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Mariangela Boccardi,1 Savino Cilla,2 Mara Fanelli,3 Carmela Romano,2 Paolo Bonome,1 Milena Ferro,1 Donato Pezzulla,1 Roberto Di Marco,4 Francesco Deodato,1,5,* Gabriella Macchia1,* 1Radiation Oncology Unit, Responsible Research Hospital, Campobasso, Italy; 2Medical Physics Unit, Responsible Research Hospital, Campobasso, Italy; 3Research Laboratories, Responsible Research Hospital, Campobasso, Italy; 4Department of Medicina e Scienze della Salute “V. Tiberio”, Università degli Studi del Molise, Campobasso, Italy; 5Istituto di Radiologia, Università Cattolica del Sacro Cuore, Roma, Italy*These authors contributed equally to this workCorrespondence: Milena Ferro, Responsible Research Hospital, L.go Gemelli, 1, Campobasso, 86100, Italy, Email milena.ferro@responsible.hospitalPurpose: The most prevalent treatment-related side effect related to adjuvant radiotherapy (RT) for breast cancer is acute skin toxicity in the irradiated area. The purpose of this single-institution pilot study is to provide preliminary clinical results on the feasibility and safety of a breast ultra-hypofractionated radiation treatment delivered using an automated hybrid-VMAT technique. Skin damage was assessed both with clinical examination and objectively using a Cutometer equipment.Patients and Methods: Patients received 26 Gy to the whole breast and 30 Gy to the tumoral bed in 5 fractions using an automated hybrid-VMAT approach with the option for the breath hold technique if necessary. Acute and late toxicities were clinically evaluated at baseline, 1- and 6-months after treatment using the CTC-AE v.5.0 scale. An instrumental evaluation of the skin elasticity was performed using a Cutometer® Dual MP580. Two parameters per patient, R0 (the total skin firmness) and Q1 (the elastic recovery), were registered at the different timelines.Results: From June 2022 to January 2024, 30 patients, stage T1-T2, N0 were enrolled in the study. Four out of 30 (13.3%) patients reported G2 acute skin toxicities. At 6 months, G2 late toxicity was registered in 3 patients (10%). A total of 2160 measures of R0 and Q1 were recorded. At 1 month after treatment, no correlation was found between measured values of R0 and Q1 and clinical evaluation. At 6 months after treatment, clinical late toxicity ≥ 1 was strongly associated with decreased R0 and Q1 values ≥ 24% (p = 0.003) and ≥ 18% (p = 0.022), respectively.Conclusion: Ultra-hypofractionated whole-breast radiotherapy, when supported by advanced treatment techniques, is both feasible and safe. No severe adverse effects were observed at any of the different timeframes. Acute and late skin toxicities were shown to be lower in contrast to data presented in the literature.Keywords: breast cancer, ultra-hypofractionated radiotherapy, Cutometer, hybrid-VMAT technique

Gabriella Macchia,1 Savino Cilla,2 Milly Buwenge,3 Alice Zamagni,3 Ilario Ammendolia,3 Claudio Zamagni,4 Giovanni P Frezza,5 Vincenzo Valentini,6,7 Francesco Deodato,1,* Alessio G Morganti3,* 1Radiotherapy Unit, Gemelli Molise Hospital, Università Cattolica Del Sacro Cuore, Campobasso, Italy; 2Medical Physics Unit, Gemelli Molise Hospital, Università Cattolica Del Sacro Cuore, Campobasso, Italy; 3Radiation Oncology Center, Department of Experimental, Diagnostic and Specialty Medicine ‑ DIMES, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy; 4Addarii Medical Oncology Unit, S. Orsola-Malpighi Hospital, Bologna, Italy; 5Radiation Oncology Unit, Bellaria Hospital, Bologna, Italy; 6Dipartimento di Scienze Radiologiche, Radioterapiche ed Ematologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, UOC di Radioterapia, Rome, Italy; 7Istituto di Radiologia, Università Cattolica Del Sacro Cuore, Rome, Italy*These authors contributed equally to this workCorrespondence: Milly BuwengeRadiation Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine – DIMES, University of Bologna, S. Orsola-Malpighi Hospital, Via Giuseppe Massarenti 9, 40138, BolognaTel +39 0512143564Fax +39 0516364336Email mbuwenge@gmail.comPurpose: A concomitant boost (CB) in patients treated with postoperative radiotherapy after conservative surgery of invasive breast cancer (BC) has been suggested for treatment time reduction and therapy intensification. The aim of this analysis was to assess long-term tolerability of a CB in patients treated with postoperative intensity Modulated Accelerated RAdiotherapy (MARA).Patients and Methods: In this phase I–II trial, 321 patients with intermediate-high risk BC (pT1-4 with at least one of the following characteristics: pre or perimenopausal status, pN2-3, positive or close margins) were enrolled. Patients were treated with forward-planned intensity modulated radiotherapy (IMRT) and CB. A total dose of 50 Gy (2 Gy/fraction) and 60 Gy (2.4 Gy/fraction) was prescribed to the whole breast and the tumor bed, respectively. The potential impact of hypertension, diabetes, smoking habit, alcohol consumption, chemotherapy, and hormone therapy on both skin and subcutaneous late toxicity-free survival (LTFS) was evaluated. Survival curves were calculated using the Kaplan–Meier method.Results: Median follow-up was 52 months (range: 3– 115). Regional node irradiation, adjuvant chemotherapy and hormonal therapy were prescribed to 29.3%, 65.4% and 81.0% of patients, respectively. Five-year G2 and G3 skin LTFS were 95.6% and 100.0%, respectively. Five-year G2 and G3 subcutaneous LTFS were 80.0% and 98.6%, respectively. Only diabetes showed a significant correlation with worse G3 subcutaneous LTFS (p: 0.024). Five-year loco-regional control, metastasis-free survival, disease-free survival, and overall survival were 98.0%, 91.8%, 89.7% and 96.3%, respectively.Conclusion: IMRT combined with CB was associated with a low risk of > G2 late toxicities (0.0% and 1.4% for skin and subcutaneous tissue, respectively). The cumulative actuarial incidence of local recurrences was 2.0% despite the exclusion of low-risk patients. Our results suggest that CB is safe and effective in patients with intermediate-high risk BC.Trial Registration: ClinicalTrials.gov: NCT03471741.Keywords: breast cancer, adjuvant radiotherapy, concomitant boost, IMRT, toxicity

Cinzia Digesù,1 Francesco Deodato,1 Gabriella Macchia,1 Savino Cilla,2 Martina Pieri,3 Alice Zamagni,4 Andrea Farioli,5 Milly Buwenge,4 Gabriella Ferrandina,6,* Alessio G Morganti4,* 1Radiotherapy Unit, General Oncology Unit, Fondazione Giovanni Paolo II, Campobasso, Italy; 2Medical Physics Unit, Fondazione Giovanni Paolo II, Campobasso, Italy; 3Radiotherapy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy; 4Radiation Oncology Center, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; 5Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; 6Department of Woman and Child Health, Gynecologic Oncology Unit, Fondazione “Policlinico Universitario A. Gemelli”, IRCSS, Universita’ Cattolica Sacro Cuore, Rome, Italy *These authors contributed equally to this work Aim: To compare late toxicity after postoperative hypofractionated radiotherapy (RT) and standard fractionated RT in patients with early-stage breast carcinoma.Methods: This retrospective study included 447 patients (Modulated Accelerated Radiotherapy [MARA-1]: 317 patients, and control group [CG]: 130 patients). In the CG, the whole breast received 50.4 Gy in 28 fractions (fx) using 3D-radiotherapy, plus a sequential electron boost (10 Gy in 4 fx) to tumor bed. In MARA-1 group, a forward-planned intensity-modulated radiotherapy technique with 40 Gy in 16 fx with a concomitant boost of 4 Gy to breast was used. The primary endpoint was to evaluate late toxicity, and secondary endpoints were acute toxicity, local control, and survival. ClinicalTrials.gov: NCT03461224.Results: Median follow-up was 52 months (range: 3–115 months). Late skin and subcutaneous toxicity were acceptable: 5-year actuarial cumulative incidence of Grade (G) 3 late skin toxicity was 1.5% in CG and 0.0% in MARA-1. Five-year actuarial cumulative incidence of G3 late subcutaneous toxicity was 0.8% in CG and 0.3% in MARA-1. On multivariate analysis, tobacco smoking and planning target volume were associated with an increased risk of late G1 skin toxicity (HR: 2.15, 95% CI: 1.38–3.34 and HR: 1.12, 95% CI: 1.07–1.18, respectively), whereas patients with a larger planning target volume also showed an increased risk of G1 and G2 late subcutaneous toxicity (HR: 1.14, CI 95%: 1.08–1.20 and HR: 1.14, 95% CI: 1.01–1.28, respectively). MARA-1 patients also showed an increased risk of late G1 and G2 subcutaneous toxicity (HR: 2.35, 95% CI: 1.61–3.41 and HR: 3.07, 95% CI: 1.11–8.53, respectively) compared to CG.Conclusion: In this retrospective analysis, postoperative accelerated-hypofractionated RT for early-stage-breast carcinoma was associated with higher incidence of subcutaneous side effects. However, this increase was limited to G1–G2 toxicity. In the future, development of predictive models could help in tailoring dose and fractionation based on the risk of toxicity. Keywords: breast cancer, radiotherapy, hypofractionation, retrospective study

Milly Buwenge,1 Gabriella Macchia,2 Alessandra Arcelli,1 Rezarta Frakulli,3 Lorenzo Fuccio,4 Sara Guerri,1 Elisa Grassi,1 Silvia Cammelli,1 Francesco Cellini,5 Alessio G Morganti1 1Department of Experimental, Diagnostic and Specialty Medicine – DIMES, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy; 2Radiation Oncology Unit, Research and Care Foundation “Giovanni Paolo II”, Catholic University of Sacred Heart, Campobasso, Italy; 3Radiation Oncology Unit, Bellaria Hospital, Bologna, Italy; 4Department of Medical and Surgical Sciences – DIMEC, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy; 5Department of Radiotherapy, “A. Gemelli” Hospital, Catholic University, Rome, Italy Abstract: Locally advanced pancreatic carcinoma (LAPC) has a poor prognosis and the purpose of treatment is survival prolongation and symptom palliation. Radiotherapy has been reported to reduce pain in LAPC. Stereotactic RT (SBRT) is considered as an emerging radiotherapy technique able to achieve high local control rates with acceptable toxicity. However, its role in pain palliation is not clear. To review the impact on pain relief with SBRT in LAPC patients, a literature search was performed on PubMed, Scopus, and Embase (January 2000–December 2017) for prospective and retrospective articles published in English. Fourteen studies (479 patients) reporting the effect of SBRT on pain relief were finally included in this analysis. SBRT was delivered with both standard and/or robotic linear accelerators. The median prescribed SBRT doses ranged from 16.5 to 45 Gy (median: 27.8 Gy), and the number of fractions ranged from 1 to 6 (median: 3.5). Twelve of the 14 studies reported the percentage of pain relief (in patients with pain at presentation) with a global overall response rate (complete and partial response) of 84.9% (95% CI, 75.8%–91.5%), with high heterogeneity (Q2 test: P

Milly Buwenge,1 Silvia Cammelli,1 Ilario Ammendolia,1 Giorgio Tolento,1 Alice Zamagni,1 Alessandra Arcelli,2 Gabriella Macchia,3 Francesco Deodato,3 Savino Cilla,4 Alessio G Morganti1 1Department of Experimental, Diagnostic and Specialty Medicine – DIMES, Radiation Oncology Center, University of Bologna, S.Orsola-Malpighi Hospital, 2Radiation Oncology Unit, Bellaria Hospital, Bologna, 3Radiation Oncology Unit, 4Medical Physics Unit, Research and Care Foundation ‘Giovanni Paolo II,’ Catholic University of Sacred Heart, Campobasso, Italy Background: Owing to highly conformed dose distribution, intensity modulated radiation therapy (IMRT) has the potential to improve treatment results of radiotherapy (RT). Postoperative RT is a standard adjuvant treatment in conservative treatment of breast cancer (BC). The aim of this review is to analyze available evidence from randomized controlled trials (RCTs) on IMRT in BC, particularly in terms of reduction of side effects. Methods: A literature search of the bibliographic database PubMed, from January 1990 through November 2016, was performed. Only RCTs published in English were included. Results: Ten articles reporting data from 5 RCTs fulfilled the selection criteria and were included in our review. Three out of 5 studies enrolled only selected patients in terms of increased risk of toxicity. Three studies compared IMRT with standard tangential RT. One study compared the results of IMRT in the supine versus the prone position, and one study compared standard treatment with accelerated partial breast IMRT. Three studies reported reduced acute and/or late toxicity using IMRT compared with standard RT. No study reported improved quality of life. Conclusion: IMRT seems able to reduce toxicity in selected patients treated with postoperative RT for BC. Further analyses are needed to better define patients who are candidates for this treatment modality. Keywords: intensity modulated radiation therapy, breast cancer, literature review

In ENGOT-cx11/GOG-3047/KEYNOTE-A18 (NCT04221945), pembro + CCRT improved PFS (HR = 0.70 [95% CI = 0.55‒0.89]; P = 0.0020) and showed a favorable trend in OS (HR = 0.73 [95% CI = 0.49‒1.07]) vs placebo (pbo) + CCRT in high-risk LACC at interim analysis 1 (IA1). Here, we report IA1 safety data. Patients (pts) with previously untreated, high-risk LACC (FIGO 2014 stage IB2‒IIB node-positive or stage III‒IVA) were randomized 1:1 to 5 cycles of pembro 200 mg or pbo Q3W + CCRT, then 15 cycles of pembro 400 mg or pbo Q6W. CCRT included 5 cycles (optional 6th dose) of cisplatin 40 mg/m2 QW + EBRT followed by brachytherapy. Safety was evaluated in all randomized and treated pts. Of 1060 randomized pts, 1058 were included in the safety analysis. At data cutoff (Jan 9, 2023), median follow-up was 17.9 mo. AE rates were similar between the treatment arms (see the Table). AEs were more common during the pembro + CCRT combination therapy phase vs pembro monotherapy phase. Exposure-adjusted AE rates generally decreased after 3 mo; hypothyroidism was most common between 3-6 mo with pembro + CCRT. Event rates for genitourinary AEs were < 10.0 events per 100 person-months of exposure during any period. Pembro + CCRT had manageable safety that was consistent with the known profiles of pembro monotherapy and chemoradiotherapy. Most AEs occurred during the combination therapy phase. [ABSTRACT FROM AUTHOR]