Impact of clinical target volume margin reduction in glioblastoma patients treated with concurrent chemoradiation.

Background: Glioblastoma (GBM) is widely treated using large radiotherapy margins, resulting in substantial irradiation of the surrounding cerebral structures. In this context, the question arises whether these margins could be safely reduced. In 2018, clinical target volume (CTV) expansion was reduced in our institution from 20 to 15 mm around the gross target volume (GTV) (ie, the contrast-enhancing tumor/cavity). We sought to retrospectively analyze the impact of this reduction. Methods: All adult patients with GBM treated between January 2015 and December 2020 with concurrent chemoradiation (60Gy/2Gy or 59.4Gy/1.8Gy) were analyzed. Patients treated using a 20 (CTV20, n = 57) or 15 mm (CTV15, n = 56) CTV margin were compared for target volumes, dose parameters to the surrounding organs, pattern of recurrence, and survival outcome. Results: Mean GTV was similar in both groups (ie, CTV20: 39.7cm3; CTV15: 37.8cm3; P = .71). Mean CTV and PTV were reduced from 238.9cm3 to 176.7cm3 (P = .001) and from 292.6cm3 to 217.0cm3 (P < .001), for CTV20 and CTV15, respectively. As a result, average brain mean dose (Dmean) was reduced from 25.2Gy to 21.0Gy (P = .002). Significantly lower values were also observed for left hippocampus Dmean, brainstem D0.03cc, cochleas Dmean, and pituitary Dmean. Pattern of recurrence was similar, as well as patient outcome, ie, median progression-free survival was 8.0 and 7.0 months (P = .80), and median overall survival was 11.0 and 14.0 months (P = .61) for CTV20 and CTV15, respectively. Conclusions: In GBM patients treated with chemoradiation, reducing the CTV margin from 20 to 15 mm appears to be safe and offers the potential for less treatment toxicity.

SMART Syndrome: Case Report and Review of the Literature.

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare condition characterized by stroke-like deficits, seizures, and headache that can occur years after radiation therapy (RT) to the brain. RT is a cornerstone in the treatment of primary brain tumours and is indicated in more than 90% of patients. It is therefore essential to be aware of this entity to prevent misdiagnosis leading to inappropriate treatment. In this article, typical imaging findings of this condition are presented through a case report and review of the literature.

Regression of a melanoma brain metastasis that had appeared after immune checkpoint inhibitor discontinuation: a hypothesis-generating case.

We present the case of a 50-year-old woman previously treated with nivolumab-ipilimumab combination therapy for a metastatic melanoma. Despite premature discontinuation of these immune checkpoint inhibitors (ICIs) after 2 cycles due to severe immune-related hepatitis, the patient achieved a complete response. Nine months later, brain magnetic resonance imaging (MRI) showed progression of a single cerebral lesion, and the patient was referred for stereotactic radiosurgery. Unexpectedly, the brain MRI acquired one month later as part of radiosurgery planning showed a spontaneous regression of this lesion, allowing for radiosurgery cancellation. Follow-up imaging showed a sustained response, although the patient did not receive any other oncological treatment. We discuss here the potential immune mechanisms involved in this unusual course and the importance of better understanding the behaviour of tumours in the era of ICIs.

Long-term survival in patients with IDH-wildtype glioblastoma: clinical and molecular characteristics.

BACKG ROUND: Glioblastoma is an aggressive tumor that has a dismal prognosis even with multimodal treatment. However, some patients survive longer than expected. The objective of this study was to revisit patients diagnosed with glioblastoma according to the 2021 WHO classification and analyze clinical and molecular characteristics associated with long-term survival (LTS). METHODS: We retrospectively analyzed 120 IDH-wildtype glioblastomas operated on at our institution between 2013 and 2018. We divided them into LTS patients, surviving more than 3 years, and non-LTS patients, and then compared their features. Additionally, we performed DNA methylation-based brain tumor classification in LTS patients. RESULTS: Sixteen patients were long-term survivors. Age < 70 years, MGMT promoter methylation, extent of resection ≥ 95%, and administration of radiochemotherapy were associated with LTS (P = 0.005, P < 0.001, P = 0.048, and P = 0.008, respectively). In addition, when these factors were combined, the probability of LTS was 74% (95% CI: 62--84). The methylome analysis confirmed the diagnosis of glioblastoma in the majority of the tested LTS patients. Regarding subtypes, 29% of cases were mesenchymal (MES), 43% were RTK1, and 29% were RTK2. Interestingly, RTK1 and RTK2 cases tended to have longer overall survival than MES cases (P = 0.057). Moreover, the only tested LTS patient with an unmethylated MGMT promoter had an "adult-type diffuse high-grade glioma, IDH-wildtype, subtype E" rather than a glioblastoma. This tumor was characterized by multinucleated giant cells and a somatic mutation in POLE. CONCLUSIONS: We suggest that glioblastoma patients with a combination of favorable prognostic factors can achieve LTS in 74% of cases. In addition, methylome analysis is important to ascertain the type of glioma in LTS patients, especially when the MGMT promoter is unmethylated.

Linear Energy Transfer and Relative Biological Effectiveness Investigation of Various Structures for a Cohort of Proton Patients With Brain Tumors.

Purpose: The current knowledge on biological effects associated with proton therapy is limited. Therefore, we investigated the distributions of dose, dose-averaged linear energy transfer (LETd), and the product between dose and LETd (DLETd) for a patient cohort treated with proton therapy. Different treatment planning system features and visualization tools were explored. Methods and Materials: For a cohort of 24 patients with brain tumors, the LETd, DLETd, and dose was calculated for a fixed relative biological effectiveness value and 2 variable models: plan-based and phenomenological. Dose threshold levels of 0, 5, and 20 Gy were imposed for LETd visualization. The relationship between physical dose and LETd and the frequency of LETd hotspots were investigated. Results: The phenomenological relative biological effectiveness model presented consistently higher dose values. For lower dose thresholds, the LETd distribution was steered toward higher values related to low treatment doses. Differences up to 26.0% were found according to the threshold. Maximum LETd values were identified in the brain, periventricular space, and ventricles. An inverse relationship between LETd and dose was observed. Frequency information to the domain of dose and LETd allowed for the identification of clusters, which steer the mean LETd values, and the identification of higher, but sparse, LETd values. Conclusions: Identifying, quantifying, and recording LET distributions in a standardized fashion is necessary, because concern exists over a link between toxicity and LET hotspots. Visualizing DLETd or dose × LETd during treatment planning could allow for clinicians to make informed decisions.

Intracranial squamous cell carcinoma of the cerebello-pontine angle mimicking a cystic acoustic schwannoma. A case report with discussion of differential diagnosis and review of literature.

We report a case of a primary intracranial squamous cell carcinoma (SCC) of the cerebello-pontine angle extending through the internal auditory canal, with the unusual presentation of a completely cystic lesion with no diffusion restriction, internal necrotic-hemorrhagic changes and peripheral enhancement, mimicking a cystic acoustic schwannoma. The lack of diffusion restriction and the peripheral enhancement along the lesion, 2 unique findings, supposedly reflected complete cancerization of the epidermoid cyst from which the SCC originated. We discuss the differential diagnosis and review the literature on primary intracranial SCC.

Prediction Models for Radiation-Induced Neurocognitive Decline in Adult Patients With Primary or Secondary Brain Tumors: A Systematic Review.

Purpose: Although an increasing body of literature suggests a relationship between brain irradiation and deterioration of neurocognitive function, it remains as the standard therapeutic and prophylactic modality in patients with brain tumors. This review was aimed to abstract and evaluate the prediction models for radiation-induced neurocognitive decline in patients with primary or secondary brain tumors. Methods: MEDLINE was searched on October 31, 2021 for publications containing relevant truncation and MeSH terms related to "radiotherapy," "brain," "prediction model," and "neurocognitive impairments." Risk of bias was assessed using the Prediction model Risk Of Bias ASsessment Tool. Results: Of 3,580 studies reviewed, 23 prediction models were identified. Age, tumor location, education level, baseline neurocognitive score, and radiation dose to the hippocampus were the most common predictors in the models. The Hopkins verbal learning (n = 7) and the trail making tests (n = 4) were the most frequent outcome assessment tools. All studies used regression (n = 14 linear, n = 8 logistic, and n = 4 Cox) as machine learning method. All models were judged to have a high risk of bias mainly due to issues in the analysis. Conclusion: Existing models have limited quality and are at high risk of bias. Following recommendations are outlined in this review to improve future models: developing cognitive assessment instruments taking into account the peculiar traits of the different brain tumors and radiation modalities; adherence to model development and validation guidelines; careful choice of candidate predictors according to the literature and domain expert consensus; and considering radiation dose to brain substructures as they can provide important information on specific neurocognitive impairments.

Development of explanatory movies for the delineation of new organs at risk in neuro-oncology.

Ten new organs at risk (OARs) were recently introduced in the updated European Particle Therapy Network neurological contouring atlas. Despite the use of the illustrated atlas and descriptive text, interindividual contouring variations may persist. To further facilitate the contouring of these OARs, educational films were developed and published on www.cancerdata.org.

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.

Hypofractionated stereotactic body radiation therapy (SBRT) in pediatric patients: preliminary toxicity results of a national prospective multicenter study.

OBJECTIVES: While hypofractionated stereotactic body radiotherapy (SBRT) has been largely adopted in the adult setting, its use remains limited in pediatric patients. This is due, among other factors, to fear of potential toxicities of hypofractionated regimens at a young age. In this context, we report the preliminary acute (<3 months from SBRT) and middle-term (3-24 months) toxicity results of a national prospective study investigating SBRT in pediatric patients. METHODS: Between 2013 and 2019, 61 patients were included. The first 40 patients (median age: 12 y, range: 3-20) who completed a 2-year-follow-up were included in the present analysis. SBRT was used for treating lung, brain or (para)spinal lesions, either as first irradiation (35%) or in the reirradiation setting (65%). RESULTS: Acute and middle-term grade ≥2 toxicities occurred in 12.5 and 7.5% of the patients, respectively. No grade ≥4 toxicities occurred. Almost all toxicities occurred in the reirradiation setting. CONCLUSION: SBRT showed a favorable safety profile in young patients treated for lung, brain, and (para)spinal lesions. ADVANCES IN KNOWLEDGE: SBRT appeared to be safe in pediatric patients treated for multiple oncology indications. These results support further evaluation of SBRT, which may have a role to play in this patient population in the future.

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.

Non-invasive imaging prediction of tumor hypoxia: A novel developed and externally validated CT and FDG-PET-based radiomic signatures.

BACKGROUND: Tumor hypoxia increases resistance to radiotherapy and systemic therapy. Our aim was to develop and validate a disease-agnostic and disease-specific CT (+FDG-PET) based radiomics hypoxia classification signature. MATERIAL AND METHODS: A total of 808 patients with imaging data were included: N = 100 training/N = 183 external validation cases for a disease-agnostic CT hypoxia classification signature, N = 76 training/N = 39 validation cases for the H&N CT signature and N = 62 training/N = 36 validation cases for the Lung CT signature. The primary gross tumor volumes (GTV) were manually defined by experts on CT. In order to dichotomize between hypoxic/well-oxygenated tumors a threshold of 20% was used for the [18F]-HX4-derived hypoxic fractions (HF). A random forest (RF)-based machine-learning classifier/regressor was trained to classify patients as hypoxia-positive/ negative based on radiomic features. RESULTS: A 11 feature "disease-agnostic CT model" reached AUC's of respectively 0.78 (95% confidence interval [CI], 0.62-0.94), 0.82 (95% CI, 0.67-0.96) and 0.78 (95% CI, 0.67-0.89) in three external validation datasets. A "disease-agnostic FDG-PET model" reached an AUC of 0.73 (0.95% CI, 0.49-0.97) in validation by combining 5 features. The highest "lung-specific CT model" reached an AUC of 0.80 (0.95% CI, 0.65-0.95) in validation with 4 CT features, while the "H&N-specific CT model" reached an AUC of 0.84 (0.95% CI, 0.64-1.00) in validation with 15 CT features. A tumor volume-alone model was unable to significantly classify patients as hypoxia-positive/ negative. A significant survival split (P = 0.037) was found between CT-classified hypoxia strata in an external H&N cohort (n = 517), while 117 significant hypoxia gene-CT signature feature associations were found in an external lung cohort (n = 80). CONCLUSION: The disease-specific radiomics signatures perform better than the disease agnostic ones. By identifying hypoxic patients our signatures have the potential to enrich interventional hypoxia-targeting trials.

Risk of radiation necrosis after hypofractionated stereotactic radiotherapy (HFSRT) for brain metastases: a single center retrospective study.

INTRODUCTION: While hypofractionated stereotactic radiotherapy (HFSRT) is being increasingly used for treating brain metastases, clinical data concerning the incidence and risk factors of its main side-effect, namely radiation necrosis (RN), remain limited. In this context, we assessed risk factors of RN in a single center series of patients with brain metastases treated with three common HFSRT dose regimens: 27 Gy in 3 fractions (27 Gy/3#), 30 Gy in 5 fractions (30 Gy/5#), and 35 Gy in 5 fractions (35 Gy/5#). METHODS: In total, 360 HFSRT treatments in 294 consecutive patients were retrospectively analysed. Univariable analysis (UVA) and multivariable analysis (MVA) were performed to evaluate the relationship between clinical and dosimetric factors and RN risk. RESULTS: The 12-month RN rate was 8.8%. On MVA, risk was higher in lesions receiving 27 Gy/3# (HR 3.07 95%CI [1.13;8.36], p = 0.03) and 35 Gy/5# (HR 4.22 95%CI [1.46,12.21], p < 0.01) than in lesions receiving 30 Gy/5#. Risk was also higher in patients having received immunotherapy within 3 months of HFSRT (HR 2.69 95%CI [1.10;6.56], p = 0.03) compared with those who did not. We found no association between RN risk and other tested factors, in particular prior irradiation, lesion histology, lesion location, lesion volume, or brain dosimetric factors. CONCLUSION: In the present series, HFSRT was associated with limited RN risk. Incidence of RN was higher with dose regimens delivering a higher biologically effective dose, as well as in patients having received immunotherapy within 3 months of HFSRT.

Technical Note: Monte Carlo methods to comprehensively evaluate the robustness of 4D treatments in proton therapy.

INTRODUCTION: Proton therapy is very sensitive to treatment uncertainties. These uncertainties can induce proton range variations and may lead to severe dose distortions. However, most commercial tools only offer a limited integration of these uncertainties during treatment planning. In order to verify the robustness of a treatment plan, this study aims at developing a comprehensive Monte Carlo simulation of the treatment delivery, including the simulation of setup and range errors, variation of the breathing motion, and interplay effect. METHOD: Most clinically relevant uncertainties have been modeled and implemented in the fast Monte Carlo dose engine MCsquare. Especially, variation of the breathing motion is taken into account by deforming the initial Four-dimensional computed tomography (4DCT) series and generating multiple new 4DCT series with scaled motion. Systematic and random errors are randomly sampled, following a Monte Carlo approach, to generate individual erroneous treatment scenarios. The robustness of treatment plans is analyzed and reported with dose-volume histogram (DVH) bands. The statistical uncertainty coming from the Monte Carlo scenario sampling is studied. RESULTS: A validation demonstrated the ability of the motion model to generate new 4DCT series with scaled motion amplitude and improved image quality in comparison to the initial 4DCT. The robustness analysis is applied to a lung tumor treatment. Considering the proposed uncertainty model, the simulation of 300 treatment scenarios was necessary to reach an acceptable level of statistical uncertainty on the DVH band. CONCLUSION: A comprehensive and statistically sound method of treatment plan robustness verification is proposed. The uncertainty model presented in this paper is not specific to protons and can also be applied to photon treatments. Moreover, the generated 4DCT series, with scaled motion, can be imported in commercial TPSs.

Effect of continuous positive airway pressure administration during lung stereotactic ablative radiotherapy: a comparative planning study.

PURPOSE: By increasing lung volume and decreasing respiration-induced tumour motion amplitude, administration of continuous positive airway pressure (CPAP) during stereotactic ablative radiotherapy (SABR) could allow for better sparing of the lungs and heart. In this study, we evaluated the effect of CPAP on lung volume, tumour motion amplitude and baseline shift, as well as the dosimetric impact of the strategy. METHODS: Twenty patients with lung tumours referred for SABR underwent 4D-computed tomography (CT) scans with and without CPAP (CPAP/noCPAP) at two timepoints (T0/T1). First, CPAP and noCPAP scans were compared for lung volume, tumour motion amplitude, and baseline shift. Next, CPAP and noCPAP treatment plans were computed and compared for lung dose parameters (mean lung dose (MLD), lung volume receiving 20 Gy (V20Gy), 13 Gy (V13Gy), and 5 Gy (V5Gy)) and mean heart dose (MHD). RESULTS: On average, CPAP increased lung volume by 8.0% (p < 0.001) and 6.3% (p < 0.001) at T0 and T1, respectively, but did not change tumour motion amplitude or baseline shift. As a result, CPAP administration led to an absolute decrease in MLD, lung V20Gy, V13Gy and V5Gy of 0.1 Gy (p = 0.1), 0.4% (p = 0.03), 0.5% (p = 0.04) and 0.5% (p = 0.2), respectively, while having no significant influence on MHD. CONCLUSIONS: In patients referred for SABR for lung tumours, CPAP increased lung volume without modifying tumour motion or baseline shift. As a result, CPAP allowed for a slight decrease in radiation dose to the lungs, which is unlikely to be clinically significant.

Correlation analysis of [18F]fluorodeoxyglucose and [18F]fluoroazomycin arabinoside uptake distributions in lung tumours during radiation therapy.

BACKGROUND: PET-guided dose painting (DP) aims to target radioresistant tumour regions in order to improve radiotherapy (RT) outcome. Besides the well-known [18F]fluorodeoxyglucose (FDG), the hypoxia positron emission tomography (PET) tracer [18F]fluoroazomycin arabinoside (FAZA) could provide further useful information to guide the radiation dose prescription. In this study, we compare the spatial distributions of FDG and FAZA PET uptakes in lung tumours. MATERIAL AND METHODS: Fourteen patients with unresectable lung cancer underwent FDG and FAZA 4D-PET/CT on consecutive days at three time-points: prior to RT (pre), and during the second (w2), and the third (w3) weeks of RT. All PET/CT were reconstructed in their time-averaged midposition (MidP). The metabolic tumour volume (MTV: FDG standardised uptake value (SUV) > 50% SUVmax), and the hypoxic volume (HV: FAZA SUV > 1.4) were delineated within the gross tumour volume (GTVCT). FDG and FAZA intratumoral PET uptake distributions were subsequently pairwise compared, using both volume-, and voxel-based analyses. RESULTS: Volume-based analysis showed large overlap between MTV and HV: median overlapping fraction was 0.90, 0.94 and 0.94, at the pre, w2 and w3 time-points, respectively. Voxel-wise analysis between FDG and FAZA intratumoral PET uptake distributions showed high correlation: median Spearman's rank correlation coefficient was 0.76, 0.77 and 0.76, at the pre, w2 and w3 time-points, respectively. Interestingly, tumours with high FAZA uptake tended to show more similarity between FDG and FAZA intratumoral uptake distributions than those with low FAZA uptake. CONCLUSIONS: In unresectable lung carcinomas, FDG and FAZA PET uptake distributions displayed unexpectedly strong similarity, despite the distinct pathways targeted by these tracers. Hypoxia PET with FAZA brought very little added value over FDG from the perspective of DP in this population.

Evolution of [18F]fluorodeoxyglucose and [18F]fluoroazomycin arabinoside PET uptake distributions in lung tumours during radiation therapy.

BACKGROUND: Dose painting (DP) aims to improve radiation therapy (RT) outcome by targeting radioresistant tumour regions identified through functional imaging, e.g., positron emission tomography (PET). Importantly, the expected benefit of DP relies on the ability of PET imaging to identify tumour areas which could be consistently targeted throughout the treatment. In this study, we analysed the spatial stability of two potential DP targets in lung cancer patients undergoing RT: the tumour burden surrogate [18F]fluorodeoxyglucose (FDG) and the hypoxia surrogate [18F]fluoroazomycin arabinoside (FAZA). MATERIALS AND METHODS: Thirteen patients with unresectable lung tumours underwent FDG and FAZA 4D-PET/CT before (pre), and during the second (w2) and third (w3) weeks of RT. All PET/CT were reconstructed in their time-averaged midposition (MidP) for further analysis. The metabolic tumour volume (MTV: FDG standardised uptake value (SUV) > 50% SUVmax) and the hypoxic volume (HV: FAZA SUV >1.4) were delineated within the gross tumour volume (GTVCT). The stability of FDG and FAZA PET uptake distributions during RT was subsequently assessed through volume-overlap analysis and voxel-based correlation analysis. RESULTS: The volume-overlap analysis yielded median overlapping fraction (OF) of 0.86 between MTVpre and MTVw2 and 0.82 between MTVpre and MTVw3. In patients with a detectable HV, median OF was 0.82 between HVpre and HVw2 and 0.90 between HVpre and HVw3. The voxel-based correlation analysis yielded median Spearman's correlation coefficient (rS) of 0.87 between FDGpre and FDGw2 and 0.83 between FDGpre and FDGw3. Median rS was 0.78 between FAZApre and FAZAw2 and 0.79 between FAZApre and FAZAw3. CONCLUSIONS: FDG and FAZA PET uptake distributions were spatially stable during the 3 first weeks of RT in patients with unresectable lung cancer, both based on volume- and voxel-based indicators. This might allow for a consistent targeting of high FDG or FAZA PET uptake regions as part of a DP strategy.