Hospital-based proton therapy implementation during the COVID pandemic: early clinical and research experience in a European academic institution.

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.

Metabolic and molecular relative percentage coreduction in patients with locally advanced rectal cancer treated with neoadjuvant therapy.

PURPOSE: Vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor-1 (EGFR) and cyclooxygenase-2 (COX-2) stimulate key processes involved in tumour progression and are important targets for cancer therapeutics. (18)F-FDG maximum standardized uptake value (SUVmax) on PET/CT is a marker of tumour metabolic activity. The purpose of this study was to measure percentage reductions in SUVmax (∆SUVmax%), VEGFR-2 (∆VEGFR-2%), EGFR (∆EGFR%) and COX-2 (∆COX-2%) in patients with locally advanced rectal cancer (LARC) after preoperative treatment, and to correlate the changes in these markers of response with pathological response in terms of tumour regression grade (TRG) using Rödel's scale and long-term clinical outcome. METHODS: VEGFR-2, EGFR and COX-2 were measured using a quantitative and qualitative compound immunohistochemistry analysis (immunoreactive score) of the pretreatment endoscopic biopsy and definitive surgical specimens. Composite indexes using ∆SUVmax% and the three molecules were developed to differentiate patients with metabolic and molecular responses from nonresponders. Cox proportional hazards model was used to explore associations between the tumour markers, disease-free survival (DFS) and overall survival (OS). RESULTS: The analysis included 38 patients with a median follow-up of 86 months (range 5 - 113 months). The ∆VEGFR-2%/∆SUVmax% index correctly identified 13 of 19 pathological responders (TRG 3 and 4) and 17 of 19 nonresponders (TRG 0 - 2) (sensitivity 68 %, specificity 89 %, accuracy 79 %, positive predictive value 87 %, negative predictive value 74 %). In multivariate analysis, only the ∆VEGFR-2%/∆SUVmax% index was associated with DFS (HR 0.11, p = 0.001) and OS (HR 0.15, p = 0.02). CONCLUSION: In patients with LARC the ∆VEGFR-2%/∆SUVmax% response index is associated with outcome. Determination of the optimal diagnostic cut-off level for this novel biomarker association should be explored. Evaluation in a clinical trial is required to determine whether selected patients could benefit from treatment with a VEGFR-targeted therapeutic agent.

Single-Institution Multidisciplinary Management of Locoregional Oligo-Recurrent Pelvic Malignancies: Long-Term Outcome Analysis.

PURPOSE: The aim of this study was to analyze long-term outcomes and prognostic factors associated with survival in patients with locoregional oligo-recurrent (LROR) pelvic malignancies treated in a multimodal protocol. METHODS: Patients with an histologic diagnosis of LROR pelvic cancer (rectal 50 %, gynecological 50 %) with absence of distant metastases, undergoing surgery with radical intent and intraoperative radiotherapy (median dose 12.5 Gy) were considered eligible for participation in this study. Additionally, 48 % received external beam radiotherapy (EBRT) (median dose 50 Gy). RESULTS: From 1995 to 2012, a total of 143 patients from a single institution were analyzed. With a median follow-up time of 48 months (range 2-189), 5-year locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) were 53, 44, and 46 %, respectively. On multivariate analysis, no EBRT treatment to the locoregional (p ≤ 0.001), R1 margin status (p = 0.03), time interval from primary tumor diagnosis to LROR <24 months (p = 0.05), and fragmentation in the resected specimen (p = 0.004) retained significance in relation to LRC. On multivariate analysis we found that only R1 margin status (p = 0.003), primary tumor diagnosis to LROR <24 months (p = 0.02), and high histological grade (p = 0.02) were significantly associated with OS. CONCLUSIONS: From this analysis emerges the fact that EBRT influences local control but, given the high risk of distant metastases, DFS remains modest. Margin status, tumor fragmentation, no EBRT to the LR, and time interval from primary tumor diagnosis to LROR are the dominant factors for subsequent locoregional recurrence (LRR). Accordingly, future prospective studies might be designed which adapt treatment according to the predicted risk of subsequent LRR.

Human cytomegalovirus and Epstein-Barr virus infection impact on (18)F-FDG PET/CT SUVmax, CT volumetric and KRAS-based parameters of patients with locally advanced rectal cancer treated with neoadjuvant therapy.

PURPOSE: It has long been debated whether human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) are associated with rectal cancer. The gene products of HCMV and EBV contribute to cell-cycle progression, mutagenesis, angiogenesis and immune evasion. The aim of this prospective study was to analyse the association between infection of a tumour by HCMV and EBV and clinical, histological, metabolic ((18)F-FDG uptake), volumetric (from CT) and molecular (KRAS status) features and long-term outcomes in a homogeneously treated group of patients with locally advanced rectal cancer. METHODS: HCMV and EBV were detected in pretreatment biopsies using polymerase chain reaction (PCR). The Cox proportional hazards regression model was used to explore associations between viral infection and disease-free survival (DFS) and overall survival (OS). RESULTS: We analysed 37 patients with a median follow-up of 74 months (range 5-173 months). Locoregional control, OS and DFS at 5 years were 93%, 74% and 71%, respectively. Patients with HCMV/EBV coinfection had a significantly higher maximum standardized uptake value than patients without viral coinfection (p = 0.02). Significant differences were also observed in staging and percentage relative reduction in tumour volume between patients with and without HCMV infection (p < 0.01) and EBV infection (p < 0.01). KRAS wildtype status was significantly more frequently observed in patients with EBV infection (p <0.01) and HCMV/EBV co-infection (p = 0.04). No significant differences were observed in OS or DFS between patients with and without EBV infection (p = 0.88 and 0.73), HCMV infection (p = 0.84 and 0.79), and EBV/CMV coinfection (p = 0.24 and 0.39). CONCLUSION: This pilot study showed that viral infections were associated with metabolic staging differences, and differences in the evolution of metabolic and volumetric parameters and KRAS mutations. Further findings of specific features will help determine the best candidates for metabolic and volumetric staging and restaging. Further toxicity profile findings will help to determine the best candidates for specific supportive treatment during pelvic chemoradiotherapy in patients with locally advanced rectal cancer.

Bibliometrics of intraoperative radiotherapy: analysis of technology, practice and publication tendencies.

PURPOSE: To analyze the performance and quality of intraoperative radiation therapy (IORT) publications identified in medical databases during a recent period in terms of bibliographic metrics. MATERIALS AND METHODS: A bibliometric search was conducted for IORT papers published in the PubMed database between 1997 and 2013. Publication rate was used as a quantity indicator; the 2012 Science Citation Index Impact Factor as a quality indicator. Furthermore, the publications were stratified in terms of study type, scientific topic reported, year of publication, tumor type and journal specialty. We performed a one-way analysis of variance (ANOVA) to determine differences between the means of the analyzed groups. RESULTS: Among the total of 207 journals, articles were reported significantly more frequently in surgery (n = 399, 41 %) and radiotherapy journals (n = 273, 28 %; p < 0.01). The highest impact factor was achieved by clinical oncology journals (p < 0.01). The majority of identified articles were retrospective cohort reports (n = 622, 64 %), followed by review articles (n = 204, 21 %; p < 0.001). Regarding primary topic, reports on cancer outcome following specific tumor therapy were most frequently published (n = 661, 68 %; p < 0.001) and gained the highest mean impact factor (p < 0.01). Gastrointestinal tumor reports were represented most frequently (n = 456, 47 %; p < 0.001) and the mean superior impact factor was earned by breast and gynecologic publications (p < 0.01). CONCLUSION: We identified a consistent and sustained scientific productivity of international IORT expert groups. Most publications appeared in journals with surgical and radiooncological content. The highest impact factor was achieved by medical oncology journals.

Practice patterns in the management of prostate cancer in Spain: results from a national survey among radiation oncologists in 2009.

INTRODUCTION: Little is known of practice patterns on advanced prostate cancer (PC) in Spain. The study objectives were to investigate practice patterns in the management of PC and to determine the adherence to the 2007 Spanish guidelines for the management of PC. MATERIALS AND METHODS: An epidemiological, cross-sectional study was undertaken. Study-specific questionnaires were distributed to all centers with radiation oncology (RO) facilities delivering megavoltage radiation therapy (RT) in Spain (n = 108). A questionnaire evaluated diagnostic and treatment approaches to PC in low-risk and high-risk cases. And a 12-item questionnaire was used to assess guidelines adherence. RESULTS: Responses were obtained from 102 centers (94.0 % response rate). In the high-risk scenario, the majority of clinicians (99.0 %) chose combined modality treatment with RT and androgen deprivation (AD) and 93.0 % recommended long-term AD. External-beam RT (EBRT) doses ranging 72-76 Gy were used in 59.5 % of centers and >76 Gy was employed in 40.5 %. In the low-risk scenario, EBRT was chosen by 59.6 %, brachytherapy by 39.4 %, and active surveillance by 1 %. The consensus was high (score 5 + 4 ≥ 90 %) on 8/12 questions assessing adherence to guidelines, being high specifically on items related to RT technique, RT dose, combination of HT and RT in intermediate/high-risk patients, and prognostic factors. CONCLUSIONS: This is the largest survey to date of Spanish RO departments dealing with PC. The study results therefore likely provide a highly reliable picture of clinical practice in Spain in this century and show how this practice is influenced by clinical evidence from randomized trials and consensus conferences.

Overview of preoperative radiochemotherapy in breast cancer: past or future?

Radiochemotherapy is a standard approach in human solid tumours, with localised stage and radical treatment intention. In the early-intermediate stages of breast cancer model, neoadjuvant radiochemotherapy is an alternative to induction chemotherapy alone and might further impact the surgical technical treatment characteristics (a downsizing effect). In the era of targeted therapy and personalised treatment for breast cancer patients with initial localised disease, radiochemotherapy needs to be explored as a component of optimised local treatment to potentially improve relevant local results, such as breast conservation, breast cosmesis and individualised breast cancer radiochemotherapy response prediction. An overview of available literature data regarding neoadjuvant treatment including radiotherapy component is analysed and discussed.

[Fractionated stereotactic-guided radiotherapy in the treatment of pituitary adenomas]. / Radioterapia estereotáxica fraccionada en adenomas de hipófisis: resultados y factores pronósticos.

AIMS: To evaluate the survival rates, prognostic factors and adverse events in patients with pituitary adenomas following fractionated stereotactic-guided radiotherapy (FSRT). MATERIAL AND METHODS: Fifty-six patients with pituitary adenomas were treated with FSRT; 23 patients (41.1%) had primary adenomas, 33 had recurrent disease; 24 (42.9%) with non-functional and 32 (57.1%) with functional adenomas. Using conventional fractionation, median total dose administered was 54 Gy (range: 24-56 Gy). RESULTS: The median follow-up was 51 months (range: 9-102) and, at the time of analysis, 49 patients were alive and disease-free, 1 patient was alive with reduced visual acuity and biochemical indications of recurrence, 2 patients had died from the disease and 1 patient had died from unrelated causes. Overall survival was 94% (50/53) and overall local tumour control was 92% (49/53). Univariate analysis indicated hormonal secretion (ACTH) and previous radiotherapy as being statistically significant. Fourteen patients (25%) had minor side-effects during treatment and 3 patients (5.4%) had late-onset events; 2 with optical neuropathy (both patients had other relevant co-existing diseases) and 1 patient had brain necrosis (re-irradiation). CONCLUSION: Fractionated stereotactic-guided radiotherapy is an effective modality for the treatment of pituitary adenomas. Care is required in patients with co-morbidities and/or previously-irradiated recurrent tumour so as to minimise late-onset secondary effects.