Background: Local cancer therapy by combining real-time surgical exploration and resection with delivery of a single dose of high-energy electron irradiation entails a very precise and effective local therapeutic approach. Integrating the benefits from minimally invasive surgical techniques with the very precise delivery of intraoperative electron irradiation results in an efficient combined modality therapy. Methods: Patients with locally advanced disease, who are candidates for laparoscopic and/or thoracoscopic surgery, received an integrated multimodal management. Preoperative treatment included induction chemotherapy and/or chemoradiation, followed by laparoscopic surgery and intraoperative electron radiation therapy. Results: In a period of 5 consecutive years, 125 rectal cancer patients were treated, of which 35% underwent a laparoscopic approach. We found no differences in cancer outcomes and tolerance between the open and laparoscopic groups. Two esophageal cancer patients were treated with IOeRT during thoracoscopic resection, with the resection specimens showing intense downstaging effects. Two oligo-recurrent prostatic cancer patients (isolated nodal progression) had a robotic-assisted surgical resection and post-lymphadenectomy electron boost on the vascular and lateral pelvic wall. Conclusions: Minimally invasive and robotic-assisted surgery is feasible to combine with intraoperative electron radiation therapy and offers a new model explored with electron-FLASH beams.

Introduction: A rapid deploy of unexpected early impact of the COVID pandemic in Spain was described in 2020. Oncology practice was revised to facilitate decision-making regarding multimodal therapy for prevalent cancer types amenable to multidisciplinary treatment in which the radiotherapy component searched more efficient options in the setting of the COVID-19 pandemic, minimizing the risks to patients whilst aiming to guarantee cancer outcomes. Methods: A novel Proton Beam Therapy (PBT), Unit activity was analyzed in the period of March 2020 to March 2021. Institutional urgent, strict and mandatory clinical care standards for early diagnosis and treatment of COVID-19 infection were stablished in the hospital following national health-authorities' recommendations. The temporary trends of patients care and research projects proposals were registered. Results: 3 out of 14 members of the professional staff involved in the PBR intra-hospital process had a positive test for COVID infection. Also, 4 out of 100 patients had positive tests before initiating PBT, and 7 out of 100 developed positive tests along the weekly mandatory special checkup performed during PBT to all patients. An update of clinical performance at the PBT Unit at CUN Madrid in the initial 500 patients treated with PBT in the period from March 2020 to November 2022 registers a distribution of 131 (26%) pediatric patients, 63 (12%) head and neck cancer and central nervous system neoplasms and 123 (24%) re-irradiation indications. In November 2022, the activity reached a plateau in terms of patients under treatment and the impact of COVID pandemic became sporadic and controlled by minor medical actions. At present, the clinical data are consistent with an academic practice prospectively (NCT05151952). Research projects and scientific production was adapted to the pandemic evolution and its influence upon professional time availability. Seven research projects based in public funding were activated in this period and preliminary data on molecular imaging guided proton therapy in brain tumors and post-irradiation patterns of blood biomarkers are reported. Conclusions: Hospital-based PBT in European academic institutions was impacted by COVID-19 pandemic, although clinical and research activities were developed and sustained. In the post-pandemic era, the benefits of online learning will shape the future of proton therapy education.

Background and purpose: Major differences exist among proton therapy (PT) centres regarding PT delivery in adult cancer patient. To obtain insight into current practice in Europe, we performed a survey among European PT centres. Materials and methods: We designed electronic questionnaires for eight tumour sites, focusing on four main topics: 1) indications and patient selection methods; 2) reimbursement; 3) on-going or planned studies, 4) annual number of patients treated with PT. Results: Of 22 centres, 19 (86%) responded. In total, 4233 adult patients are currently treated across Europe annually, of which 46% consists of patients with central nervous system tumours (CNS), 15% head and neck cancer (HNC), 15% prostate, 9% breast, 5% lung, 5% gastrointestinal, 4% lymphoma, 0.3% gynaecological cancers. CNS are treated in all participating centres (n = 19) using PT, HNC in 16 centres, lymphoma in 10 centres, gastrointestinal in 10 centres, breast in 7 centres, prostate in 6 centres, lung in 6 centres, and gynaecological cancers in 3 centres. Reimbursement is provided by national health care systems for the majority of commonly treated tumour sites. Approximately 74% of centres enrol patients for prospective data registration programs. Phase II-III trials are less frequent, due to reimbursement and funding problems. Reasons for not treating certain tumour types with PT are lack of evidence (30%), reimbursement issues (29%) and/or technical limitations (20%). Conclusion: Across European PT centres, CNS tumours and HNC are the most frequently treated tumour types. Most centres use indication protocols. Lack of evidence for PT and reimbursement issues are the most reported reasons for not treating specific tumour types with PT.

Background The optimal duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains controversial. The DART 01/05 trial was designed to determine whether long-term androgen deprivation is superior to short-term androgen deprivation when combined with high-dose radiotherapy. The 5-year results showed that 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy significantly improved biochemical control, metastasis, and overall survival, especially in patients with high-risk disease. In this report, we present the 10-year final results of the trial. Methods This open-label, phase 3, randomised, controlled trial was done in ten hospitals in Spain. The eligibility criteria included patients aged 18 years or older with histologically confirmed T1c to T3, N0, and M0 adenocarcinoma of the prostate, according to the 2002 classification of the American Joint Committee on Cancer, with intermediaterisk and high-risk factors, prostate-specific antigen (PSA) less than 100 ng/mL, and a Karnofsky performance score of at least 70%. Patients were randomly assigned (1:1) to receive 4 months of neoadjuvant and concomitant short-term androgen deprivation (STAD) plus high-dose radiotherapy (minimum dose 76 Gy; median dose 78 Gy) or to receive the same treatment followed by 24 months of adjuvant long-term androgen deprivation (LTAD), via a randomisation scheduled generated by Statistical Analysis Software programme (version 9.1) and an interactive web response system. Patients assigned to the STAD group received 4 months of neoadjuvant and concomitant androgen deprivation (oral flutamide 750 mg per day or oral bicalutamide 50 mg per day) with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy was added during the first 2 months of treatment. Patients assigned to LTAD continued with goserelin every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival at 5 years. For this 10-year study we analysed overall survival, metastasis-free survival, biochemical disease-free survival, and cause-specific survival. Analysis was by intention to treat. This trial is closed and is registered at ClinicalTrials.gov (NCT02175212) and in the EU Clinical Trials Register (EudraCT 2005-000417-36). Findings Between Nov 7, 2005, and Dec 20, 2010, 355 patients were enrolled. One patient in the STAD group withdrew from the trial, hence 354 participants were randomly assigned to STAD (n=177) or LTAD (n=177). The median follow-up was 119,4 months (IQR 100, 6-124,3). The 10-year biochemical disease-free survival for LTAD was 70,2% (95% CI 63,1-77,3) and for STAD was 62,3% (54, 9-69,7; hazard ratio [ HR] 0,84; 95% CI 0 ,50- 1,43; p=0,52). At 10 years, overall survival was 78,4% (72,1-84 ,8) for LTAD and 73,3% (66,6-80,0) for STAD (HR 0 ,84; 95% CI 0,55-1,27; p=0,40), and metastasis- free survival was 76,0% (69,4- 82,7) for LTAD and 70, 9% (64,0-77 ,8) for STAD (HR 0,90; 95% CI, 0,37-2,19; p=0,81). For the subgroup of high-risk patients, the 10-year biochemical disease-free survival was 67,2% (57,2-77,2) for LTAD and 53,7% (43,3-64,1) for STAD (HR 0,90; 95% CI 0,49-1,64; p=0,73), the 10-year overall survival was 78,5% (69,6-87 ,3) for LTAD and 67,0% (57,3- 76,7) for STAD (HR 0,58; 95% CI 0,33-1,01; p=0,054), and the 10-year metastasis-free survival was 76,6% (95% CI 67,6-85 ,6) for LTAD and 65,0% (55,1-74,8) for STAD (HR 0,89; 95% CI 0,33-2,43; p=0, 82). Only 11 (3%) of 354 patients died from prostate cancer, all of them in the high-risk subgroup (five in the LTAD group and six in the STAD group). 76 (21%) patients died from other causes (mainly second malignancies in 31 [9%] and cardiovascular disease in 21 [6%]). No treatment-related deaths were observed. Interpretation After an extended 10-year follow-up, we were unable to support the significant benefit of LTAD reported at 5 years. However, the magnitude of the benefit was clinically relevant in high-risk patients. Intermediate-risk patients treated with high-dose radiotherapy do not benefit from LTAD. A biological characterisation with the inclusion of genomic testing is needed in the decision-making process.

Background: Oligo-recurrent disease has a consolidated evidence of long-term surviving patients due to the use of intense local cancer therapy. The latter combines real-time surgical exploration/resection with high-energy electron beam single dose of irradiation. This results in a very precise radiation dose deposit, which is an essential element of contemporary multidisciplinary individualized oncology. Methods: Patient candidates to proton therapy were evaluated in Multidisciplinary Tumor Board to consider improved treatment options based on the institutional resources and expertise. Proton therapy was delivered by a synchrotron-based pencil beam scanning technology with energy levels from 70.2 to 228.7 MeV, whereas intraoperative electrons were generated in a miniaturized linear accelerator with dose rates ranging from 22 to 36 Gy/min (at Dmax) and energies from 6 to 12 MeV. Results: In a period of 24 months, 327 patients were treated with proton therapy: 218 were adults, 97 had recurrent cancer, and 54 required re-irradiation. The specific radiation modalities selected in five cases included an integral strategy to optimize the local disease management by the combination of surgery, intraoperative electron boost, and external pencil beam proton therapy as components of the radiotherapy management. Recurrent cancer was present in four cases (cervix, sarcoma, melanoma, and rectum), and one patient had a primary unresectable locally advanced pancreatic adenocarcinoma. In re-irradiated patients (cervix and rectum), a tentative radical total dose was achieved by integrating beams of electrons (ranging from 10- to 20-Gy single dose) and protons (30 to 54-Gy Relative Biological Effectiveness (RBE), in 10-25 fractions). Conclusions: Individual case solution strategies combining intraoperative electron radiation therapy and proton therapy for patients with oligo-recurrent or unresectable localized cancer are feasible. The potential of this combination can be clinically explored with electron and proton FLASH beams.

Background Pelvic recurrences from previously irradiated gynecological cancer lack solid evidence for recommendation on salvage. Methods A total of 58 patients were included in this clinical analysis. Salvage surgery was performed for locoregional relapse within previously irradiated pelvic area after initial surgery and adjuvant radiotherapy or radical external beam radiotherapy. The primary tumor diagnosis included cervical cancer (n = 47, 81%), uterine cancer (n = 4, 7%), and other types (n = 7, 12%). Thirty-three patients received adjuvant IOERT (1984-2000) at a median dose of 15 Gy (range 10-20 Gy) and 25 patients received adjuvant PHDRB (2001-2016) at a median dose of 32 Gy (range 24-40 Gy) in 6, 8, or 10 b.i.d. fractions. Results The median follow-up was 5.6 years (range 0.5-14.2 years). Twenty-nine (50.0%) patients had positive surgical margins. Grade >= 3 toxic events were recorded in 34 (58.6%) patients. The local control rate at 2 years was 51% and remained stable up to 14 years. Disease-free survival rates at 2, 5, and 10 years were 17.2, 15.5, and 15.5%, respectively. Overall survival rates at 2, 5, and 10 years were 58.1, 17.8, and 17.8%, respectively. Conclusions IOERT and PHDRB account for an effective salvage in oligorecurrent gynecological tumors. Patients with previous pelvic radiation suitable for salvage surgery and at risk of inadequate margins could benefit from adjuvant reirradiation in form of IOERT or PHDRB. However, the rate of severe grade >= 3 toxicity associated with the entire treatment program is relevant and needs to be closely counterbalanced against the expected therapeutic gain.