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Salvage radiotherapy (SRT) is one of the most widely used approaches in case of biochemical recurrence after radical prostatectomy for prostate cancer. Macroscopic recurrence within the prostate bed in this scenario is often detected through PSMA PET/CT or Magnetic resonance imaging (MRI). Stereotactic salvage radiotherapy (SSRT) has been proposed as a method to improve disease control by dose escalation in these patients. STARR is a prospective trial exploring clinical outcomes after SSRT on macroscopic recurrence within prostate bed after radical prostatectomy. STARR trial is a prospective multicenter study enrolling subjects affected by prostate bed macroscopic recurrence. All relapses were detected by Choline, PSMA CT-PET or MRI performed after a post prostatectomy PSA rise above 0.2 ng/ml. All patients with regional or distant metastatic disease were excluded. SSRT consisting in a total dose of 35 Gy in 5 fractions every other day was administered on macroscopic relapse defined through CT-PET and/or MRI co-registration with planning CT. Androgen Deprivation therapy (ADT) was not prescribed. A PSA nadir <0.2 ng/ml and <50% of baseline, respectively, were defined as complete biochemical response (CBR) or biochemical response (BR). Sixty-one patients were enrolled between March 2021 and November 2023. The current analysis included 50 enrolled patients at the promoting institution with > 3 months of follow up. After a median follow up of 10 months (95% CI = 7-17), Acute genitourinary and gastrointestinal toxicity occurred in 4 (3 G1 and 1 G2), and 5 patients (3 G1 and 2 G2), respectively. Late genitourinary and gastrointestinal toxicity were identified in 7 (all G1) and 1 patient (G2), respectively. BR and CBR were detected at 3 months in 41 (82%) and 23 (46%) cases, respectively. Seven recurrences were detected (3 biochemical and 4 metastatic recurrences detected through PSMA PET-CT) Forty-six patients (92%) were free from ADT at the end of follow up. SSRT yielded optimal results in terms of safety, with only mild adverse events. Biochemical outcomes are promising, with a significant benefit in terms of clinically meaningful outcomes (i.e. new distant metastases occurrence and need for ADT start). [ABSTRACT FROM AUTHOR]

Objectives: Postoperative prostate cancer patients are a heterogeneous population, and many prognostic factors (e.g., local staging, PSA kinetics, margin status, histopathological features) may influence their clinical management. In this complex scenario, univocal recommendations are often lacking. For these reasons, the present survey was developed by the Italian Association of Radiotherapy and Clinical Oncology (AIRO) to collect the opinion of Italian radiation oncologists and delineate a representation of current clinical practice in our country. Methods: A questionnaire was administered online to AIRO (Italian Association of Radiotherapy and Clinical Oncology) members registered in 2020 with a clinical interest in uro-oncological disease. Results: Sixty-one per cent of AIRO members answered the proposed survey. Explored topics included career and expertise, indications to adjuvant RT, additional imaging in biochemical recurrence setting, use of salvage radiotherapy (SRT), management of clinically evident locoregional recurrence and future considerations. Conclusions: Overall, good level of agreement was found between participants for most of the topics. Most debated issues regarded, as expected, implementation of new imaging methods in this setting. Notably, trend in favour of early SRT vs. immediate adjuvant RT was underlined, and preference for global evaluation rather than isolated risk factors for RT indications was noticed. [ABSTRACT FROM AUTHOR]

A phase II trial was conducted to assess the feasibility, safety, and activity of a single 21 Gy preoperative robotic radiosurgery (prRS) in early breast cancer patients, 50+ years old, hormonal receptors positive/human epidermal growth factor receptor 2 negative (HR+/HER2-), sized up to 25 mm. Breast surgery was performed 2 to 4 weeks after radiosurgery. A translational study was carried out to explore the modulation of tumor-immune microenvironment before and after irradiation and the transcriptome on tumor samples before irradiation. Among the 70 patients recruited, 22 patients were successfully treated with prRS. Fresh pre-treatment tumor biopsies and fresh post-radiosurgery and post-operative tumor samples were retrieved. For immunohistochemistry analysis, pre-radiosurgery biopsies and post-operative tumors were stained with specific antibodies to evaluate the expression of different immune-related biomarkers. For the transcriptome analysis, total RNA was extracted from frozen pre-treatment samples and RNA sequencing was performed by using a total of 10 ng/uL. The statistical analyses aiming at detecting differences in gene expression according to tumor downstaging were conducted by fitting age-adjusted linear regression models, and applying the false discovery rate (FDR) method for correcting for multiple tests. As clinical output, we considered tumor downstaging according to pTNM and patients were classified as Radio-Responders (R-R = 8) and non-Radio-Responders (nR-R = 13) after prRS. IHC was performed on available 19 pairs of pre- and post-irradiation tissues for evaluation of CD68, CD163, CD4, CD8, CD56 and CD16: preliminary analysis showed a marked increase in CD68, CD163 and CD4 staining after tumor prRS. RNAseq results showed 170 differentially expressed genes between R-R and nR-R. Statistical analysis identify CCDC97 and MDIFC as genes that were significantly up- and down-regulated respectively in R-R patients. CCD97 is an orphan gene previously described as part of a nuclear interactome with functional role in DNA damage repair, while MDFIC is reported to be associated with pro- or anti-tumoral functions as chemoresistance induction or cell proliferation inhibition. The phase II trial enrolled 22 patients; this little number limits the statistical power of results obtained in the translational analysis. Based on the preliminary results, IHC analysis showed that prRS modulates the immune microenvironment composition in early breast cancer patients. Furthermore, we hypothesized that the differential expression of CCDC97 and MDFIC may play a role in prRS response. The role of orphan genes CCDC97 and MDFIC in response to radiation and to hypofractionation makes worthy further pre- and clinical investigations. [ABSTRACT FROM AUTHOR]

Prescription of ablative doses in pancreas SBRT requires steep dose fall-off to fulfill OARs dose limits. Both geometric errors and organ deformation may lead to OARs doses violation. We aimed at evaluating effects of intra-fraction errors and inter-fraction deformation on OARs doses, investigating their predictability in terms of target-to -OAR proximity Twenty patients, treated for pancreatic cancer in 5 fraction prescribing 40Gy/50Gy to PTV/GTV, were considered. Plan optimization required for duodenum, stomach and bowel V35Gy< 0.5 cc. Target-to-OAR proximity was quantified for each patient computing the expansion-intersection volume (EIV) on the planning CT (pCT), as the intersection between the PTV expanded by 5 mm and duodenum, stomach and bowel. All patients were treated at a frameless robotic radiosurgery system using fiducial real time respiratory tracking modality. Residual tracking errors were extracted for 100 fractions using the system log-files. Standard uncertainties (mean values + 2 standard deviations) along the three directions (SI, LR; AP) were used as descriptive statistics. To simulate the effects of tracking errors on OARs doses, a perturbed plan was created modifying each CK beam coordinates by the corresponding errors and a perturbed dose distribution was calculated. Inter-fraction OARs deformation was evaluated acquiring pre-fraction CT scans with a maximum of 2 repeated scans per patient. Deformed OARs were contoured by the same physician who contoured the pCT. Planned doses were re-calculated on the deformed anatomy using the fiducials alignment center, to rigidly register the pCT to each pre-fraction scan. OARs constraints of perturbed plan and deformed anatomy were considered met at V35 Gy < 1 cc. EIV values ranged from 0.5 to 28 cc (median 9.6 cc). Tracking errors standard uncertainties ranged from 0.6 mm to 7.2 mm, with respective median values 3.5 mm (SI), 2.4 mm (LR), 2.0 mm (AP). For plans perturbed by tracking errors, OARs constraints were violated only in 2 / 20 patients (V35Gy respectively 1.4 cc and 1.2 cc). For these two patients, EIV values were above 25 cc, and errors uncertainties were above 5 mm along at least one direction. The recalculated doses on deformed OARs, contoured on repeated CT scans, showed constraints violation in 13/20 cases with V35Gy values up to 5 cc (median 2.1 cc). The 7 patients for whom constraints were still met on the deformed anatomy (V35Gy<1cc) showed EIV values below 1.5 cc. CK tracking errors have small effects on OAR doses, but attention must be paid to minimize these errors for patients with large EIV values. Although OARs deformation has larger effects, constraints were still met in 33% of patients. EIV is a promising parameter to predict who is at risk of exceeding OARs constraints during pancreas SBRT, needing plan adaptation. [ABSTRACT FROM AUTHOR]

The use of ablative Stereotactic Body Radiotherapy for the treatment of mediastinal and hilar lymph nodal metastases (MHL) has been traditionally limited due to proximity of critical organs and uncertainty in target recognition and treatment administration due to respiratory motion, potentially resulting in fatal adverse events. Fiducial-markers implanted via EBUS may allow delivery of ablative SBRT by Real-time tumor tracking (RTTT) or by refining CBCT image guidance. We report preliminary follow-up data from an observational prospective clinical study (FLUXUS) assessing the use of ablative SBRT in oligometastatic or oligoprogressive MHL. Data from a prospective cohort of patients treated from December 2021 to December 2023 with ablative SBRT for oligometastatic or oligoprogressive MHL from miscellaneous primary tumors were collected. Gold-anchor 25G FM were placed intralesionally via EBUS under general anesthesia following rigid bronchoscopy. One week later, blank and contrast enhanced simulation CT was acquired: in order to verify the solidarity between the FM and the tumor across the respiratory cycle an additional 4D CT was obtained. SBRT was delivered using RTTT with a robotic-arm Linac or surface and CBCT guided deep-inspiration breath hold (DIBH). Preliminary outcome and toxicity results were assessed. Eighteen patients, accounting for 21 MHL were included. Median age was 73 (range 48-87) years. Median follow-up was 6 months. Primary tumor locations were lung (n = 8), breast (n = 4), gastroesophageal (n = 3), and other (n = 3). Disease setting was oligometastatic and oligoprogressive MHL in 7 and 11 patients, respectively. MHL were located in nodal station 10-11 (n = 7), 4 (n = 6), 7 (n = 5), 2-3 (n = 2) and 8 (n = 1). Median number of implanted FM was 3 (range 2-3): no periprocedural complication or migration was observed. RTT and DIBH were used in 15 and 3 patients, respectively. In 3 patients, 2 MHL were simultaneously treated during the same treatment course, the remaining patients receiving SBRT to a single nodal site. Median prescription dose was 35 Gy (range, 30-40 Gy) in 5 fractions, corresponding to a median EQD2 of 49.5 Gy (range, 48-100 Gy) assuming α/β = 10. Local control (LC) was 95% at 1 year. Distant relapse-free (DRFS) and overall survival (OS) were 54% and 73% at 1 year, respectively. All 6 patients who were chemotherapy-naïve before SBRT were free from systemic therapy at the time of the analysis. Acute transient toxicity, consisting of grade 1 cough and pyrosis was observed in 2 patients. Only one patient experienced a grade≥3 late toxicity, consisting of aorto-esophageal fistula resulting in fatal hematemesis. FM placement is a minimally invasive and well tolerated procedure in elderly patients and allow the delivery of ablative SBRT to MHL with promising outcome and toxicity results. Caution is required in case of suspicion of mediastinal organ infiltration. [ABSTRACT FROM AUTHOR]

Over the past decades, the optimal target volume for patients with head and neck squamous cell carcinoma has been widely investigated. The "5+5" expansion rule for CTV-P was postulated by the latest international consensus guidelines [1]. As per our local standard of practice (SoP), since Jan 2015 the 10 mm margin expansion from gross tumor volume (GTV) of the primary tumor (CTV-P2) was not part of target delineation for oropharyngeal cancer (OPC). Thus, in the context of a controlled, prospective, single-center cohort of patients (pts) we aimed to assess the pattern of failure after the omission of CTV-P2 while exploring its impact on toxicity and potential dosimetric implications Target definition for pts affected by OPC has been performed in accordance with our SoP. The CTV-P1 consisted of primary GTV with an isotropic expansion of 5 mm margin, edited for air cavities and anatomical barriers. A 3-mm margin was added to CTV-P1 (PTV-P1). An IMRT-SIB Tomotherapy technique was adopted. A 3-dose level prescription was applied: high, intermediate and low risk PTVs received 69.9, 59.4 and 52.8 Gy in 33 fractions, respectively. Concurrent cisplatin-based chemotherapy (cht) was administered as per SoP. According to international guidelines [1], a CTV-P2 was retrospectively delineated by 3 radiation oncologists, blinded to the clinical outcome data, and then expanded by 3 mm (PTV-P2). Median local control (LC), progression-free survival (PFS) and overall survival (OS) were assessed by the Kaplan-Meier method. To describe whether the incidence of > G2 oral mucositis was correlated with PTV-P2 coverage, a Mann Whitney test was used. From Jan 2015 to Sep 2020, 100 pts were included in our cohort. The median age was 63 years. The vast majority (69%) had HPV-related OPC and received concurrent cht (91%). According to TNM 7th edition, 80% of pts had stage III/IV disease. At a median follow-up of 55 months (range = 1-109), 77 patients were alive and 57 had no evidence of disease. Median LC and PFS were not reached while 3-year LC and PFS rates of 85 % and 68 %were found. The median OS was 97 months (95% CI = 81.2-96.6). The main pattern of failure was distant (23%). Overall, a low crude rate of local failure was reported (15%). Out of 15 local events (6 HPV + and 9 HPV - cases), 12 in-field and 3 marginal relapses, referring to the high-risk volume (PTV-P1), were collected. No correlation was found when comparing the incidence of > G2 oral mucositis in respect to PTV-P2 coverage above or below 95%, corresponding to 56.4 Gy (p = 0.68). In a cohort of OPC pts treated uniformly with a 3-dose level prescription, our SoP based on the omission of 10 mm expansion for CTV-P2 did not result in a detrimental effect on LC. Longer follow-up is needed to ascertain its impact on oncologic outcome and late toxicity. [ABSTRACT FROM AUTHOR]

Management of locally advanced Soft Tissue Sarcoma (STS) is based on surgery and external beam radiation therapy (EBRT). Theoretical benefits of neoadjuvant EBRT include reduced volume and dose requirements and possible tumor shrinkage, particularly in association with concurrent chemotherapy (CT), that may facilitate clear margin resection, although at the price of increased wound complications rate in up to 35% of patients. The aim of this study is to evaluate outcome and toxicity results of neoadjuvant radiotherapy in STS patients candidate to surgical excision and to assess prognostic-related features to guide treatment personalization. Clinical and treatment related data were retrospectively retrieved from a consecutive cohort of non-metastatic STS patients treated at our Institution with neoadjuvant RT followed by surgery from 1991 to 2023. CT consisted of an Epirubicin-Ifosfamide regimen for 3 cycles during EBRT delivery in selected candidates. Overall survival (OS), Distant-metastasis free survival (DMFS), Local control (LC) data were extrapolated using Kaplan-Meier method. Chi-square, log-rank test and Cox model were performed to identify factors related with outcome and toxicity. 156 patients were included in our study. Median age was 55 years. Tumors were mostly located in the limbs (94%). Disease stage was T≥3 in 71% of cases. Most represented histologic subtypes were liposarcoma (LPS) (34%), undifferentiated pleomorphic sarcoma (UPS) (24%) and synovial sarcoma (5%). Neoadjuvant EBRT was administered to a dose of 50 Gy in 25 daily fractions concurrently with CT in 82 % patients. IMRT was used in 34% of case. R0 and R1 resection were obtained in 93% and 7% of patients respectively. Wound complications were observed in 16% of patients. Grade (G) 3 disease was found in 70% patients. After a median follow-up of 32 months, 5-year OS, DMFS and LC rates were 72%, 57% and 82%, respectively. At multivariate analysis only R1 resection was significantly associated to worse LC rates (p = 0.0214), while G3 disease was correlated with impaired DMFS (p = 0.0029). UPS (p = 0.0028), G3 (p = 0.004) and R1 (p = 0.05) correlated with poorer OS rates. None of the examined variables, particularly use of IMRT and CT, were associated with higher occurrence of wound complications. In this large STS cohort, neoadjuvant RT resulted in excellent RO rate and favorable outcomes. Wound complications rate was inferior to historical data from landmark trials. R1 resection and G3 disease correlated respectively with impaired LC and DMFS. Both factors were associated with poorer OS, as well as UPS subtype, suggesting an unmet need for treatment intensification in selected patients. Use of IMRT and concurrent CT were not correlated with wound complications occurrence. [ABSTRACT FROM AUTHOR]

Following reports of improved efficacy in vertebral metastases, Stereotactic Body Radiotherapy has been increasingly applied for local palliation and disease control in non-spinal bone metastases. However, its use in the management of rib metastases (RM) has been traditionally limited due to purported risk of iatrogenic fracture, possibly resulting in impaired pain control. For this reason, SBRT in this setting has been scarcely reported in literature. The aim of our study is to evaluate pain control and local failure rates in RM treated with SBRT. We collected data from a cohort of RM patients treated from October 2014 to December 2023 with SBRT. Clinical and treatment-related data were collected. Pain Control (PC) was defined as absence or reduction of pain allowing for decreased medication intake. Local Failure (LF) was defined as radiologic progression on follow-up imaging. Univariable analysis with the log-rank test and multivariable analysis with the Cox model were performed to investigate predictors of PC and LF. Data from 55 patients accounting for 64 RM were collected. Median age was 70 (range = 37-78) years. Most represented primary tumors were prostate (41%, n = 26) and non-small cell lung cancer (21%, n = 13). Baseline pain before SBRT was reported in 26 (41%) lesions, requiring daily opioid intake in 12 cases (20%). SBRT was delivered with C-arm (92%, n = 59) and robotic-arm (8%, n = 5) Linac using the following regimens: 16 Gy/1 fraction, 24 Gy/2 fractions, 24-30 Gy/3 fractions, 30-55 Gy/5 fractions. Median EQD2 (assuming an α/β = 10) was 47 Gy (range = 35-96.25). Median follow-up was 14 (range = 1-76) months. PC was 87% at 6 months and 82% at 1 year. Age> 70 (P = 0.002), EQD2 ≤40 Gy (P = 0.009) and baseline pain (P = 0.004) were correlated with impaired PC although only EQD2 ≤40 Gy (P = 0.007) and baseline pain (P = 0.012) proved significant at multivariate analysis. LF rate was 2.0% at 6 months and 4.8% at 1 year. Median OS was 60 (95% CI= 25-70) months. No predictive factors of LF were identified at statistical analysis. Pain flare was observed in 1 patient. No rib fracture and/or skin fibrosis was observed. SBRT for RM is associated with low rates of local failure and durable pain control. Administration of SBRT before the onset of symptoms and use dose intensive regimens may result in improved pain control. [ABSTRACT FROM AUTHOR]