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NG2 and ICAM-1 staining are increased by combined treatment

There is growing interest in the association of radiotherapy and immunotherapy for the treatment of solid tumors. Here, we report an extremely effective combination of local irradiation (IR) and Shiga Toxin B (STxB)–based human papillomavirus (HPV) vaccination for the treatment of HPV-associated head and neck squamous cell carcinoma (HNSCC). The efficacy of the irradiation and vaccine association was tested using a model of HNSCC obtained by grafting TC-1/luciferase cells at a submucosal site of the inner lip of immunocompetent mice. Irradiation and the STxB-E7 vaccine acted synergistically with both single and fractionated irradiation schemes, resulting in complete tumor clearance in the majority of the treated mice. A dose threshold of 7.5 Gy was required to elicit the dramatic antitumor response. The combined treatment induced high levels of tumor-infiltrating, antigen-specific CD8+ T cells, which were required to trigger the antitumor activity. Treatment with STxB-E7 and irradiation induced CD8+ T-cell memory, which was sufficient to exert complete antitumor responses in both local recurrences and distant metastases. We also report for the first time that a combination therapy based on local irradiation and vaccination induces an increased pericyte coverage (as shown by αSMA and NG2 staining) and ICAM-1 expression on vessels. This was associated with enhanced intratumor vascular permeability that correlated with the antitumor response, suggesting that the combination therapy could also act through an increased accessibility for immune cells. The combination strategy proposed here offers a promising approach that could potentially be transferred into early-phase clinical trials. Mol Cancer Ther; 14(6); 1336–45. ©2015 AACR.

PSICHE (NCT05022914) is a prospective trial to test a [68Ga]Ga- PSMA-11 PET/CT imaging tailored strategy. All evaluable patients had biochemical relapse after surgery and underwent centralized [68Ga]Ga-PSMA-11 PET/CT imaging. The treatment was performed according pre-defined criteria. Observation and re-staging at further PSA progression were proposed to patients with negative PSMA and previous postoperative RT. Prostate bed SRT was proposed to all patients with a negative staging or positive imaging within prostate bed. Stereotactic body radiotherapy (SBRT) to all sites of disease was used for all patients with pelvic nodal recurrence (nodal disease

Background (1): Our goal was to investigate if and how pre-operative inflammatory status can influence the long-term prognosis of patients undergoing lung surgery for cancer. Materials and Methods (2): This prospective observational study includes the agreement of all operable patients to the study, who were referred to our department between 1 January 2017 and 30 December 2018. The inflammatory pre-operative status of the patients was investigated by calculating albumin, CPR (c-protein reactive), complete blood count (neutrophils, lymphocytes, platelets, hemoglobin), and some other indexes referring to inflammatory status, namely the HALP amalgamated index, platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocytes ratio (NLR), systemic immune-inflammation index (SII), and advanced lung cancer inflammation Index (ALI). The follow-up ended in November 2021. Patient overall survival was assessed using the Kaplan–Meier method. The log-rank test was used to compare survival rates. Variables significantly associated with survival at univariate analysis were entered int Cox multivariate analysis (stepwise mode) to assess their independent character. Hazard ratios and their 95% confidence intervals were calculated. Variables associated with p < 0.05 were considered significative. Results (3): We enrolled 257 patients in our study. The overall survival of the cohort was as follows: 1 year, 96.1%; 3 year, 81.3%; and 4 year, 74.2%. Univariate analysis showed risk factors for overall survival as follows: Thoracoscore ≥ 2 (p = 0.002); histology (p = 0.002); HALP < 32.2 (p = 0.0002); SII ≥ 808.9 (p = 0.0004); ALI < 34.86 (p = 0.0005); NLr ≥ 2.29 (p = 0.01); hemoglobin < 13 g/dl (p = 0.01); PLR ≥ 196.1 (p = 0.005); pN+ (p < 0.0001); pleural invasion (p = 0.0002); and presence of vascular or lymphatic tumor emboli (p = 0.0002). Multivariate Cox analysis (stepwise model) identified Thoracoscore ≥ 2 (p = 0.02); histology, HALP < 32.2 (p = 0.004), and pN (p < 0.0001) as independent predictors of death. Conclusion (4): Pre-operative inflammatory status strongly influences long-term prognosis in patients affected by NSCLC and undergoing surgery.

Biochemical recurrences after radical prostatectomy (RP) can be managed with curative purpose through salvage radiation therapy (SRT). RT dose escalation, such as stereotactic RT (SSRT), may improve relapse-free survival in this setting. STARR trial (NCT05455736) is a prospective multicenter study including patients affected by macroscopic recurrence within the prostate bed after RP treated with SSRT. Recurrence was detected with a Choline or PSMA CT-PET. In the current analysis, the early biochemical response (BR) rate and toxicity profile after three months of follow-up were assessed. Twenty-five patients were enrolled, and data about BR and toxicity at three months after treatment were available for 19 cases. Overall, BR was detected after three months in 58% of cases. Four G1–G2 adverse events were recorded; no G ≥ 3 adverse events were detected. SSRT appears feasible and safe, with more than half of patients experiencing BR and an encouraging toxicity profile. The STARR trial is one of the few prospective studies aimed at implementing this promising treatment strategy in this scenario.

Recent findings confirmed benefit from metastasis-directed therapy in oligometastatic hormone sensitive prostate cancer (omHSPC). However, current landscape of systemic treatment suggests that patients could benefit, at the same time, from early initiation of intensified hormonal treatments. In this commentary, we performed an overview about literature evidence aiming to overcome this issue and provide the maximum clinical benefit to the patients, taking advantage of modern imaging (e.g. PSMA PET/CT), ablative local treatment and newest systemic therapies.

The goal of the study is to evaluate the different risk factors and stratify the patients, before the surgery, into distinct risk classes. We retrospectively reviewed pre, peri, and postoperative outcomes of 366 consecutive patients who underwent pneumonectomy for lung cancer between the last 10 years (2009-2019). We classified the patients into four classes, depending on preoperative assessments. Differences between groups were assessed with the log-rank test. Multivariable Cox proportional hazards regression analysis was used to assess the independent prognostic significance of the variables associated with the development of BPF at univariate analysis. Finally, we performed non-linear [artificial neural network (ANN)] multiple regression analyses. All tests were two-sided, and p values 0.05 were considered significant. Fifty-one patients (13.9%) out of 366 developed BPF. Male sex (p = 0.048), right side (p = 0.015), postoperative pulmonary complications (p = 0.0139) and adjuvant treatments (p = 0.0169) were the independent predicting factors of fistulas in multivariate analysis. The right side (p = 0.043) and adjuvant treatments (p = 0.032) were the independent predicting factors of BPF after the ANN analysis. Based on multivariate and artificial neural network analysis and our experience, we observed a trend of growing risk of BPF in the first 4 weeks (early fistula), considering the four classes. Preoperative differentiation of the patients into four risk classes could allow a correct stratification of the growing risk of developing early BPF. This information could be significant to share with patients and the other physicians during the decision-making process, to minimise the risk of BPF.

To report on the anti-tumor activity of a novel combination in high-risk locally advanced head and neck squamous cell carcinoma.At a fixed dose of 1500 mg every 28 days, anti PD-L1 Durvalumab was given concomitantly to Radiotherapy and Cetuximab starting from the first week of combined treatment, followed by adjuvant Durvalumab to a maximum of 6 months after completion of radiation. The primary endpoint of the study was 2-year progression-free survival (PFS). A safety run-in was planned. Due to regulatory issues which prevented from opening multiple centers, COVID-19 pandemic and withdrawal of Durvalumab from supporting company, the study was prematurely terminated in April 2021.Between July 2019 and August 2020, 9 patients were enrolled in the study. All tumors had a PD-L1 Combined Positive Score 1. Optimal drug exposure was observed, with mean relative dose intensity of 85.5% and 87.5% for Cetuximab and Durvalumab, respectively. No radiation breaks were necessary. A grade 4 mucositis lasting for 14 days corresponded to the only dose limiting toxicity we reported. At a median follow-up of 11.5 months (IQR 7.7-16.7) all surviving patients (6 out of 9) are disease-free, with 1 and 2-year PFS rates of 77.7% and 58.3%, respectively. A selective sparing of node levels in the elective volume was performed in all cases, yielding a cumulative mean dose of 37.6 Gy (SD 8.4).Albeit limited by the small sample size, our preliminary observation of anti-tumor activity and tolerability of Durvalumab in addition to Cetuximab and radiation may warrant further investigations.

Aims In 2018, we published early results from a cohort of patients treated with stereotactic body radiotherapy (SBRT) after previous radiotherapy with definitive or postoperative intent. We sought to provide extended follow-up of this cohort to confirm the safety and efficacy of this approach in a real-world scenario. Materials and methods Fifty patients affected by local relapse after previous definitive or postoperative radiotherapy were treated with SBRT. Treatment provided a total dose of 30 Gy in five fractions. Data about biochemical relapse-free survival (BRFS) and metastasis-free survival (MFS), together with adverse events, were analysed. Toxicity was reported according to Common Terminology Criteria for Adverse Events (CTCAE) score v.4.03. Results After a median follow-up of 48.2 months, the median BRFS was 43 months. A Gleason score >7 and concomitant androgen deprivation therapy were shown to be predictors of the worst BRFS (hazard ratio 2.42, 95% confidence interval 1.09–5.41, P = 0.02; hazard ratio 2.83, 95% confidence interval 1.17–6.8, P = 0.02, respectively). The median MFS was not reached; concomitant androgen deprivation therapy was confirmed to be predictive of the worst MFS (hazard ratio 4.75, 95% confidence interval 1.52–14.8, P = 0.007). Late grade 1 and 2 rectal and bladder toxicity occurred in three (6%) and 13 (26%) patients, respectively. One patient experienced both grade 3 acute and chronic bladder toxicity. Conclusion Salvage SBRT re-irradiation after previous postoperative or definitive radiotherapy for local prostate cancer recurrence confirmed promising results in terms of oncological outcomes and the safety of this approach.

Non-small cell lung cancer (NSCLC) is frequently complicated by central nervous system (CNS) metastases affecting patients’ life expectancy and quality. At the present clinical trials including neurosurgery, radiotherapy (RT) and systemic treatments alone or in combination have provided controversial results. CNS involvement is even more frequent in NSCLC patients with EGFR activating mutations or ALK rearrangement suggesting a role of target therapy in the upfront treatment in place of loco-regionals treatments (i.e. RT and/or surgery). So far clinical research has not explored the potential role of accurate brain imaging (i.e. MRI instead of the routine total-body contrast CT and/or PET/CT staging) to identify patients that could benefit of local therapies. Moreover, for patients who require concomitant RT there are no clear guidelines on the timing of intervention with respect to innovative precision medicine approaches with Tyrosine Kinase Inhibitors, ALK-inhibitors and/or immuno-oncological therapies. On this basis the present review describes the therapeutic strategies integrating medical and radiation oncology in patients with metastatic NSCLC (mNSCLC) adenocarcinoma with CNS involvement and EGFR activating mutations or ALK rearrangement.

Introduction Hepatocellular Carcinoma (HCC) is characterized, in Western countries, by higher incidence and mortality rates in the older adult population. In frail patients, limited therapeutic resources are available due to limited expected benefit concerning the risk of treatment-related toxicity. The aim of our study is to evaluate the role of Stereotactic Body Radiotherapy (SBRT) in the clinical management of older old adults (age ≥ 80 years) HCC patients and to identify predictors of efficacy and toxicity. Material and Methods Clinical and treatment-related data of older old adults HCC patients treated with SBRT at our institution were retrospectively reviewed. Statistical analysis was carried out to identify variables correlated with impaired outcome and toxicity. Results Forty-two patients were included, accounting for 63 treated tumors. Median age was 85 (range 80–91) years. Median Charlson Comorbidity Index (CCI) and G8 scores were 10 (range 7–16) and 11 (range 8–14), respectively. SBRT was administered to a median BED10 of 103 Gy10. Median follow-up interval was 11 (range 3–40) months. Two years Local Control (LC), Progression-Free Survival (PFS), and Overall Survival (OS) were 93%, 31%, and 43%, respectively. Acute toxicity occurred in 28% (n = 13) of treatments. A G8 score > 10 was associated with improved survival (p = 0.045), while a CCI ≥10 was correlated with increased acute toxicity (p = 0.021). Conclusions SBRT is a safe and effective option in older old adults HCC patients. A comprehensive geriatric assessment (CGA) is advised before treatment decisions to select optimal candidates for SBRT.

In our institution, a prospective observational trial testing micro-RNA (miRNA) and ARV7 mutational status in metastatic, castration resistant prostate cancer (mCRPC), is currently recruiting (PRIMERA trial, NCT04188275). A pre-planned interim analysis was performed when 50% of the planned accrual was reached. In this report, we explored the predictive value of Circulating Tumor Cell (CTC) detection in mCRPC patients undergoing 1st line therapy. Moreover, ARV7, ARFL, PSMA and PSA expression on CTC was reported to explore potential correlation with patient prognosis and response to therapy. PRIMERA is a prospective observational trial enrolling mCRPC patients undergoing standard treatment (ARTA + ADT) after I line ADT failure. Clinical and pathological features were collected. Outcomes selected for this preliminary analysis were time to castration resistance (TTCR), PSA at 8 weeks after ARTA therapy start, PSA drop at 8 weeks, Overall PSA drop, PSA nadir. Correlation between these outcomes and CTC detection was tested. Expression of ARV7, ARFL, PSA and PSMA was explored in CTC+ patients to assess their prevalence in this cohort and their impact on selected outcomes. Median TTCR was significantly shorter in CTC+ vs CTC− patients (32.3 vs 75 months, respectively, p = 0.03) and in ARFL+ vs ARFL− patients (30.2 vs 51.1 months, respectively, p = 0.02). ARV7, PSMA and PSA expression on CTC had no impact on median TTCR, nor on biochemical response to therapy. Patients in whom CTC and ARFL expression were detected had significant reduced TTCR. However, PSA response was not influenced by CTCs detection and specific biomarkers expression.

Authors retrospectively analyzed possible prognostic factors in a series of patients affected by Ewing sarcoma of extremities (eEWS) and treated over a 20-year period at a single institution. Between 1997 and 2017, 88 bone eEWS were treated at our institution. Staging, age, gender, tumoral volume, local treatment, surgical margins, post-ChT necrosis were investigated for prognostic correlation with overall survival (OS) and event-free survival (EFS). Median follow-up was 74 months (1–236). Staging of disease correlated with OS (81% vs 59%, p = 0.01) and not with EFS (68% vs 57%, p = 0.28) in localized vs metastatic eEWS at presentation. Age ≥ 14 years (p = 0.002) and volume ≥ 100 cm3 (p = 0.04) were significant negative prognostic factors. No difference was found in local treatment: OS was 76% vs 63% (p = 0.33), while EFS was 68% vs 49% (p = 0.06) after surgery alone or surgery + radiotherapy, respectively. Regarding surgical margins, OS was 76% vs 38% (p = 0.14), and EFS was 65% vs 33% (p = 0.14) in adequate vs not adequate, respectively. OS was 86% and 68% in good and poor responders, respectively (p = 0.13). In eEWS, metastatic disease at presentation, age > 14 years and tumoral volume > 100 cm3 are negative prognostic factors. Intensified adjuvant ChT can improve prognosis in poor responders and metastatic patients.

The purpose of this study was to report preliminary data of a randomized phase III trial comparing hypofractionated whole breast irradiation (HWBI) and accelerated partial breast irradiation (APBI) using volumetric modulated arc therapy (VMAT).The HYPAB trial enrolled postmenopausal women with biopsy-proven infiltrating breast cancer, clinically negative axilla, single T1 to T2 tumors, who were treated with breast-conserving surgery. Patients were randomized 1:1 after surgery to HWBI (40.5 Gy whole breast, 48.0 Gy to surgical bed, 15 fractions over 3 weeks) or APBI (30 Gy delivered in 5 fractions of 6 Gy given on alternate days on the surgical bed). Cosmetic outcome was the primary end point of the study.A total of 172 patients were enrolled. After a median follow-up of 36 months, 5 local failures and 3 locoregional failures were recorded, with no difference between the 2 treatment arms. Use of HWBI as compared with APBI was significantly correlated with increased incidence of overall (62% vs. 14%; P .001) and grade 2 (18% vs. 1%; P .001) acute skin toxicity. APBI was correlated with a lower incidence of overall late toxicity as compared with HWBI (18% vs. 41%; P = .001), but no significant difference was found in term of occurrence of grade 2 events (1% vs. 4%; P = NS). At comparative assessment between baseline and post-radiotherapy evaluation, impairment in cosmetic outcome was reported in 19 (11%) patients. Owing to premature closure of the study, no per-protocol comparison between the treatment arms was performed.APBI with the VMAT technique is safe and feasible, with lower acute toxicity when compared with HWBI.

The aim of this study is to compare the dose delivered to the organs at risk (OAR), using static beams (SF) and a dynamic conformational arc (DCA) with flattening filter free (FFF) beams, for lung stereotactic body radiation therapy (SBRT).100 patients with lung cancer were treated with SBRT, using FF beams (TrueBeam STx, 6 MV, IQ = 0.67, 600 MU/min), separated into two groups: DCA (50 patients) and SF (50 patients). These patients were retrospectively re-planned using 6XFFF beams, IQ = 0.63, 1400 MU/min. The beam-on time and dosimetric gain on planning target volume (PTV) and OARs (heart, spinal cord, planning risk volume (PRV) of spinal cord, esophagus, lungs and ribs) were analyzed according to tumor location. The comparison of median values was performed using the non-parametric Wilcoxon test (significance level:PTV coverage was 98.90% versus 98.40% (DCA) and 98.8% versus 98.3% (SF) for the FF and FFF beams, respectively. The median dosimetric gain to the heart, spinal cord, PRV spinal cord, esophagus and lungs was 6% (4-11%) in the central region and 8% (2-23%) in the peripheral region, using FFF (The FFF beams reduce the dose received by all OARs, regardless of the used technique or tumor location, reducing treatment delivery time as well.

Circulating tumor cells detection and ARV7 expression are associated with worse clinical outcomes in metastatic Castration-Resistant Prostate Cancer (mCRPC) undergoing Androgen Receptor Targeted Agents. ARFL, PSMA and PSA may help to refine prognostic models. In our institution, a prospective observational trial testing CTC detection in mCPRC undergoing I line ARTA therapy terminated the planned enrollment in 2020. Here, we present a pre-planned interim analysis with 18 months of median follow-up. RT-qPCR was used to determine the CTC expression of PSA, PSMA, AR and ARV7 before starting ARTA. PSA-drop, Progression-Free and Overall Survival (PFS and OS) and their correlation with CTC detection were reported. Forty-four patients were included. CTC were detected in 43.2% of patients, of whom 8.94% expressed PSA, 15.78% showed ARV7, 63.15% and 73.68% displayed ARFL and PSMA, respectively. Biochemical response was significantly improved in CTC + vs CTC- patients, with median PSA-drop of 18.5 vs 2.5 ng/ml (p = 0.03). After a median follow-up of 18 months, 50% of patients progressed. PFS was significantly longer in CTC- patients (NR vs 16 months). Eight (18.2%) patients died, a non-significant trend in terms of OS was detected in favor of CTC- patients (NR vs 29 months, p = 0.05). AR, PSA and PSMA expression in CTC + had no significant impact on PSA-drop, PFS or OS. PRIMERA-trial confirmed the CTC detection predictive importance in mCRPC patients.

Background: The purpose of the study was to evaluate the toxicity and outcome of nasopharyngeal carcinoma patients treated using 3-dimensional conformal radiotherapy (3DCRT) or volumetric modulated arc therapy (VMAT) technique. Materials and methods: 68 patients treated between 2006 and 2018 were retrospectively analysed. Since 2009 patients received 3DCRT with 50/70 Gy to the elective/boost volumes in 35 fractions; from then, VMAT with simultaneous integrated boost (SIB) with 54.45/69.96 Gy in 33, or 54/66 Gy in 30 fractions. Induction chemotherapy was administered in 74% of the patients, concomitant cisplatinum in 87%. Acute and late toxicity data, progression-free survival PSF and overall survival OS, and toxicity correlations with dose metrics were reported. Results: With a median follow-up of 64 months, complete remission at the last evaluation was in 68% of the patients, while 28% and 9% had locoregional relapse and distant disease, respectively. The 5- and 10-year progression free survival (PFS) rates were 62.7±6.5% and 53.2±8.7%, respectively. The 5- and 10-year OS rates were 78.9 ± 5.5% and 61.4 ± 9.2%, respectively. At the multivariate Cox analysis TNM stage (p = 0.02) and concomitant chemotherapy (p = 0.01) resulted significant for PFS, concomitant chemotherapy (p = 0.04) for OS. Improvements in acute toxicity were presented for VMAT patients due to its ability to spare OARs. Odds ratio (OR) for acute salivary toxicity, between VMAT and 3DCRT, was 4.67 (p = 0.02). Dosimetrically, salivary toxicity correlated with mean parotid dose (p = 0.05), dysphagia with laryngeal (p = 0.04) and mean oral cavity (p = 0.06) doses, when dose-volume histograms (DVHs) are corrected for fractionation. Conclusion: This study is a proof of a significant benefit of the VMAT technique compared with 3DCRT in terms of side effects in nasopharynx patients, and adds dosimetric correlations.

To report the long-term outcome of a multicenter phase II study with FOLFIRINOX followed by stereotactic body radiotherapy (LAPC-1 trial) in patients with locally advanced pancreatic cancer (LAPC).Patients with histological confirmation of LAPC inoperable at diagnosis were enrolled. Induction therapy with 8 cycles of FOLFIRINOX was administered. If no disease progression was found after chemotherapy, patients received stereotactic body radiotherapy (SBRT) at a total dose of 40 Gy in 5 fractions.In LAPC-1 trial, 50 patients were included, but due to disease progression in 11 patients under chemotherapy, 39 patients received stereotactic SBRT after FOLFIRINOX treatment. In whole population, the 1- and 3-year overall survival (OS) were 62% and 10%, respectively. Median follow-up was 13 months. The SBRT group had median OS of 18 months (95% CI 13.2-21.5) versus 5 months (95% CI 4.1-6.7) in non-SBRT group (p0.001). After chemoradiotherapy, seven patients underwent surgery achieving a radical resection. Patients who underwent surgery had a 3-years OS of 43% compared to 6.5% in the unresected group (p=0.03). Four patients developed grade ≥ 3 adverse events during SBRT.Long-term survival has been found in patients with LAPC underwent FOLFIRINOX followed by SBRT. This approach increased the probability of a radical surgery. The resected patients achieved a significant better survival compared to unresected group.

489 Background: Radical cystectomy (RC) with or without perioperative chemotherapy is considered the standard treatment option for Muscle invasive bladder cancer (MIBC), despite poor oncological outcomes. However, RC is often burdened by significant impact on quality of life (QoL); Continence preserving methods (e.g continent cutaneous urinary diversion and orthotopic neobladder-ONB), have been proposed as alternatives to improve the postoperative QoL, but real benefit of these approaches is questioned. Bladder sparing approach, such as trimodal therapy (TMT) emerged as an alternative to surgery. Aiming to assess the impact of these treatment options from the patients’ perspective, we undertook a systematic review and meta-analysis of literature, focusing on studies specifically reporting QoL data about each of the above mentioned approaches. Main purpose of this review is to compare available treatment options from the QoL point of view and highlight the potential advantage of a bladder sparing approach if compared to different postoperative urinary diversion methods. Methods: A systematic review was carried out including all prospective and retrospective studies enrolling patients treated with radical intent for non-metastatic MIBC from 1999 to 2021 (either RC or TMT). All studies included specifically reported QoL for one of the main treatment approaches explored (RC followed by ileal conduit urinary diversion-ICUD, ONB or TMT). Review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement Results: Fifty studies were included in the final analysis, assessing QoL after RC followed by ICUD or ONB in 6 and 15 cases, respectively. Six studies addressed QoL after TMT. ICUD vs ONB and TMT vs ICUD/ONB comparisons were carried out in 21 and 1 studies, respectively. Pooled analysis for EORTC QLQ- C30 and BLM-30 questionnaires showed that ONB yielded a significant advantage if compared to ICUD only for Physical Functioning (pooled mean standardized difference -0.73 SD, p-value 0.019, I 2 =93%) and for Emotional Functioning (pooled mean standardized difference -0.16 SD, p-value 0.029, I 2 =0%). A trend in favour of higher mean reported values after TMT for Global Health Score, Physical Functioning and Role Functioning was found, if compared to both RC approaches. Conclusions: Significant benefit for ONB if compared to ICUD was detected only for specific subdomains of QoL questionnaires. No direct comparison with TMT is available, but data suggest advantage of this approach if compared to both reconstructive scenarios. These data should be used in clinical practice to help well informed patients decision about local treatment choice.

Recent findings from literature evidenced that metastatic prostate cancer often shows heterogeneous response to therapy, with persistent sensibility to systemic treatments after biochemical, clinical, or radiographic progression. This highlights the advantage of integrated approaches in which local ablative treatments (e.g., stereotactic body radiation therapy) could prolong clinical benefit of systemic therapies beyond oligo-progression. Of course, development of predictive biomarker could be helpful in order to select patients who could much benefit from this treatment strategy. Circulating tumor cell detection and analysis could also have a crucial role in this field. A joint effort of two prospective ongoing trials (ARTO, clinical.gov identifier NCT03449719 and PRIMERA, clinical.gov identifier NCT04188275) might help to improve criteria to select patients in whom a local ablative approach might confer significant benefit. In this commentary, we summarized recent data from literature to support this thesis.

Introduction The purpose of this study was to evaluate the impact of breast size on long-term toxicity and cosmesis in patients with breast cancer treated with hypofractionated simultaneous integrated boost (SIB) using volumetric modulated arc therapy (VMAT). Patients and Methods Patients with early stage breast cancer were treated with 3-week hypofractionated SIB-VMAT to the whole breast (40.5 Gy) and tumor bed (48 Gy). Two cohorts were identified: small/medium- ( 1000 cm3) breasted patients. Acute and late (at 2 and 5 years) skin toxicity and cosmetic data were analyzed. Univariate and multivariate analysis evaluated associations between toxicity and dosimetric/anatomical variables. Results From August 2010 to March 2017, a total of 1160 patients were treated; 831 had at least 2 years of follow-up and were analyzed. Treated skin area (TSA) receiving at least 20 Gy > 400 cm2 and V105% of Boost > 5 cm3 were significant predictors for acute skin toxicity. Multivariate analysis at 2 years was significant for boost volume > 70 cm3, TSA > 400 cm2, and breast size > 1500 cm3. At 5 year analysis (352 patients), none of the analyzed variables was significant. For cosmetic outcome, only the breast size (> 1000 cm3) and the boost size > 70 cm3 at 2 and 5 years, respectively, confirmed significance. Conclusions The TSA > 400 cm2 resulted as a significant predictor of both acute and late skin toxicity at 2 years; however, at 5 years, no breast size or dosimetric parameter suggested indications for increased toxicity. A worse cosmetic outcome was recorded at the 2-year follow up for large breasts, but was not confirmed at the 5-year follow-up. These long-term data suggest that hypofractionated SIB-VMAT is a viable modality also in large-breasted patients.

The use of Stereotactic Body Radiotherapy (SBRT) is controversial in Ultra-Central lung tumors, a subset of central lung tumors characterized by proximity to critical mediastinal structures. This is of interest in oligometastatic (≤3 metastases) patients, who can yield survival benefit from local treatments. The aim of our study is to assess the determinants of efficacy and toxicity in this setting. Clinical and dosimetric parameters were reviewed in a cohort of oligometastatic patients treated with SBRT for ultra-central tumors. Local control rate (LC) and toxicity were assessed. Statistical Analysis was carried out to assess the impact of those predictors on local recurrence and adverse events. One-hundred-nine consecutive patients were included. A median Biologic Effective Dose (BED) of 105 (75–132) Gy10 was prescribed. At a median follow-up of 17 (range 3–78) months, 2-year LC was 87%. Improved LC was correlated to Planning Treatment Volume (PTV) covered by 95% of the prescription dose (V95% PTV) > 85% (HR 0.15, 95%CI 0.05–0.49, p = 0.0017) and to Gross Tumor Volume (GTV) 85% and GTV

Stereotactic Body Radiotherapy (SBRT) emerged as a valuable option in early to advanced-stage Hepatocellular Carcinoma (HCC) as defined by Barcelona Clinic Liver Cancer (BCLC) system. The aim of our study is to evaluate SBRT in HCC patients and to identify predictors of outcome and toxicity. A retrospective review of HCC patients treated at our Institution between November 2011 and December 2018 was carried out. SBRT was delivered in 3-10 fractions to a median Biologically Effective Dose (BED10) of 103 Gy10. SBRT was performed in 128 patients to 217 HCC localizations, accounting for 142 treatment courses. BCLC stage was A, B, C in, respectively, 40 (31%), 72 (56%) and 16 (13%) patients. Local Control (LC), Progression Free Survival (PFS) and Overall Survival (OS) at 2 years were, respectively: 78%, 15% and 58%. LC was influenced by BED10 > 120 Gy10 (Hazard Ratio, HR: 0.08, 95% CI 0.01–0.59; p = 0.013) and size ≥ 3 cm (HR: 2.71, 95% CI 1.10–6.66; p = 0.03). BCLC stage was correlated to PFS (median 14 vs 12 vs 5 months, p = 0.012). In BCLC stage A-B disease (n = 112), LC was associated with improved survival (median 30 months vs not reached, p = 0.036). Acute and late toxicity rate was 26% (n = 37) and 8% (n = 11). Patients with BCLC B-C stage disease showed increased acute toxicity (HR: 2.9, 95% CI 1.10–7.65; p = 0.032). Delivery of ablative doses > 120 Gy10 and tumor size are determinants of LC. Prolonged PFS and improved OS can be obtained in BCLC A-B patients. Grade 3 liver dysfunction is infrequent.

OBJECTIVE Anaplastic gliomas (AGs) are an extremely heterogeneous group of primary brain tumors. More recently, new discoveries have indicated that isocitrate dehydrogenase (IDH) mutation status is the most important parameter predicting survival. The primary aim of the present analysis was to identify prognostic factors, other than IDH status, that eventually impact survival. METHODS Patients with available clinical, imaging, and molecular profile data who were amenable to resection were evaluated. The extent of resection (EOR) was defined as gross-total resection (GTR), near-total resection (NTR), subtotal resection (STR), or partial resection (PR). Residual tumor volume (RTV) was quantified. Following surgery, patients received adjuvant chemotherapy alone, radiation therapy plus concomitant and adjuvant temozolomide (TMZ), or sequential radio-chemotherapy. Clinical outcome was evaluated by neurological examination and MRI 1 month after treatment and every 4 months thereafter. Tumor progression was defined according to the Response Assessment in Neuro-Oncology (RANO) working group. RESULTS Among 402 patients referred to the authors’ institution for AG, 142 were included in the present analysis. Eighty-eight (62%) were male and 54 (38%) were female, with a median age of 43 years (range 19–70 years). At admission, most patients had a Karnofsky Performance Scale score of 90–100 (84.5%) and were symptomatic (93.7%). Forty-eight (33.8%) patients had newly diagnosed anaplastic oligodendrogliomas (AOs), and 94 (66.2%) had anaplastic astrocytomas (AAs). Most of them had mutant IDH tumors (67.6%) and methylated O 6-methylguanine-DNA-methyltransferase (MGMT) promoter status (71.8%). GTR was performed in more than half of the patients (56.3%). RTV was detected in 83 (58.5%) patients. Following surgery, 72 (50.7%) patients received radiotherapy with concomitant and adjuvant TMZ, 48 (33.8%) received sequential radio-chemotherapy, and 22 (15.5%) received adjuvant chemotherapy alone. The median follow-up time was 40 months (range 16–146 months). The median PFS time and the 1-, 3-, and 5-year PFS rates were 35 months (95% CI 27–76) and 78.9% ± 3.4%, 49.7% ± 4.6%, and 42.7% ± 5.4%, respectively. The median OS time and the 1-, 3-, and 5-year OS rates were 91 months (95% CI 66–95) and 90.1% ± 2.5%, 70.9% ± 4.2%, and 61.8% ± 4.9%, respectively. Prognostic factors predicting survival other than molecular profile were the EOR and the RTV (p < 0.0001). Sequential radio-chemotherapy was the more effective treatment administered. CONCLUSIONS In addition to IDH status, EOR and the RTV have proved to statistically impact survival. The pivotal role of adjuvant radiotherapy has been recorded in all AG patients, regardless of tumor features.

International audience; ABSTRACT Caloric starvation, as well as various diets, has been proposed to increase the oxidative DNA damage induced by radiotherapy (RT). However, some diets could have dual effects, sometimes promoting cancer growth, whereas proposing caloric restriction may appear counterproductive during RT considering that the maintenance of weight is a major factor for the success of this therapy. A systematic review was performed via a PubMed search on RT and fasting, or caloric restriction, ketogenic diet (>75% of fat-derived energy intake), protein starvation, amino acid restriction, as well as the Warburg effect. Twenty-six eligible original articles (17 preclinical studies and 9 clinical noncontrolled studies on low-carbohydrate, high-fat diets popularized as ketogenic diets, representing a total of 77 patients) were included. Preclinical experiments suggest that a short period of fasting prior to radiation, and/or transient caloric restriction during treatment course, can increase tumor responsiveness. These regimens promote accumulation of oxidative lesions and insufficient repair, subsequently leading to cancer cell death. Due to their more flexible metabolism, healthy cells should be less sensitive, shifting their metabolism to support survival and repair. Interestingly, these regimens might stimulate an acute anticancer immune response, and may be of particular interest in tumors with high glucose uptake on positron emission tomography scan, a phenotype associated with poor survival and resistance to RT. Preclinical studies with ketogenic diets yielded more conflicting results, perhaps because cancer cells can sometimes metabolize fatty acids and/or ketone bodies. Randomized trials are awaited to specify the role of each strategy according to the clinical setting, although more stringent definitions of proposed diet, nutritional status, and consensual criteria for tumor response assessment are needed. In conclusion, dietary interventions during RT could be a simple and medically economical and inexpensive method that may deserve to be tested to improve efficiency of radiation.

Lymph nodes are common sites of oligometastases for several primaries. Stereotactic body radiation therapy (SBRT) represents an effective treatment but no consensus exists regarding dose and fractionation. Aim of this trial was to evaluate safety and efficacy of high-dose SBRT. We included patients with 1 to 3 lymph node metastases. Primary end-point was safety, while secondary end-points were in-field local control (LC), out-field lymph nodal progression free survival (LPFS), distant metastasis free survival (DMFS), progression free survival (PFS) and overall survival (OS). 64 lesions in 52 patients were treated from 2015 to 2019. Most common primary tumor was genitourinary cancer (75%), in particular prostate cancer (65.4%). With a median follow-up of 24.4 months (range 3-49), treatment was very well tolerated, with only 4 (7.7%) patients reporting acute side effects, all classified as grade 1, in the form of pain, fatigue, nocturia and dysuria. No toxicity ≥ grade 2 were reported. Rates of LC at 1, 2 and 3 years were 97.9%, 82.1% and 82.1%. Male sex (HR 0.12, p value 0.014) was associated with improved LC. LPFS at 1, 2 and 3 years were 69.6%, 49.6% and 46.1%, respectively, and DMFS was 81.74%, 67.5% and 58.5%, respectively. Presence of lesions in other organs was correlated with inferior DMFS (HR 3.82, p = 0.042). PFS at 1, 2 and 3 years were 67.4%, 42.4% and 31.86%, respectively. OS at 1, 2 and 3 years were 97.3%, 94.2%, 84%, respectively and significantly correlated with in-field recurrence (HR 8.72, p = 0.000). Our prospective trial confirms safety and efficacy of SBRT in the management of lymph node metastases. Registered Clinical trial NCT02570399.

Liver and lung are common sites of metastases from colorectal cancer (CRC). Stereotactic body radiation therapy (SBRT) represents a valid treatment, with high rates of local control (LC). In this study, we applied recursive partitioning model-based analysis (RPA) to define class risks for overall survival (OS) and progression free survival (PFS) in oligometastatic CRC patients. In this monocentric analysis, we included patients with lung or liver metastases. Patients were candidate to SBRT if a maximum of 5 metastases. End points of the present analysis were LC, PFS, and OS. The binary classification tree approach with RPA was applied to stratify the patients into risk groups based on OS and PFS. 218 patients were treated with SBRT on 371 metastases. Majority of patients (56%) was treated on single lesion, followed by 2 (26.1%) and 3 lesions (14.7%). Median follow-up was 22.7 months. Rates of LC were 84.2% at 1 year and 73.8% at 3 years. Rates of PFS at 1 and 3 years were 42.2% and 14.9%, respectively. RPA identified 3 classes for PFS, according to age and number of metastases with 3-year PFS of 30.6%, 13.5% and 8.4%. Overall survival was 87.2% at 1 year, 51.9% at 3 years, and 36.8% at 5 years. RPA identified 3 nodes. Class 1 included patients with liver metastases (3-year OS 35.2%). Class 2 included patients with lung metastases and DFI ≤ 48 months (3-year OS 65%). Class 3 included patients with lung metastases and DFI > 48 months (3-year OS 73.5%). Stereotactic body radiation therapy can be considered an effective treatment for the management of liver and lung metastases from CRC. With RPA, we identified prognostic risk class to define patients who could benefit the most from SBRT.

Hemosuccus Pancreaticus (HP) is a very rare upper gastro-intestinal haemorrhagic event whose causes can be aneurismal lesions, acute and chronic pancreatic inflammatory conditions, and pancreatic masses. We present 2 cases of patients who underwent stereotactic radiotherapy for pancreatic lesions who manifested signs of HP after treatment. Two male patients were diagnosed with an inoperable locally advanced pancreatic cancer and underwent 8 cycles of chemotherapy followed by stereotactic radiotherapy to the pancreatic lesion delivering 40 Gy in 8 fractions. The first patient complained of melena and had a necrotic tumoural mass with a new aneurysmal bulge 3 months after the SBRT. A stent was placed in the aneurysmal lesion, however, a few days later, the bleeding occurred again and the patient died. The other patient had local tumour progression 12 months after SBRT with a pancreatic mass eroding the near vessels. He developed a fast and massive bleeding. HP may occur after SBRT. Inflammation of the tumour mass can lead to erosion of the vessels with subsequent bleeding. The radiotherapy treatment may have contributed to the HP genesis. The treatment is complex and consists of the placement of a stent or surgery.

Purpose To explore the benefit yielded by radiotherapy (RT), we report a series of metastatic renal cell carcinoma (RCC) patients treated with concomitant RT plus Nivolumab. Methods/patients Patients undergoing Nivolumab treatment plus concomitant RT (ablative or palliative) were included. RT was defined Ablative if >5 Gy/fraction were delivered. Results Ablative RT intent was the only independent predictor of both progression free and overall survival (HR 3.51, 95% CI 1.6–7.5, p = 0.0012 and HR 2.8, 95% CI 0.99–8.07, p = 0.05, respectively). Conclusion Ablative RT may improve oncologic outcomes in selected patients with metastatic RCC treated with Nivolumab as compared to palliative RT.

Bone metastases are a frequent and important source of morbidity in cancer patients. Stereotactic body radiation therapy (SBRT) is an established treatment option for local control and pain relief of bone metastases, and it is increasingly used as upfront treatment, postoperative consolidation or salvage treatment after prior RT. However, heterogeneity of dose schedules described in literature represents a severe limitation in the definition of the role of SBRT as a standard of care. No consensus is available on the use of single versus multiple fraction SBRT for bone metastases. Advantages of single-fraction SBRT include shorter overall duration of treatment, absence of inter-fraction uncertainty, improved compliance, theoretical increased efficacy, and lower costs. However, caution has been advised due to reports of severe late toxicities, in particular, vertebral collapse fracture (VCF). The aim of this paper is to review dose fractionation and indications for the management of bone metastases using SBRT.

Background ARTO trial was designed to evaluate the difference in terms of outcomes between patients affected by oligo metastatic castrate resistant prostate cancer (mCRPC) treated with Abiraterone acetate and randomized to receive or not SBRT on all sites of disease. Here, we present a preliminary analysis conducted on patients enrolled at promoting institution. Objective To present a preliminary overview about population features, clinical outcomes, adverse events, quality of life and explorative translational research. Design, setting, and participants ARTO (NCT03449719) is a phase II trial including patients affected by oligo mCRPC, randomized to receive standard of care (GnRH agonist or antagonist plus abiraterone acetate 1000 mg and oral prednisone 10 mg daily) with or without SBRT on all metastatic sites of disease. All subjects have Outcome measurements and statistical analysis Data about a mono-centric cohort of 42 patients enrolled are presented in the current analysis, with focus on baseline population features, PSA drop at 3 months, biochemical response, and quality of life outcomes. Descriptive statistics regarding translational research are also presented. Results and limitation Significant difference in terms of PSA drop at three months was not detected (p = 0.68). Biochemical response (PSA reduction > 50%) was reported in 73.7 versus 76.5% of patients in control vs SBRT arm, respectively (p = 0.84). All patients are alive. Progression occurred in 1 versus 0 patients in the control versus SBRT arm, respectively. After 3 months, an average decrease of 13 points in terms of Global Health Score was reported for the overall population. However, complete recovery was noticed at 6 months. Circulating tumor cells detection rate was 40%. Conclusions SBRT + Abiraterone treatment was safe and well tolerated, non-significant trend in terms of PSA drop and biochemical response at 3 months was detected in SBRT arm. Interestingly, CTCs detection in this selected cohort of oligo-mCRPC was lower if compared to historical data of unselected mCRPC patients.

Metastatic soft tissue sarcoma (STS) patients may benefit from local ablative treatments due to modest efficacy of systemic chemotherapy. However, use of stereotactic body radiotherapy (SBRT) is controversial because of presumed radioresistance of STS.Patients treated with SBRT for oligometastatic and oligoprogressive metastatic STS were retrospectively reviewed to assess results in terms of local control (LC), disease-free survival (DFS), and overall survival (OS). Incidence and grade of adverse events were reported. Statistical analysis was performed to identify variables correlated with outcome and toxicity.Forty patients were treated with SBRT to a median biologic effective dose (BED) of 105 (66-305) Gy5 to 77 metastases. Two-year LC, DFS, and OS were 67%, 23%, and 40%. Improved LC was shown in patients receiving a BED150 Gy5 (hazard ratio [HR], 3.9; 95% confidence interval [CI], 1.6-9.7; P = 0.028). A delay24 months between primary tumor diagnosis and onset of metastases was associated with improved DFS (HR, 0.46; 95% CI, 0.22-0.96; P = 0.01) and OS (HR, 0.48; 95% CI, 0.23-0.99; P = 0.03). No toxicity grade ≥3 was observed.Stereotactic body radiotherapy is effective in metastatic STS with a benign toxicity profile. A BED150 Gy5 is required to maximize tumor control rates. Metastatic relapse24 months after diagnosis is correlated to improved survival.

Introduction: Stereotactic body radiotherapy (SBRT) reported excellent outcomes and a good tolerability profile in case of central lung tumors, as long as risk-adapted schedules were adopted. High grade toxicity was more frequently observed for tumors directly touching or overlapping the trachea, proximal bronchial tree (PBT), and esophagus. We aim to identify prognostic factors associated with survival for Ultra-Central (UC) tumors. Methods: We retrospectively evaluated patients treated with SBRT for primary or metastatic UC lung tumors. SBRT schedules ranged from 45 to 60 Gy. Results: A total number of 126 ultra-central lung tumors were reviewed. The Median follow-up time was 23 months. Median Overall Survival (OS) and Progression Free Survival (PFS) was 29.3 months and 16 months, respectively. Local Control (LC) rates at 1 and 2 were 86% and 78%, respectively. Female gender, age < 70 years, and tumor size < 5 cm were significantly associated with better OS. The group of patients with tumors close to the trachea but further away from the PBT also correlated with better OS. The acute G2 dysphagia, cough, and dyspnea were 11%, 5%, and 3%, respectively. Acute G3 dyspnea was experienced by one patient. Late G3 toxicity was reported in 4% of patients. Conclusion: risk-adaptive SBRT for ultra-central tumors is safe and effective, even if it remains a high-risk clinical scenario.

Introduction: Targeted dose-escalation and reduction of dose to adjacent organs at risk have been the main goal of radiotherapy in the last decade. Prostate cancer benefited the most from this process. In recent years, the development of Intensity Modulated Radiation Therapy (IMRT) and Stereotactic Body Radiotherapy (SBRT) radically changed clinical practice, also thanks to the availability of modern imaging techniques. The aim of this paper is to explore the relationship between diagnostic imaging and prostate cancer radiotherapy techniques. Materials and Methods: Aiming to provide an overview of the integration between modern imaging and radiotherapy techniques, we performed a non-systematic search of papers exploring the predictive value of imaging before treatment, the role of radiomics in predicting treatment outcomes, implementation of novel imaging in RT planning and influence of imaging integration on use of RT in current clinical practice. Three independent authors (GF, IM and ID) performed an independent review focusing on these issues. Key references were derived from a PubMed query. Hand searching and clinicaltrials.gov were also used, and grey literature was searched for further papers of interest. The final choice of papers included was discussed between all co-authors. Results: This paper contains a narrative report and a critical discussion of the role of new modern techniques in predicting outcomes before treatment, in radiotherapy planning and in the integration with systemic therapy in the management of prostate cancer. Also, the role of radiomics in a tailored treatment approach is explored. Conclusions: Integration between diagnostic imaging and radiotherapy is of great importance for the modern treatment of prostate cancer. Future clinical trials should be aimed at exploring the real clinical benefit of complex workflows in clinical practice.

Simple Summary This review based on a literature search aims at showing the impact of Texture Analysis in the prediction of response to neoadjuvant radiotherapy and/or chemoradiotherapy. The manuscript explores radiomics approaches in different fields of neoadjuvant radiotherapy, including esophageal cancer, lung cancer, sarcoma and rectal cancer in order to shed a light in the setting of neoadjuvant radiotherapy that can be used to tailor the best subsequent therapeutical strategy. Abstract Introduction: Neoadjuvant radiotherapy is currently used mainly in locally advanced rectal cancer and sarcoma and in a subset of non-small cell lung cancer and esophageal cancer, whereas in other diseases it is under investigation. The evaluation of the efficacy of the induction strategy is made possible by performing imaging investigations before and after the neoadjuvant therapy and is usually challenging. In the last decade, texture analysis (TA) has been developed to help the radiologist to quantify and identify the parameters related to tumor heterogeneity, which cannot be appreciated by the naked eye. The aim of this narrative is to review the impact of TA on the prediction of response to neoadjuvant radiotherapy and or chemoradiotherapy. Materials and Methods: Key references were derived from a PubMed query. Hand searching and ClinicalTrials.gov were also used. Results: This paper contains a narrative report and a critical discussion of radiomics approaches in different fields of neoadjuvant radiotherapy, including esophageal cancer, lung cancer, sarcoma, and rectal cancer. Conclusions: Radiomics can shed a light on the setting of neoadjuvant therapies that can be used to tailor subsequent approaches or even to avoid surgery in the future. At the same, these results need to be validated in prospective and multicenter trials.

OBJECTIVES The aim of this study was to analyze patterns of care in elderly soft tissue sarcoma (STS) patients and their impact on clinical outcome and treatment-related toxicity. MATERIALS AND METHODS We retrospectively collected data of >65-year-old patients diagnosed with locally advanced STS between 1991 and 2017 in a single institution. RESULTS The study included 111 patients: 105 (94.6%) patients underwent surgery, associated with preoperative (n=19, 17.1%) or postoperative radiotherapy (n=72, 64.8%). Anthracycline-based chemotherapy was prescribed in 41.4% of patients (n=46). Acute grade ≥3 postoperative radiotherapy-related radiation dermatitis and all grades of chemotherapy-induced neutropenia were significantly correlated to age >80 years (P=0.02) and >70 years (P=0.045), respectively. The mean follow-up was 4.1 years (range, 0.1 to 17.7). Three-year and 5-year local recurrence-free survival were 80.3% and 75.7%, respectively; neither treatment-related nor patient-related characteristics affected local recurrence. Three-year and 5-year distant relapse-free survival were 59.6% and 44.6%, respectively. On multivariate Cox regression, undifferentiated pleomorphic sarcoma histology and Charlson Comorbidity Index >7 were independent factors associated with distant relapse-free survival (P=0.026 and P=0.0001). Overall survival was 62% and 46.6% at 3 and 5 years, respectively. On multivariate Cox regression, surgery and Charlson Comorbidity Index