Towards a European prospective data registry for particle therapy.

The evidence for the value of particle therapy (PT) is still sparse. While randomized trials remain a cornerstone for robust comparisons with photon-based radiotherapy, data registries collecting real-world data can play a crucial role in building evidence for new developments. This Perspective describes how the European Particle Therapy Network (EPTN) is actively working on establishing a prospective data registry encompassing all patients undergoing PT in European centers. Several obstacles and hurdles are discussed, for instance harmonization of nomenclature and structure of technical and dosimetric data and data protection issues. A preferred approach is the adoption of a federated data registry model with transparent and agile governance to meet European requirements for data protection, transfer, and processing. Funding of the registry, especially for operation after the initial setup process, remains a major challenge.

5-Years Analysis of Effectivity and Toxicity of Ultra-Hypofractionated Proton Radiotherapy in the Treatment of Low- and Intermediate-Risk Prostate Cancer-A Retrospective Analysis.

BACKGROUND: We retrospectively analyzed the 5-year biochemical disease-free survival (bDFS) and occurrence of late toxicity in prostate cancer patients treated with pencil beam scanning (PBS) proton radiotherapy. METHODOLOGY: In the period from January 2013 to June 2018, 853 patients with prostate cancer were treated with an ultra-hypofractionated schedule (36.25 GyE/five fractions). The mean PSA value was 6.7 (0.7-19.7) µg/L. There were 318 (37.3%), 314 (36.8%), and 221 (25.9%) patients at low (LR), favorable intermediate (F-IR), and unfavorable intermediate risk (U-IR), respectively. Neoadjuvant hormonal therapy was administered to 197 (23.1%) patients, and 7 (0.8%) patients had adjuvant hormonal therapy. The whole group of patients reached median follow-up time at 62.7 months, and their mean age was 64.8 (40.0-85.7) years. The bDFS rates and late toxicity profile were evaluated. RESULTS: Median treatment time was 10 (7-38) days. Estimated 5-year bDFS rates were 96.5%, 93.7%, and 91.2% for low-, favorable intermediate-, and unfavorable intermediate-risk groups, respectively. Cumulative late toxicity (CTCAE v4.0) of G2+ was as follows: gastrointestinal (GI)-G2: 9.1%; G3: 0.5%; genitourinary (GU)-G2: 4.3%, and no G3 toxicity was observed. PSA relapse was observed in 58 (6.8%) patients: 16 local, 22 lymph node, 4 bone recurrences, and 10 combined sites of relapse were detected. Throughout the follow-up period, 40 patients (4.7%) died, though none due to prostate cancer. CONCLUSION: Ultra-hypofractionated proton beam radiotherapy is an effective treatment for low- and favorable intermediate-risk prostate cancer, with long-term bDFS rates comparable to other techniques. It is promising for unfavorable intermediate-risk prostate cancer and has acceptable long-term GI and favorable GU toxicity.

The European Particle Therapy Network (EPTN) consensus on the follow-up of adult patients with brain and skull base tumours treated with photon or proton irradiation.

PURPOSE: Treatment-related toxicity after irradiation of brain tumours has been underreported in the literature. Furthermore, there is considerable heterogeneity on how and when toxicity is evaluated. The aim of this European Particle Network (EPTN) collaborative project is to develop recommendations for uniform follow-up and toxicity scoring of adult brain tumour patients treated with radiotherapy. METHODS: A Delphi method-based consensus was reached among 24 international radiation-oncology experts in the field of neuro-oncology concerning the toxicity endpoints, evaluation methods and time points. RESULTS: In this paper, we present a basic framework for consistent toxicity scoring and follow-up, using multiple levels of recommendation. Level I includes all recommendations that are considered minimum of care, whereas level II and III are optional evaluations in the advanced clinical or research setting, respectively. Per outcome domain, the clinical endpoints and evaluation methods per level are listed. Where relevant, the organ at risk threshold doses for recommended referral to specific organ specialists are defined. CONCLUSION: These consensus-based recommendations for follow-up will enable the collection of uniform toxicity data of brain tumour patients treated with radiotherapy. With adoptation of this standard, collaboration will be facilitated and we can further propel the research field of radiation-induced toxicities relevant for these patients. An online tool to implement this guideline in clinical practice is provided at www.cancerdata.org.

Update of the EPTN atlas for CT- and MR-based contouring in Neuro-Oncology.

BACKGROUND AND PURPOSE: To update the digital online atlas for organs at risk (OARs) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging with new OARs. MATERIALS AND METHODS: In this planned update of the neurological contouring atlas published in 2018, ten new clinically relevant OARs were included, after thorough discussion between experienced neuro-radiation oncologists (RTOs) representing 30 European radiotherapy-oncology institutes. Inclusion was based on daily practice and research requirements. Consensus was reached for the delineation after critical review. Contouring was performed on registered CT with intravenous (IV) contrast (soft tissue & bone window setting) and 3 Tesla (T) MRI (T1 with gadolinium & T2 FLAIR) images of one patient (1 mm slices). For illustration purposes, delineation on a 7 T MRI without IV contrast from a healthy volunteer was added. OARs were delineated by three experienced RTOs and a neuroradiologist based on the relevant literature. RESULTS: The presented update of the neurological contouring atlas was reviewed and approved by 28 experts in the field. The atlas is available online and includes in total 25 OARs relevant to neuro-oncology, contoured on CT and MRI T1 and FLAIR (3 T & 7 T). Three-dimensional (3D) rendered films are also available online. CONCLUSION: In order to further decrease inter- and intra-observer OAR delineation variability in the field of neuro-oncology, we propose the use of this contouring atlas in photon and particle therapy, in clinical practice and in the research setting. The updated atlas is freely available on www.cancerdata.org.

Ultrahypofractionated Proton Radiation Therapy in the Treatment of Low and Intermediate-Risk Prostate Cancer-5-Year Outcomes.

PURPOSE: To analyze the 5-year biochemical disease-free survival (bDFS) and late toxicity profile in patients with prostate cancer treated with pencil beam scanning (PBS) proton radiation therapy. METHODS AND MATERIALS: Between January 2013 and March 2016, 284 patients with prostate cancer were treated using intensity modulated proton therapy (IMPT), with an ultrahypofractionated schedule (36.25 GyE in 5 fractions). Five patients were immediately lost from follow-up and thus were excluded from analysis. Data for 279 patients were prospectively collected and analyzed with a median follow-up time of 56.5 (range, 3.4-87.5) months. The mean age at time of treatment was 64.5 (40.1-85.7) years, and the median prostate-specific antigen (PSA) value was 6.35 µg/L (0.67-17.3 µg/L). A total of 121 (43.4%) patients had low-risk, 125 patients (44.8%) had favorable, and 33 (11.8%) unfavorable intermediate-risk cancer. In addition, 49 (17.6%) patients underwent neoadjuvant hormonal therapy, and no patients had adjuvant hormonal therapy. bDFS and late toxicity profiles were evaluated. RESULTS: The median treatment time was 9 days (range, 7-18 days). The 5-year bDFS was 96.9%, 91.7%, and 83.5% for the low-, favorable, and unfavorable intermediate-risk group, respectively. Late toxicity (Common Terminology Criteria for Adverse Events v.4) was as follows: gastrointestinal: grade 1, 62 patients (22%), grade 2, 20 patients (7.2%), and grade 3, 1 patient (0.36%); genitourinary: grade 1, 80 patients (28.7%), grade 2, 14 patients (5%), and grade 3, 0 patients. PSA relapse was observed in 17 patients (6.1%), and lymph node or bone recurrence was detected in 11 patients. Four (1.4%) local recurrences were detected. Nine patients (3.2%) died of causes unrelated to prostate cancer. No deaths related to prostate cancer were reported. CONCLUSION: Ultrahypofractionated proton beam radiation therapy for prostate cancer is effective with long-term bDFS comparable with other fractionation schedules and with minimal serious long-term GI and GU toxicity.

Pencil Beam Scanning (PBS) Intensity-Modulated Proton Therapy (IMPT) Chemoradiotherapy for Anal Canal Cancer-Single Institution Experience.

Background: A favourable dose distribution has been described for proton beam therapy (PBT) of anal cancer in dosimetric studies. The relationship between dosimetric parameters in bone marrow and haematologic toxicity, treatment interruptions, and treatment efficacy has also been documented. There are only few references on clinical results of PBT for anal cancer. The primary objective of the retrospective study was to assess the efficacy of pencil beam scanning intensity-modulated proton therapy (PBS IMPT) in the definitive chemoradiotherapy of anal cancer. Secondary objectives were established to identify the risks of acute chronic toxicity risks and to assess colostomy rates. Materials and methods: Patients were treated for biopsy-proven squamous cell cancer (SCC) of the anus at initial or advanced stages. Eligible patients received PBS IMPT at a single institution. Treatment was administered in two volumes: 1-tumour with margins plus involved lymph nodes; 2-regional lymph node groups: perirectal (mesorectal), obturatory, inguinal, internal, external, and common iliac. The total doses of 57.5 GyE and 45 GyE, respectively, were administered in volumes 1 and 2 in 25 fractions, 5 fractions per week, respectively (a simultaneous integrated boost). Concomitant chemotherapy cisplatinum (CDDP) plus 5-FU or CDDP plus capecitabine was administered as per protocol. The treatment effect was assessed using DRE (digital rectal examination) and MRI (magnetic resonance imaging) within the follow-up period. Toxicity was scaled using CTCAE version 4.0 criteria. Results: 39 of 41 patients treated during the period of February 2014-August 2021 were eligible for analysis. All patients completed treatment, 76.9% without interruption. The median treatment time was 35 days (32-35). The median follow-up period was 30 months, 34 patients are alive to-date, 5 patients died prior to the date of analysis, and 2 deaths were unrelated to the primary disease. The 2-year overall survival, relapse-free survival, and colostomy-free survival were 94.2%, 93.8%, and 91.0%, respectively. Complete regression was achieved in 36 patients (92.3%), partial regression was achieved in 2 (5.1%), and immediate progression at end of treatment occurred in 1 patient (2.6%). Salvage resection was indicated for two patients in partial regression and due to severe chronic dermatologic toxicity. The grade 3 and 4 haematological toxicity rates were 7.7% and 5.1%, respectively. The most frequent non-haematological acute toxicities of grade 3-4 observed were dermatitis (23.1%), diarrhoea (7.7%), and dehydration (7.7%). Chronic toxicity emerged predominantly as skin atrophy/ulceration grade 2 (26.5%) and grade 3-4 (5.8%), and radiation proctitis grade 2 (38.2%) and grade 3 (2.9%). Discussion, conclusions: This single-institution study showed the high efficacy of PBS IMPT, achieving a high rate of complete regression. The haematological acute toxicity of grade 3-4 remained low; however, the impact of altered chemotherapy (CDDP instead of mitomycin C) remains unclear. The incidence of other acute toxicities shares similarity with photon therapy investigated in large studies. The acute toxicity completely resolved in all patients, had no lethal outcomes, and never resulted in the necessity for colostomy. By contrast, it was chronic toxicity, skin ulceration, perirectal fistulation, and fibrosis that resulted in salvage surgery and/or the need for a colostomy. A challenging question remains: to what extent can PBT prevent chronic toxicity? Longer follow-up remains necessary.

Pseudomyxoma Peritonei.

BACKGROUND: Pseudomyxoma peritonei is a rare tumorous disease with various grades of malignancy and is characterized by production of mucinous and gelatinous masses. Development of pseudomyxoma peritonei is usually associated with rupture of appendiceal mucinous tumors and other mucinous tumors of the gastrointestinal tract or ovaries. Pseudomyxoma peritonei is usually divided into three types: low-grade, high-grade, and high-grade with signet ring cells. Staging of the disease is determined by the peritoneal cancer index. Clinical findings are highly variable depending on disease staging. The typical finding of “jelly belly” syndrome worsens with disease progression. The diagnosis is based on the pre-operative cure by imaging methods, especially computed tomography. METHODS: The Sugarbaker method involves maximal removal of tumorous masses, so-called cytoreductive surgery, and perioperative intraabdominal application of hot cytostatics (hyperthermic intraperitoneal chemotherapy) with the aim of achieving maximal liquidation of tumorous processes. RESULTS: Our results are comparable with previous published data and confirm high effectivness of this method. The results show statistically very significant extention of overall survival, disease free interval with acceptable lethality 0-12 % and morbidity 27-56%. These results promote this method as the gold standard of treatment of pseudomyxoma peritonei in selected patients.

Extreme hypofractionated proton radiotherapy for prostate cancer using pencil beam scanning: Dosimetry, acute toxicity and preliminary results.

INTRODUCTION: Extreme hypofractionated radiotherapy for prostate cancer is a common modality in photon therapy. Pencil beam scanning (PBS) in similar fractionation allows better dose distribution and makes proton therapy more available for such patients. The purpose of this study is the feasibility of extreme proton hypofractionated radiotherapy and publication of early clinical results. METHODS: Two hundred patients with early-stage prostate cancer were treated with IMPT (intensity-modulated proton therapy), extreme hypofractionated schedule (36.25 GyE in five fractions) between February 2013 and December 2015. Mean age of the patients was 64.3 years, and the mean value of prostate-specific antigen (PSA) before treatment was 6.83 µg/L (0.6-17.3 µg/L). Ninety-three patients (46.5%) were in the low-risk group. One hundred and seven patients (53.5%) were in the intermediate-risk group. Twenty-nine patients (14.5%) had neoadjuvant hormonal therapy, and no patients had adjuvant hormonal therapy. Acute toxicity, late toxicity and short-term results were evaluated. RESULTS: All patients finished radiotherapy without interruptions. The median follow-up time was 36 months. The mean treatment time was 9.5 days (median 9 days). Acute toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 was (gastrointestinal toxicity) GI (grade) G1-17%, G2-3.5%; (genitourinary toxicity) GU G1-40%, G2-19%; and no G3 toxicity was observed. Late toxicity was GI G1-19%, G2-5.5%; GU G1-17%, G2-4%; and no G3 toxicity was observed. PSA relapse was observed in one patient (1.08%) in the low-risk group (pelvic lymph node involvement was detected) and in seven patients (6.5%) in the intermediate-risk group (three lymph node metastases, two lymph node and bone metastases, two PSA relapses). No patient died of prostate cancer, and three patients died from other reasons. No local recurrence of cancer in the prostate was observed. CONCLUSIONS: Proton beam radiotherapy for prostate cancer is feasible with a low rate of acute toxicity and promising late toxicity and effectivity.

Radiation dose constraints for organs at risk in neuro-oncology; the European Particle Therapy Network consensus.

PURPOSE: For unbiased comparison of different radiation modalities and techniques, consensus on delineation of radiation sensitive organs at risk (OARs) and on their dose constraints is warranted. Following the publication of a digital, online atlas for OAR delineation in neuro-oncology by the same group, we assessed the brain OAR-dose constraints in a follow-up study. METHODS: We performed a comprehensive search to identify the current papers on OAR dose constraints for normofractionated photon and particle therapy in PubMed, Ovid Medline, Cochrane Library, Embase and Web of Science. Moreover, the included articles' reference lists were cross-checked for potential studies that met the inclusion criteria. Consensus was reached among 20 radiation oncology experts in the field of neuro-oncology. RESULTS: For the OARs published in the neuro-oncology literature, we summarized the available literature and recommended dose constraints associated with certain levels of normal tissue complication probability (NTCP) according to the recent ICRU recommendations. For those OARs with lacking or insufficient NTCP data, a proposal for effective and efficient data collection is given. CONCLUSION: The use of the European Particle Therapy Network-consensus OAR dose constraints summarized in this article is recommended for the model-based approach comparing photon and proton beam irradiation as well as for prospective clinical trials including novel radiation techniques and/or modalities.

The EPTN consensus-based atlas for CT- and MR-based contouring in neuro-oncology.

PURPOSE: To create a digital, online atlas for organs at risk (OAR) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging. METHODS: CT and 3 Tesla (3T) MR images (slice thickness 1 mm with intravenous contrast agent) were obtained from the same patient and subsequently fused. In addition, a 7T MR without intravenous contrast agent was obtained from a healthy volunteer. Based on discussion between experienced radiation oncologists, the clinically relevant organs at risk (OARs) to be included in the atlas for neuro-oncology were determined, excluding typical head and neck OARs previously published. The draft atlas was delineated by a senior radiation oncologist, 2 residents in radiation oncology, and a senior neuro-radiologist incorporating relevant available literature. The proposed atlas was then critically reviewed and discussed by European radiation oncologists until consensus was reached. RESULTS: The online atlas includes one CT-scan at two different window settings and one MR scan (3T) showing the OARs in axial, coronal and sagittal view. This manuscript presents the three-dimensional descriptions of the fifteen consensus OARs for neuro-oncology. Among these is a new OAR relevant for neuro-cognition, the posterior cerebellum (illustrated on 7T MR images). CONCLUSION: In order to decrease inter- and intra-observer variability in delineating OARs relevant for neuro-oncology and thus derive consistent dosimetric data, we propose this atlas to be used in photon and particle therapy. The atlas is available online at www.cancerdata.org and will be updated whenever required.

Urinary neopterin concentration and toxicity of radiotherapy in patients with head and neck carcinoma during external beam radiation.

AIM: Increased serum or urinary concentrations of neopterin are predictive of poor prognosis in patients with tumors across a spectrum of primary locations. Less information is available about the significance of changes of urinary neopterin concentrations during therapy. The aim of the present study was to examine the association between urinary neopterin and toxicity of radiotherapy. PATIENTS AND METHODS: We analyzed changes of urinary neopterin and toxicity of therapy in 12 patients with head and neck carcinoma during external-beam radiation. Urinary neopterin was determined daily by high-performance liquid chromatography. RESULTS: In addition to a trend for increased neopterin concentrations during radiation therapy, a significant association between changes of neopterin and toxicity and vice versa was observed with a rise of neopterin predicting a later manifestation of toxicity as well as manifestion of toxicity predicting a later rise of neopterin. CONCLUSION: Urinary neopterin is predictive of toxicity in patients with head and neck carcinoma. An association between toxicity and subsequent rise of urinary neopterin concentrations was also observed.

Metastasis of dermatofibrosarcoma from the abdominal wall to the thyroid gland: case report.

Metastases in the thyroid gland are very rare. Even the rarer are sarcoma metastases. A 52-year-old woman was referred to our department for evaluation of a nodule in the right lobe of the thyroid gland. She had a history dermatosarcoma of the abdominal wall with known metastasis in the lung. Clinically she had neck pain and worsened swallowing. Objective assessment (ultrasound, computed tomography, and magnetic resonance) indicated a voluminous right lobe nodule with mechanical syndrome, and a fine-needle aspiration biopsy revealed a very suspicious malignant finding. After surgery, the diagnosis was metastasis of dermatofibrosarcoma protuberans. Subsequent treatment was radio- and chemotherapy.

Prognostic significance of serum retinol, serum alpha-tocopherol, and urinary neopterin in patients with head and neck carcinoma treated with external beam radiation.

High serum or urinary neopterin concentrations are associated with poor prognosis in patients with tumors of different primary locations, but reports on neopterin in patients with head and neck carcinoma are relatively less numerous. It has been established that decreased circulating concentrations of retinol and alpha-tocopherol are common in this population. We have evaluated the prognostic significance of urinary neopterin, serum retinol, and alpha-tocopherol in 44 patients with head and neck carcinoma. Urinary neopterin, serum retinol, and alpha-tocopherol were determined with high-performance liquid chromatography. High urinary neopterin and low serum retinol were predictive of poor prognosis, while the prognostic significance of low alpha-tocopherol was of borderline significance. Serum retinol significantly decreased during external beam radiation, but a less marked decrease of alpha-tocopherol during therapy did not reach statistical significance. An increase of urinary neopterin was evident late during the course of treatment. In conclusion, high urinary neopterin and low serum retinol are predictive of poor prognosis in patients with head and neck carcinoma.

The updated ESTRO core curricula 2011 for clinicians, medical physicists and RTTs in radiotherapy/radiation oncology.

INTRODUCTION: In 2007 ESTRO proposed a revision and harmonisation of the core curricula for radiation oncologists, medical physicists and RTTs to encourage harmonised education programmes for the professional disciplines, to facilitate mobility between EU member states, to reflect the rapid development of the professions and to secure the best evidence-based education across Europe. MATERIAL AND METHODS: Working parties for each core curriculum were established and included a broad representation with geographic spread and different experience with education from the ESTRO Educational Committee, local representatives appointed by the National Societies and support from ESTRO staff. RESULTS: The revised curricula have been presented for the ESTRO community and endorsement is ongoing. All three curricula have been changed to competency based education and training, teaching methodology and assessment and include the recent introduction of the new dose planning and delivery techniques and the integration of drugs and radiation. The curricula can be downloaded at http://www.estro-education.org/europeantraining/Pages/EuropeanCurricula.aspx. CONCLUSION: The main objective of the ESTRO core curricula is to update and harmonise training of the radiation oncologists, medical physicists and RTTs in Europe. It is recommended that the authorities in charge of the respective training programmes throughout Europe harmonise their own curricula according to the common framework.

Hodgkin's lymphoma in the elderly: the results of 10 years of follow-up.

Elderly patients with Hodgkin's lymphoma carry a worse prognosis than younger patients because of a higher incidence of advanced stages, a worse performance status and the intolerance of full-dose curative treatment. A retrospective analysis of patients treated at our institution was performed. Our retrospective study summarizes the treatment results for 52 Hodgkin's lymphoma patients aged older than 60 years between 1973 and 1993. These patients were treated with combination of less toxic chemotherapy schedule (cyclophosphamide, vincristine, procarbazine and prednisone) and/or involved-field radiotherapy. The aim was to maintain an acceptable quality of life in spite of lower remission rate. The 5- and 10-year overall survival rates were 48% and 33%, respectively. We found two independent prognostic factors for overall survival: (i) stage of the disease and (ii) accomplishment of the treatment. Combined modality treatment yielded better results than chemotherapy. Tolerance of the treatment was acceptable. The present study demonstrates that a combination of mild chemotherapy with limited radiotherapy is a feasible way of treating elderly patients with Hodgkin's lymphoma.