, respectively. Median TTNS was 15.8 months for OR patients, and 13.9 months for OP patients. No grade 3 or higher toxicities were reported for both groups. SBRT may be considered an effective safe option in the multidisciplinary management of both OR and OP metastases from kidney cancer., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Almost 30% of non-small cell lung cancer (NSCLC) patients have locally advanced-stage disease. In this setting, definitive radiotherapy concurrent to chemotherapy plus adjuvant immunotherapy (cCRT + IO) is the standard of care, although only 40% of these patients are eligible for this approach., Aims: A comparison between cCRT and hypofractionated radiotherapy regimens (hypo-fx RT) with the addition of sequential chemotherapy (sCHT) could be useful for future combinations with immunotherapy. We developed a recommendation about the clinical question of whether CHT and moderately hypo-fx RT are comparable to cCRT for locally advanced NSCLC MATERIALS AND METHODS: The panel used GRADE methodology and the Evidence to Decision (EtD) framework. After a systematic literature search, five studies were eligible. We identified the following outcomes: progression-free survival (PFS), overall survival (OS), freedom from locoregional recurrence (FFLR), deterioration of quality of life (QoL), treatment-related deaths, severe G3-G4 toxicity, late pulmonary toxicity G3-G4, and acute esophageal toxicity G3-G4., Results: The probability of OS and G3-G4 late lung toxicity seems to be worse in patients submitted to sCHT and hypo-fx RT. The panel judged unfavorable the balance benefits/harms., Conclusions: The final recommendation was that sCHT followed by moderately hypo-fx RT should not be considered as an alternative to cCRT in unresectable stage III NSCLC patients., (© 2021. Italian Society of Medical Radiology.)

Babesia gibsoni (B. gibsoni) infection was sporadically described in Europe. In Italy, in particular, it was detected by PCR analysis only in one dog with unclear source of infection, while it has never been found in molecular studies involving more subjects. The aim of this retrospective, cross-sectional study was to determine the presence and the proportion of B. gibsoni infected dogs in a convenient Italian canine population. Babesia spp PCR analysis reports of canine blood samples collected from January 2016 to December 2019 were selected from the San Marco veterinary laboratory database and evaluated. Piroplasms PCR analysis was performed on 18S rRNA gene and positive samples were sequenced. Available data about signalment, living area and season of diagnosis were evaluated and statistically analyzed. The studied canine population had a median age of 62 months (interquartile range, IQR: 72.5) and was composed of male/female purebred and mixed breed dogs. Through sequencing, B. canis (26/40, 65%), B. vogeli (7/40, 17.5%), B. gibsoni (6/40, 15%) and B. vulpes (1/40, 2.5%) infections were reported. The proportion of B. gibsoni infected dogs in the described population was of 0.99%. The infection resulted more likely in male (6/6, 100%), purebred (5/6, 83.3%) dogs with median age of 40.5 months (IQR:32.3). In one case, the clinical signs and parasitemia appeared after a dogfight with a cohabitant infected dog. No other plausible sources of infection were detected. Likely, this could be considered the first autochthonous B. gibsoni infection case documented in Italy. Our results underline the need of considering B. gibsoni not only an exotic, random and rare cause of disease for dogs in Italy, but a possible emerging pathogen to take into account during diagnostic and epidemiological investigations, in symptomatic as well as in asymptomatic patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To perform a meta-analysis to determine the effect of loco-regional radiation therapy (RT) compared to no loco-regional RT for operated patients in clinical stage cN2 breast cancer at diagnosis and ypN0 after preoperative chemotherapy (PST)., Material and Methods: Eligible studies were identified through a systematic search of the medical literature performed independently by two researchers using a validated search strategy. An electronic search of Medline via PubMed and Embase (Breast cancer AND preoperative chemotherapy AND radiation therapy) was conducted with no language or publication status restrictions. The effect of loco-regional RT on overall (OS), disease free (DFS), loco-regional recurrence-free (LRRFS) survival and local recurrence was evaluated. An electronic search of Medline via PubMed and Embase (Toxicity AND radiation therapy breast cancer AND preoperative therapy; toxicity AND breast surgery AND preoperative chemotherapy) was conducted for outcomes of harm: major acute and late skin toxicity, lymphedema and cardiac events., Results: Of 333 studies identified, 4 retrospective studies reporting on a total of 1107 patients were included in the meta-analysis. Six and 3 reported data of acute and late skin toxicity, while 2 studies provided information on cardiac events. Pooled results showed no difference in terms of hazard ratio for loco-regional RT versus no loco-regional RT [hazard ratio (HR) = 0.82, 95% confidence interval (CI) 0.63-1.68]. Loco-regional RT was associated with an OS benefit in the subgroup analysis: IIIB-C (loco-regional RT 79.3% vs no loco-regional RT 71.2%, p = 0.027) and T3-T4 (loco-regional RT 82.6% vs no loco-regional RT 76.6%, p = 0.025). No difference was shown in terms of 5-year DFS (loco-regional RT 91.2% vs no loco-regional RT 83%, p = 0.441) and LRRFS (loco-regional RT 98.1% vs no loco-regional RT 92.3%, p = 0.148). There was no significant difference between the groups in terms of acute and late skin toxicities, lymphedema and cardiac events., Conclusions: Because of the limitations due to the small number of studies and heterogeneity in the analysis, the present study does not allow to draw any definitive conclusion, highlighting the need for well-controlled trials to determine the effect of loco-regional RT in patients with cN2 having a pathological complete response in the axillary nodes after preoperative chemotherapy., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Radiotherapy (RT) is rarely used in the palliative management of muscle-invasive bladder cancer (MIBC). This survey aims to explore current care patterns within the Italian Radiation Oncologist community on this topic. In 2020, the uro-oncological study group of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) conducted a survey evaluating the RT role in advanced MIBC. An electronic questionnaire was administered online to the society members asking for: general considerations, patients' selection, and aim of the treatment, RT schedule and practical consideration, past and future perspective. Sixty-one questionnaires were returned (33% response rate). Most responders (62.30%) declared to work in a Center with a multidisciplinary uro-oncological team, and 8.20% to evaluate more than 20 patients with MIBC/year for palliative RT. Elderly patients were the most frequently evaluated (46.7%) and life expectancy was the most common selection criteria (44.60%). Thirty Gy in 10 fractions (58.9%), whole bladder as GTV (62.5%), PTV isotropic margins of 1.5-2 cm (44.6%) and IMRT/VMAT technique (58.14%) were the most common treatment choices. Patients amenable for bladder palliative RT were most commonly referred by the urologist (43.86%) or the multidisciplinary team (38%). The reported main reasons for the low involvement of radiation oncologist in the management of MIBC patients were low attention to the palliative setting in bladder cancer (37.5%); radiation oncologist not involved in the management of these patients (32.1%); cases not discussed in the multidisciplinary board (26.8%). This survey illustrated the current use of palliative RT for patients with advanced MIBC in Italy and suggested the need for a greater involvement of radiation oncologists in their management.

Over the past century, technologic advances have promoted the evolution of radiation therapy into a precise treatment modality allowing for the maximal administration of dose to tumors while sparing normal tissues. In parallel with this technological maturation, the rapid expansion in understanding the basic biology and heterogeneity of cancer has led to the development of several compounds that target specific pathways. Many of them are in advanced steps of clinical development for combination treatments with radiotherapy, and can be incorporated into radiation oncology practice for a personalized approach to maximize the therapeutic gain. This review describes the rationale for combining novel agents with radiation, and provides an overview of the current landscape focused on treatment efficacy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Clinical development and use of novel systemic agents in combination with radiotherapy (RT) is at nowadays most advanced in the field of treatment of solid tumors. Although for many of these substances preclinical studies provide sufficient evidences on their principal capability to enhance radiation effects, the majority of them have not been investigated in even phase I clinical trials for safety in the context of RT. In clinical practice, unexpected acute and late side effects may emerge especially in combination with RT. As a matter of fact, despite combined modality treatment holds potential for enhancing the therapeutic ratio, some concerns are raised from the lack of high-quality clinical data to guide the care of patients who are treated with novel compounds in conjunction with RT. The aim of this review is to provide, from a radio-oncological point of view, an overview of the most advanced combined treatment concepts for solid tumors focusing on treatment toxicity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: To investigate the role of Radiation Oncology in the management of genito-urinary (GU) cancer excluding prostate and penile cancer., Methods: The questionnaire was focused on the evaluation of the degree of involvement of radiation oncologists in the work-up of bladder, renal cell carcinoma and testicular cancer (TC)., Results: Eighty-eight radiation oncologists completed the survey. The majority (85.4%) of participating radiation oncologists were senior consultants (> 5 years of experience). Sixty-four (73.6%) carried out a multidisciplinary tumor board discussion of GU cases, while 23 (26.4%) did not. Seventy-five percent of responders reported that, every year, visited < 50 GU patients (pts), 18.1% visited 50-100 pts and 6.9% visited > 100 pts. Bladder cancer, curative radiotherapy (RT) as part of trimodality approach was claimed to be adopted in less than 10 cases per year. Regarding renal cell carcinoma (RCC) patients, primary tumor directed RT was adopted only in 8 cases (9.4%) in at least 10 pts per year. Palliative RT was more frequent in RCC (48.2%) in over than 10 pts per year. In case of TC, the prescription of RT was limited (< 10 patients per year) due to the low incidence of disease and recent shift to surveillance as a first option in stage I seminoma., Conclusions: Our survey showed that radiation oncologists are rarely involved in the decision making strategy of GU cancer, despite many clinical trials support RT use. These patients probably deserve a more uniform approach based on updated, detailed and evidence-based recommendations.

Aim: To retrospectively investigate outcomes, and acute and late complications following postoperative hypofractionated 3D conformal radiotherapy., Patients and Methods: Sixty-nine consecutive patients underwent radical prostatectomy. Radiotherapy was delivered to the prostatic fossa by means of a7-fieldLINACwith 6-15 MV to a total dose of 62.5 Gy in 25 fractions (2.5 Gy per fraction) in five consecutive weeks., Results: Median follow-up was 54.7 months (range=38-76 months). Five-year overall survival, metastasis-free survival and biochemical relapse-free survival were 91.1%, 84.6% and 66.7%, respectively. Grade 2 or more genitourinary and gastrointestinal acute toxicity was reported in 12% and 5% of patients, respectively. Urinary incontinence grade 2 or more was recorded in 19%., Conclusion: Postoperative radiotherapy either in the adjuvant or salvage setting resulted in acceptable rates of acute and late toxicity with good tumor control while reducing overall treatment time. Confirmatory results from an ongoing prospective trial are awaited., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Renal Cell Carcinoma (RCC) has historically been considered a radioresistant cancer, and radiotherapy was usually delivered with a palliative goal. Stereotactic ablative radiotherapy (SABR) allows the delivery of high doses on small treatment volumes in a safe and effective way, thus opening the doors to new applicationsof radiotherapy both in the treatment of the primary and oligometastasic disease. Aim of the current review is to explore the state of art of SABR in the therapeutic approach to RCC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Small cell lung cancer (SCLC) is relative rare histology in lung cancer patients. The standard treatment, in patients with an intra-thoracic disease, is represented by the use of concurrent chemo-radiotherapy; while patients with early SCLC stage, surgical resection could be recommended. Stereotactic body radiotherapy (SBRT) is a recently introduced technique allowing the delivery of very high radiation doses to limited target volumes and it is considered the standard approach in the treatment of not operable stage I Non Small-Cell Lung Cancer (NSCLC). The successful role option of SBRT in early NSCLC in terms of local control and toxicity profile opened the issue in the use of this approach in early stage small cell lung cancer (SCLC). Aim of this review is to discuss the current literature in the safety and efficacy of SBRT in the treatment of patients with stage I SCLC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To perform a critical review focusing on the applicability in clinical daily practice of data from three randomized controlled trials (RCTs): SWOG 8794, EORTC 22911, and ARO/AUO 96-02., Methods and Materials: An analytical framework, based on the identified population, interventions, comparators, and outcomes (PICO) was used to refine the search of the evidence from the three large randomized trials regarding the use of radiation therapy after prostatectomy as adjuvant therapy (ART)., Results: With regard to the inclusion criteria: (1) POPULATION: in the time since they were designed, in two among three trial (SWOG 8794 and EORTC 22911) patients had a detectable PSA at the time of randomization, thus representing de facto a substantial proportion of patients who eventually received salvage RT (SRT) at non-normalised PSA levels rather than ART. (2) INTERVENTIONS: although all the trials showed the benefit of postoperative ART compared to a wait-and-see approach, the dose herein employed would be now considered inadequate; (3) COMPARATORS: the comparison arm in all the 3 RCTs was an uncontrolled observation arm, where patients who subsequently developed biochemical failure were treated in various ways, with up to half of them receiving SRT at PSA well above 1 ng/mL, a level that would be now deemed inappropriate; (4) OUTCOMES: only in one trial (SWOG 8794) ART was found to significantly improve overall survival compared to observation, with a ten-year overall survival rate of 74% vs. 66%, although this might be partly the result of imbalanced risk factors due to competing event risk stratification., Conclusions: ART has a high level of evidence due to three RCTs with at least 10-year follow-up recording a benefit in biochemical PFS, but its penetrance in present daily clinics should be reconsidered. While the benefit of ART or SRT is eagerly expected from ongoing randomized trials, a dynamic risk-stratified approach should drive the decisions making process., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Patients with metastatic prostate cancer (PC) represent a heterogeneous group with survival rates varying between 13 and 75 months. The current standard treatment in this setting is hormonal therapy, with or without docetaxel-based chemotherapy. In the era of individualized medicine, however, maximizing treatment options, especially in long-term surviving patients with limited disease burden, is of capital importance. Emerging data, mainly from retrospective surgical series, show survival benefits in men diagnosed with metastatic PC following definitive therapy for the prostate. Whether the irradiation of primary tumor in a metastatic disease might improve the therapeutic ratio in association with systemic treatments remains investigational. In this scenario, modern radiation therapy (RT) can play a significant role owing to its intrinsic capability to act as a more general immune response modifier, as well as to the potentially better toxicity profile compared to surgery. Preclinical data, clinical experience, and challenges in local treatment in de novo metastatic PC are reviewed and discussed., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The most popular therapeutic option in the management of radio-recurrent prostatic carcinoma is represented by the androgen deprivation therapy, that however should be considered only palliative and hampered by potential adverse effects of testosterone suppression. Local therapies such as surgery, cryoablation or brachytherapy might be curative choices for patients in good conditions and with a long-life expectancy, but at cost of significant risk of failure and severe toxicity. The administration of stereotactic body radiation therapy (SBRT) in this setting have come about because of tremendous technologic advances in image guidance and treatment delivery techniques that enable the delivery of large doses to tumor with reduced margins and high gradients outside the target, thereby reducing the volume of rectum which already received significant doses from primary radiotherapy. So far, very modest data are available to support its employment. Rationale, clinical experience, and challenges are herein reviewed and discussed.

Background/aim: Based on a radiobiological assumption of a low alpha/beta (α/β) ratio for prostate cancer, hypofractionated radiotherapy has increasingly gained traction in the clinical practice and recent guidelines have confirmed the non-inferiority of this approach. Nevertheless, the largest studies that have used hypofractionation so far, employed image-guided radiation therapy/intensity modulated radiation therapy (IGRT/IMRT) facilities that might have overcome the radiobiological advantages, which remain to be fully confirmed. The aim of this trial was to evaluate the feasibility of a hypofractionated schedule delivered with 3D-Conformal Radiotherapy to prostate and seminal vesicles in combination with hormonal therapy., Patients and Methods: The study included 97 consecutive patients with localized prostate cancer (PCa), irrespective of risk class, treated with a schedule of 62 Gy in 20 fractions over 5 weeks (4 fractions of 3.1 Gy each per week). According to National Comprehensive Cancer Network (NCCN) prognostic classification, patients were divided into a favourable group (19%), intermediate group (41%) and unfavourable group (40%). Early and late toxicities were scored using the radiation toxicity grading/European Organisation for Research and Treatment of Cancer (RTOG/EORTC) criteria. Additionally, the international prostate symptom index (IPSS) for benign prostate hypertrophy was used to evaluate obstructive urinary symptoms. Biochemical outcome was reported according to the Phoenix definition for biochemical failure. Hormonal therapy (HT) was administrated in 92% of patients., Results: After a median follow-up of 39 months (range=25-52), maximum ≥G2 late genitourinary (GU) and gastrointestinal (GI) toxicities occurred in 8% and 11% patients, respectively. The corresponding figures for acute toxicities were 24% and 15%. Patients with higher IPSS score before enrolment had significantly worse urinary function after treatment. Only 2% of patients died from PCa. Biochemical non-evidence of disease (bNED) was 83% for all patients., Conclusion: Our study confirms that 3D conformal radiotherapy (3DCRT) remains a safe and effective method to deliver a dose-escalated hypofractionated regimen for PCa patients in all risk classes with acceptable toxicity rates and optimal biochemical control., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: Despite the numerous prospective and retrospective studies published during the last 2 decades aiming at testing the safety and the efficacy of trimodality therapy (TMT) as a conservative treatment, an optimal therapeutic strategy has not yet been identified. We made a systematic overview of the 5-year outcomes from 31 trials of combined chemotherapy and radiation (CRT) after transurethral resection of muscle-infiltrating bladder tumours (TURBT), the so-called trimodality therapy. We took into consideration the results of each trial i.e. the rate of complete response (CR), local muscle-invasive local failure (LF), salvage cystectomy (SC), 5-year overall survival (OS) and 5-year bladder intact survival (BIS) from 3315 patients., Results: About half of the patients were treated with a preliminary induction followed by a consolidation CRT course in CR, or SC in non-CR patients (split treatment). The remaining half of the patients underwent an upfront full-dose CRT course (continuous treatment) with SC reserved to non-CR patients. Excellent results were obtained by trimodality therapy (TMT), with 78% CR, 28% muscle infiltrating LF and 21% SC in patients with MIBC. The 5-year OS and BIS rates were 56% and 42%, respectively. At univariate analysis, CR, and SC rates appeared to be significantly better in the continuous than in the split treatment group. Multivariate analysis confirmed the former regimen as a significant prognostic variables only for CR, while CP-based regimen was a significant prognostic factor for SC. The subgroup analysis revealed a significant improvement in 5-year OS rate of continuous over split treatment in later stage tumours. No relevant benefit was observed with the addition of other drugs to cisplatin (CP) or neo-adjuvant chemotherapy (NATC) to CRT, although, in patients receiving NACT, significantly better CR and OS rates were seen in the continuous than split treatment., Conclusions: The results of this overview seem to indicate that TMT is able to produce excellent 5-year OS rates, no matter how it is done (continuous or split). No significant difference in 5-year OS rates could be observed between the two treatment regimens, although the continuous may offer some advantage compared to split treatment in terms of higher CR and, likely lower SC rates. The highest benefit might be achieved in later stage tumours, using a total radiation equivalent dose when delivered in 2Gy/fraction (EQD2) of more than 60Gy in combination with CP based regimes and preceded by 2-3 NACT cycles. Appropriate randomized trials should be addressed to confirm the results of the present review., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Currently, androgen deprivation therapy (ADT) has a well-defined role when administered together with radiotherapy (RT): neo-adjuvant and concurrent combination for intermediate risk-disease and adjuvant therapy for high risk disease. Evidence of this association was generated by randomized trials designed and led approximately 30 years ago; thus the question which arises is how relevant and portable are these data in our current clinical practice? In the present review, we examine the pitfalls of these published randomized controlled trials, their relevance to present daily clinics, where high-dose external beam RT or brachytherapy is applied, as well as the adoption of ADT in patients with concomitant cardiovascular disorders., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To evaluate the feasibility of high-dose stereotactic body radiation therapy (SBRT) in the treatment of unresectable liver metastases., Methods and Materials: Patients with 1 to 3 liver metastases, with maximum individual tumor diameters less than 6 cm and a Karnofsky Performance Status of at least 70, were enrolled and treated by SBRT on a phase 2 clinical trial. Dose prescription was 75 Gy on 3 consecutive days. SBRT was delivered using the volumetric modulated arc therapy by RapidArc (Varian, Palo Alto, CA) technique. The primary end-point was in-field local control. Secondary end-points were toxicity and survival., Results: Between February 2010 and September 2011, a total of 61 patients with 76 lesions were treated. Among the patients, 21 (34.3%) had stable extrahepatic disease at study entry. The most frequent primary sites were colorectal (45.9%) and breast (18%). Of the patients, 78.7% had 1 lesion, 18.0% had 2 lesions, and 3.3% had 3 lesions. After a median of 12 months (range, 2-26 months), the in-field local response rate was 94%. The median overall survival rate was 19 months, and actuarial survival at 12 months was 83.5%. None of the patients experienced grade 3 or higher acute toxicity. No radiation-induced liver disease was detected. One patient experienced G3 late toxicity at 6 months, resulting from chest wall pain., Conclusions: SBRT for unresectable liver metastases can be considered an effective, safe, and noninvasive therapeutic option, with excellent rates of local control and a low treatment-related toxicity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To report long-term results and patterns of failure after conventional and hypofractionated radiation therapy in high-risk prostate cancer., Methods and Materials: This randomized phase III trial compared conventional fractionation (80 Gy at 2 Gy per fraction in 8 weeks) vs hypofractionation (62 Gy at 3.1 Gy per fraction in 5 weeks) in combination with 9-month androgen deprivation therapy in 168 patients with high-risk prostate cancer. Freedom from biochemical failure (FFBF), freedom from local failure (FFLF), and freedom from distant failure (FFDF) were analyzed., Results: In a median follow-up of 70 months, biochemical failure (BF) occurred in 35 of the 168 patients (21%) in the study. Among these 35 patients, local failure (LF) only was detected in 11 (31%), distant failure (DF) only in 16 (46%), and both LF and DF in 6 (17%). In 2 patients (6%) BF has not yet been clinically detected. The risk reduction by hypofractionation was significant in BF (10.3%) but not in LF and DF. We found that hypofractionation, with respect to conventional fractionation, determined only an insignificant increase in the actuarial FFBF but no difference in FFLF and FFDF, when considering the entire group of patients. However, an increase in the 5-year rates in all 3 endpoints-FFBF, FFLF, and FFDF-was observed in the subgroup of patients with a pretreatment prostate-specific antigen (iPSA) level of 20 ng/mL or less. On multivariate analysis, the type of fractionation, iPSA level, Gleason score of 4+3 or higher, and T stage of 2c or higher have been confirmed as independent prognostic factors for BF. High iPSA levels and Gleason score of 4+3 or higher were also significantly associated with an increased risk of DF, whereas T stage of 2c or higher was the only independent variable for LF., Conclusion: Our results confirm the isoeffectiveness of the 2 fractionation schedules used in this study, although a benefit in favor of hypofractionation cannot be excluded in the subgroup of patients with an iPSA level of 20 ng/mL or less. The α/β ratio might be more appropriately evaluated by FFLF than FFBF results, at least in high-risk disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Stereotactic body radiation therapy (SBRT) is a novel treatment modality in radiation oncology that delivers a very high dose of radiation to the tumor target with high precision using single or a small number of fractions. SBRT is the result of technological advances in patient/tumor immobilization, image guidance, and treatment planning and delivery. This modality is safe and effective in both early stage primary cancer and oligometastases. Compared to the use of stereotactic radiosurgery for other tumor sites, SBRT is slow to be adopted in the management of genitourinary malignancies. Emerging data show the safety and efficacy of this treatment modality in prostate cancer. Preclinical data, clinical experience, and challenges are reviewed and discussed., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Recently, the use of hypo-fractionated treatment schemes for the prostate cancer has been encouraged due to the fact that alpha/beta ratio for prostate cancer should be low. However a major concern on the use of hypofractionation is the late rectal toxicity, it is important to be able to predict the risk of toxicity for alternative treatment schemes, with the best accuracy. The main purpose of this study is to evaluate the response of rectum wall to changes in fractionation and to quantify the alpha/beta ratio for late rectal toxicity, Methods: 162 patients with localized prostate cancer, treated with conformal radiotherapy, were enrolled in a phase II randomized trial. The patients were randomly assigned to 80 Gy in 40 fractions over 8 weeks (arm A) or 62 Gy in 20 fractions over 5 weeks (arm B). The median follow-up was 30 months. The late rectal toxicity was evaluated using the Radiation Therapy Oncology Group (RTOG) scale. It was assumed >or= Grade 2 (G2) toxicity incidence as primary end point. Fit of toxicity incidence by the Lyman-Burman-Kutcher (LKB) model was performed., Results: The crude incidence of late rectal toxicity >or= G2 was 14% and 12% for the standard arm and the hypofractionated arm, respectively. The crude incidence of late rectal toxicity >or= G2 was 14.0% and 12.3% for the arm A and B, respectively. For the arm A, volumes receiving >or= 50 Gy (V50) and 70 Gy (V70) were 38.3 +/- 7.5% and 23.4 +/- 5.5%; for arm B, V38 and V54 were 40.9 +/- 6.8% and 24.5 +/- 4.4%. An alpha/beta ratio for late rectal toxicity very close to 3 Gy was found., Conclusion: The >or= G2 late toxicities in both arms were comparable, indicating the feasibility of hypofractionated regimes in prostate cancer. An alpha/beta ratio for late rectal toxicity very close to 3 Gy was found.

Dose and volume and their correlation with the development of pulmonary toxicity are among the most widely studied and validated factors in radiotherapy. Most common treatment planning systems allow prompt assessment of Vdose and Mean Lung Dose (MLD). The former represents the percentage of normal lung parenchyma receiving a dose equal to or higher than the established threshold dose; the latter corresponds to the mean dose delivered to the normal lung parenchyma. Most important studies reported on the subject and threhold values recommended for Vdose and MLD are analyzed. The monitoring system of late toxicity used by the authors is presented.

The case of a patient undergoing quadrantectomy of lower quandrants of the right breast and ipsilateral axillary lymph node dissection for breast cancer followed by adjuvant radiotherapy is discussed. The stage of the disease and prognostic factors are analyzed for prognosis. Comorbidities ruled out chemotherapy. Radiation therapy was planned followed by clinicoinstrumental controls. After the second control ipsilateral costal bone metastases were observed; radiation therapy for palliation was prescribed.

Despite the low local recurrence rate that can be achieved by adequate surgery (total mesorectal excision--TME), radiation therapy was shown to play a significant role in reducing this risk. The widespread use of TME in many European Centers has introduced a new terminology and the need to identify the area at major risk for local failure using this surgical procedure. In the surgical series where extended extra-mesorectal surgery was performed, the role of lymphatic spread was evidenced, especially for low rectal cancer, through the pelvic parietal fascia and lateral pelvic spaces. The aim of this study was to better define some anatomic concepts and the main risk factors which impact on CTV contouring and field conformation in rectal cancer treatment. This information helps formulating guidelines for CTV contouring in daily radiotherapy practice, in order to define the best therapy, according to the tumor stage and location.