The 50 most-cited articles in Radiotherapy and Oncology, 2021

BACKGROUND AND PURPOSE: The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results. MATERIALS AND METHODS: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint. RESULTS: For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the…

BACKGROUND AND PURPOSE: Brain metastasis impacts greatly on patients' quality of life and survival. The phase I NANO-RAD trial assessed the safety and maximum tolerated dose of systemic administration of a novel gadolinium-based nanoparticle, AGuIX, in combination with whole brain radiotherapy in patients with multiple brain metastases not suitable for stereotactic radiotherapy. MATERIALS AND METHODS: Patients with measurable brain metastases received escalating doses of AGuIX nanoparticles (15, 30, 50, 75, or 100 mg/kg intravenously) on the day of initiation of WBRT (30 Gy in 10 fractions) in 5 cohorts of 3 patients each. Toxicity was assessed using NCI Common Terminology Criteria for Adverse Events v4.03. RESULTS: MRI enhancement, tumor selectivity) and persistence of AGuIX contrast enhancement were observed in metastases from patients with primary melanoma, lung, breast, and colon cancers. The concentration of AGuIX in metastases after administration was proportional to the injected dose. Thirteen of 14 evaluable patients had a clinical benefit, with either stabilization or…

BACKGROUND AND PURPOSE: Delineating organs at risk (OARs) on computed tomography (CT) images is an essential step in radiation therapy; however, it is notoriously time-consuming and prone to inter-observer variation. Herein, we report a deep learning-based automatic segmentation (AS) algorithm (WBNet) that can accurately and efficiently delineate all major OARs in the entire body directly on CT scans. MATERIALS AND METHODS: We collected 755 CT scans of the head and neck, thorax, abdomen, and pelvis and manually delineated 50 OARs on the CT images. The CT images with contours were split into training and test sets consisting of 505 and 250 cases, respectively, to develop and validate WBNet. The volumetric Dice similarity coefficient (DSC) and 95th-percentile Hausdorff distance (95% HD) were calculated to evaluate delineation quality for each OAR. We compared the performance of WBNet with three AS algorithms: one commercial multi-atlas-based automatic segmentation (ABAS) software, and two deep learning-based AS algorithms, namely, AnatomyNet and nnU-Net. We have also evaluated the…

BACKGROUND AND PURPOSE: Preclinical studies indicate a normal tissue sparing effect using ultra-high dose rate (FLASH) radiation with comparable tumor response. Most data so far are based on electron beams with limited utility for human treatments. This study validates the effect of proton FLASH delivered with pencil beam scanning (PBS) in a mouse leg model of acute skin damage and quantifies the normal tissue sparing factor, the FLASH factor, through full dose response curves. MATERIALS AND METHODS: The right hind limb of CDF1 mice was irradiated with a single fraction of proton PBS in the entrance plateau of either a 244 MeV conventional dose rate field or a 250 MeV FLASH field. In total, 301 mice were irradiated in four separate experiments, with 7-21 mice per dose point. The endpoints were the level of acute moist desquamation to the skin of the foot within 25 days post irradiation. RESULTS: The field duration and field dose rate were 61-107 s and 0.35-0.40 Gy/s for conventional dose rate and 0.35-0.73 s and 65-92 Gy/s for FLASH. Full dose response curves for five levels of…

PURPOSE: This study aimed to evaluate whether high-energy X-rays (HEXs) of the PARTER (platform for advanced radiotherapy research) platform built on CTFEL (Chengdu THz Free Electron Laser facility) can produce ultrahigh dose rate (FLASH) X-rays and trigger the FLASH effect. MATERIALS AND METHODS: EBT3 radiochromic film and fast current transformer (FCT) devices were used to measure absolute dose and pulsed beam current of HEXs. Subcutaneous tumor-bearing mice and healthy mice were treated with sham, FLASH, and conventional dose rate radiotherapy (CONV), respectively to observe the tumor control efficiency and normal tissue damage. RESULTS: The maximum dose rate of HEXs of PARTER was up to over 1000 Gy/s. Tumor-bearing mice experiment showed a good result on tumor control (p < 0.0001) and significant difference in survival curves (p < 0.005) among the three groups. In the thorax-irradiated healthy mice experiment, there was a significant difference (p = 0.038) in survival among the three groups, with the risk of death decreased by 81% in the FLASH group compared to that in the CONV…

BACKGROUND AND PURPOSE: A comprehensive individual toxicity risk profile is needed to improve radiation treatment optimisation, minimising toxicity burden, in head and neck cancer (HNC) patients. We aimed to develop and externally validate NTCP models for various toxicities at multiple time points. MATERIALS AND METHODS: Using logistic regression, we determined the relationship between normal tissue irradiation and the risk of 22 toxicities at ten time points during and after treatment in 750 HNC patients. The toxicities involved swallowing, salivary, mucosal, speech, pain and general complaints. Studied predictors included patient, tumour and treatment characteristics and dose parameters of 28 organs. The resulting NTCP models were externally validated in 395 HNC patients. RESULTS: The NTCP models involved 14 organs that were associated with at least one toxicity. The oral cavity was the predominant organ, associated with 12 toxicities. Other important organs included the parotid and submandibular glands, buccal mucosa and swallowing muscles. In addition, baseline toxicity,…

MR Imaging is regarded asthe gold standardfor Image Gudied Adaptive Brachytherapy (IGABT) for cervical cancer. However, its wide applicability is limited by its availability, logistics and financial implications. Use of alternative imaging like CTand Ultrasound (US) for IGABT has been attempted. In order to arrive at a systematic, uniform and international approach for CT based definition and contouring of target structures, GEC ESTRO, IBS and ABS agreed to jointly develop such recommendations based on the concepts and terms as published in the ICRU Report 89. The minimum requirements are clinical examination & documentation, CT or MR imaging at diagnosis and at a minimum, CT imaging with the applicator in place. The recommendations are based on (i) assessment of the GTV at diagnosis and at brachytherapy, (ii) categorizing the response to external radiation into different clinical remission patterns, (iii) defining various clinico-radiological environments and (iv) definition & delineation of a target on CT imaging at the time of brachytherapy with the applicator in situ. CT based…

BACKGROUND AND PURPOSE: Recent observations in animal models show that ultra-high dose rate ("FLASH") radiation treatment significantly reduces normal tissue toxicity maintaining an equivalent tumor control. The dependence of this "FLASH" effect on target oxygenation has led to the assumption that oxygen "depletion" could be its major driving force. MATERIALS AND METHODS: In a bottom-up approach starting from the chemical track evolution of 1 MeV electrons in oxygenated water simulated with the TRAX-CHEM Monte Carlo code, we determine the oxygen consumption and radiolytic reactive oxygen species production following a short radiation pulse. Based on these values, the effective dose weighted by oxygen enhancement ratio (OER) or the in vitro cell survival under dynamic oxygen pressure is calculated and compared to that of conventional exposures, at constant OER. RESULTS: We find an excellent agreement of our Monte Carlo predictions with the experimental value for radiolytic oxygen removal from oxygenated water. However, the application of the present model to published radiobiological…

Linear Energy Transfer (LET) is widely used to express the radiation quality of ion beams, when characterizing the biological effectiveness. However, averaged LET may be defined in multiple ways, and the chosen definition may impact the resulting reported value. We review averaged LET definitions found in the literature, and quantify which impact using these various definitions have for different reference setups. We recorded the averaged LET definitions used in 354 publications quantifying the relative biological effectiveness (RBE) of hadronic beams, and investigated how these various definitions impact the reported averaged LET using a Monte Carlo particle transport code. We find that the kind of averaged LET being applied is, generally, poorly defined. Some definitions of averaged LET may influence the reported averaged LET values up to an order of magnitude. For publications involving protons, most applied dose averaged LET when reporting RBE. The absence of what target medium is used and what secondary particles are included further contributes to an ill-defined averaged LET.…

PURPOSE: To quantifiy the range uncertainty in proton treatment planning using dual-energy computed tomography (DECT) for a direct stopping-power prediction (DirectSPR) algorithm and its clinical implementation. METHODS AND MATERIALS: To assess the overall uncertainty in stopping-power ratio (SPR) prediction of a DirectSPR implementation calibrated for different patient geometries, the influencing factors were categorized in imaging, modeling as well as others. The respective SPR uncertainty was quantified for lung, soft tissue and bone and translated into range uncertainty for several tumor types. The amount of healthy tissue spared was quantified for 250 patients treated with DirectSPR and the dosimetric impact was evaluated exemplarily for a representative brain-tumor patient. RESULTS: For bone, soft tissue and lung, an SPR uncertainty (1σ) of 1.6%, 1.3% and 1.3% was determined for DirectSPR, respectively. This allowed for a reduction of the clinically applied range uncertainty from currently (3.5% + 2 mm) to (1.7% + 2 mm) for brain-tumor and (2.0% + 2 mm) for prostate-cancer…

BACKGROUND AND PURPOSE: With daily, MR-guided online adapted radiotherapy (MRgART) it may be possible to reduce the PTV in pelvic RT. This study investigated the potential reduction in normal tissue complication probability (NTCP) of MRgART compared to standard radiotherapy for high-risk prostate cancer. MATERIALS AND METHODS: Twenty patients treated with 78 Gy to the prostate and 56 Gy to elective pelvic lymph nodes were included. VMAT plans were generated with standard clinical PTV margins. Additionally to the planning MR, patients had three MRI scans during treatment to simulate an MRgART. A reference plan with PTV margins determined for MRgART was created per patient and adapted to each of the following MRs. Adapted plans were warped to the planning MR for dose accumulation. The standard plan was rigidly registered to each adaptation MR before it was warped to the planning MR for dose accumulation. Dosimetric impact was compared by DVH analysis and potential clinical effects were assessed by NTCP modeling. RESULTS: MRgART yielded statistically significant lower doses for the…

Clinical treatment with protons uses the concept of relative biological effectiveness (RBE) to convert the absorbed dose into an RBE-weighted dose that equals the dose for radiotherapy with photons causing the same biological effect. Currently, in proton therapy a constant RBE of 1.1 is generically used. However, empirical data indicate that the RBE is not constant, but increases at the distal edge of the proton beam. This increase in RBE is of concern, as the clinical impact is still unresolved, and clinical studies demonstrating a clinical effect of an increased RBE are emerging. Within the European Particle Therapy Network (EPTN) work package 6 on radiobiology and RBE, a workshop was held in February 2020 in Manchester with one day of discussion dedicated to the impact of proton RBE in a clinical context. Current data on RBE effects, patient outcome and modelling from experimental as well as clinical studies were presented and discussed. Furthermore, representatives from European clinical proton therapy centres, who were involved in patient treatment, laid out their current…

PURPOSE: The optimal treatment strategy for low-grade glioma (LGG) is still a matter of controversy. Considering that the prognosis is typically favorable, the prevention of late sequelae is of particular importance. Proton beam therapy (PRT) has the potential to further reduce the burden of treatment related side effects. We set out to evaluate the clinical outcome of proton irradiation with a particular focus on morphologic features on magnetic resonance imaging (MRI). METHODS: We assessed prospectively 110 patients who received radiotherapy with protons for histologically proven LGG. Clinical and radiological information were analyzed resulting in more than 1200 available MRI examinations with a median follow-up of 39 months. Newly diagnosed contrast-enhancing lesions on MRI were delineated and correlated with parameters of the corresponding treatment plan. A voxel-based dose-matched paired analysis of the linear energy transfer (LET) inside vs outside lesions was performed. RESULTS: Proton beam irradiation of patients with low-grade glioma results in overall survival (OS) of 90%…

Patients with locally advanced cervical cancer (LACC) treated with chemoradiation often experience hematologic toxicity (HT), as chemoradiation can induce bone marrow (BM) suppression. Studies on the relationship between BM dosimetric parameters and clinically significant HT might provide relevant indices for developing BM sparing (BMS) radiotherapy techniques. This systematic review studied the relationship between BM dose and HT in patients with LACC treated with primary cisplatin-based chemoradiation. A systematic search was conducted in Embase, Medline, and Web of Science. Eligibility criteria were treatment of LACC-patients with cisplatin-based chemoradiation and report of HT or complete blood cell count (CBC). The search identified 1346 papers, which were screened on title and abstract before two reviewers independently evaluated the full-text. 17 articles were included and scored according to a selection of the TRIPOD criteria. The mean TRIPOD score was 12.1 out of 29. Fourteen studies defining BM as the whole pelvic bone contour (PB) detected significant associations with…

Purpose The aim of this study is to establish the relative impact of physician-rated toxicities and patient-rated symptoms in head and neck cancer (HNC) on quality of life (QOL) and to weigh the various toxicities and symptoms during treatment plan optimization and selection. Materials and methods This prospective cohort study comprised 1083 HNC patients (development: 750, validation: 333) treated with definitive radiotherapy with or without chemotherapy. Clinical factors were scored at baseline. Physician-rated and patient-rated outcome measures and QOL (EORTC QLQ-HN35 and QLQ-C30) were prospectively scored at baseline and 6, 12, 18 and 24 months after radiotherapy. The impact of 20 common toxicities and symptoms (related to swallowing, salivary function, speech, pain and general complaints) on QOL (0–100 scale) was established for each time point by combining principal component analysis and multivariable linear regression. Results Radiation-induced toxicities and symptoms resulted in a significant decline in QOL of patients with 12.4 ± 12.8 points at 6 months to 16.6 ± 17.1…

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…

PURPOSE OR OBJECTIVES: The FLAME trial (NCT01168479) showed that by adding a focal boost to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical disease-free survival increased, without significantly increasing toxicity. The aim of the present study was to investigate the association between radiation dose to the bladder and urethra and genitourinary (GU) toxicity grade ≥2 in the entire cohort. MATERIAL AND METHODS: The dose-effect relations of the urethra and bladder dose, separately, and GU toxicity grade ≥2 (CTCAE 3.0) up to five years after treatment were assessed. A mixed model analysis for repeated measurements was used, adjusting for age, diabetes mellitus, T-stage, baseline GU toxicity grade ≥1 and institute. Additionally, the association between the dose and separate GU toxicity subdomains were investigated. RESULTS: , with adjusted odds ratios of 1.14 (95% CI 1.12-1.16, p < 0.0001) and 1.12 (95% CI 1.11-1.14, p < 0.0001), respectively. Additionally, associations between the dose to the urethra and bladder and the…

BACKGROUND AND PURPOSE: The purpose of this study was to investigate the effectiveness of photobiomodulation therapy (PBMT) for the prevention of acute radiation dermatitis (ARD) in head and neck cancer (HNC) patients. MATERIALS AND METHODS: A randomised, placebo-controlled trial (RCT) with 46 HNC patients who underwent radiotherapy (RT) with or without concomitant chemotherapy was set up (DERMISHEAD trial). Patients were randomised to receive PBM or placebo treatments from the first day of RT (2×/week) alongside the institutional skincare. The severity of skin reactions was assessed by the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.03 (NCI-CTCAE v4.03) and the Radiotherapy-Induced Skin Reaction Assessment Scale (RISRAS). Quality of life (QoL) was evaluated using the Skindex-16 questionnaire. RESULTS: PBMT significantly reduced NCI-CTCAE grade 2-3 ARD with 49% at the end of RT. CONCLUSION: The results of the first RCT in HNC patients showed that PBMT is an effective method to prevent the development of severe ARD. These results support the…

Purpose Analyze the pattern of disease failure after anti-CD19-directed chimeric antigen receptor T-cell therapy (CART) for non-Hodgkin lymphoma, assess the local control rate of bridging radiotherapy (bRT) and characterize in-field recurrences. Methods We retrospectively reviewed 120 patients with NHL who received CART between 2018 and 2020. Baseline characteristics and treatment outcomes were compared between patients who received bRT and those who did not (noRT). Results Of the 118 patients included, 14 (12%) received bRT, while 104 (88%) did not. bRT group had more localized and extranodal disease. bRT was delivered with a median dose of 20 Gy (range: 15–36) in 5 fractions (range: 3–24). Pattern of failure analysis revealed that progression involving pre-existing sites was the predominant pattern of failure in both the bRT and noRT groups (86% and 88%, respectively). Median duration of response was 128 days (range: 25–547) for bRT group and 93 days (range: 22–965) for noRT group ( p = 0.78). In the bRT group, only 2/15 sites irradiated had infield recurrence and where…

Background and purpose To compare 68 Ga-fibroblast activation protein inhibitor (FAPI) and 18 F-FDG PET/CT in imaging locally advanced oesophageal cancer, and evaluate the potential usefulness of 68 Ga-FAPI PET/CT on gross target volume (GTV) delineation aimed at radiotherapy planning for oesophageal cancer as compared with contrast-enhanced CT (CE-CT) and 18 F-FDG PET/CT. Materials and methods Twenty-one patients with newly diagnosed oesophageal cancer who underwent both 18 F-FDG and 68 Ga-FAPI PET/CT scans were selected. GTVs of the primary tumours based on CE-CT (GTV CT ), PET/CT, and CE-CT plus PET/CT were delineated. Gross tumour lengths were measured by GTVs and endoscopy and recorded. Results The 68 Ga-FAPI PET showed significantly higher radiotracer uptake than 18 F-FDG PET (median SUVmax 16.71 vs. 11.23; P = 0.002) in the primary tumours. SUV thresholds of FAPI ×20%, 30%, 40%, and FDG ×40% showed similar lesion lengths compared with that in endoscopic examination ( P > 0.05). GTV CT demonstrated the largest volume (median: 48.80 mm 3 , range: 14.83–162.23 mm 3 ) than…

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…

PURPOSE: Osteoradionecrosis (ORN) of the mandible is a serious complication of head and neck radiotherapy. This study aims to investigate the effect of hyperbaric oxygen (HBO) treatment on ORN in two randomized, controlled multicentre trials. METHODS AND MATERIALS: Patients with ORN with indication for surgical treatment were randomised to either group 1: surgical removal of necrotic mandibular bone supplemented by 30 pre- and 10 postoperative HBO exposures at 243 kPa for 90 min each, or group 2: surgical removal of necrotic bone only. Primary outcome was healing of ORN one year after surgery evaluated by a clinically adjusted version of the Common Toxicity Criteria of Adverse Events (CTCAE) v 3.0. Secondary outcomes included xerostomia, unstimulated and stimulated whole salivation rates, trismus, dysphagia, pain, Activities of Daily Living (ADL) and quality of life according to EORTC. Data were combined from two separate trials. Ninety-seven were enrolled and 65 were eligible for the intent-to-treat analysis. The 33% drop-out was equally distributed between groups. RESULTS: In…

BACKGROUND: Inevitably, the emergence of COVID-19 has impacted non-COVID care. Because timely diagnosis and treatment are essential, especially for patients with head and neck cancer (HNC) with fast-growing tumours in a functionally and aesthetically important area, we wished to quantify the impact of the COVID-19 pandemic on HNC care in the Netherlands. MATERIAL AND METHODS: This population-based study covered all, in total 8468, newly diagnosed primary HNC cases in the Netherlands in 2018, 2019 and 2020. We compared incidence, patient and tumour characteristics, primary treatment characteristics, and time-to-treatment in the first COVID-19 year 2020 with corresponding periods in 2018 and 2019 (i.e. pre-COVID). RESULTS: The incidence of HNC was nearly 25% less during the first wave (n = 433) than in 2019 (n = 595) and 2018 (n = 598). In April and May 2020, the incidence of oral cavity and laryngeal carcinomas was significantly lower than in pre-COVID years. There were no shifts in tumour stage or alterations in initial treatment modalities. Regardless of the first treatment…