Differences in the association of time to treatment initiation and survival according to various head and neck cancer sites in a nationwide cohort.

OBJECTIVES: To assess whether there are differences in the effects of time to treatment interval (TTI) on patient survival for head and neck cancer (HNC) sites in order to provide evidence that can support decision-making regarding prioritizing treatment. MATERIALS AND METHODS: Patients in the Netherlands with a first primary HNC without distant metastasis between 2010 and 2014 were included for analysis (N = 10,486). TTI was defined as the time from pathologic diagnosis to the start of initial treatment. Overall survival (OS), cox regression analyses and cubic spline hazard models were calculated and visualized. RESULTS: Overall, the hazard of dying was higher (HR = 1.003; 95 % CI 1.001-1.005) with each additional day until treatment initiation. The pattern, as visualized in cubic spline graphs, differed by site the hazard increased more steeply with increasing TTI for oral cavity cancer. For oropharyngeal and laryngeal cancer, a slight increase commenced after a longer TTI than for oral cavity cancer, while there was hardly an increase in hazard with increasing TTI for hypopharyngeal cancer. CONCLUSION: The relationship between longer TTI and decreased survival was confirmed, but slight variations in the pattern of the hazard of dying by TTI by tumour site were observed. These findings could support decisions on prioritizing treatment. However, other aspects such as extent of treatment and quality of life should be investigated further so this can also be included.

Predicting stereotactic radiosurgery outcomes with multi-observer qualitative appearance labelling versus MRI radiomics.

Qualitative observer-based and quantitative radiomics-based analyses of T1w contrast-enhanced magnetic resonance imaging (T1w-CE MRI) have both been shown to predict the outcomes of brain metastasis (BM) stereotactic radiosurgery (SRS). Comparison of these methods and interpretation of radiomics-based machine learning (ML) models remains limited. To address this need, we collected a dataset of n = 123 BMs from 99 patients including 12 clinical features, 107 pre-treatment T1w-CE MRI radiomic features, and BM post-SRS progression scores. A previously published outcome model using SRS dose prescription and five-way BM qualitative appearance scoring was evaluated. We found high qualitative scoring interobserver variability across five observers that negatively impacted the model's risk stratification. Radiomics-based ML models trained to replicate the qualitative scoring did so with high accuracy (bootstrap-corrected AUC = 0.84-0.94), but risk stratification using these replicated qualitative scores remained poor. Radiomics-based ML models trained to directly predict post-SRS progression offered enhanced risk stratification (Kaplan-Meier rank-sum p = 0.0003) compared to using qualitative appearance. The qualitative appearance scoring enabled interpretation of the progression radiomics-based ML model, with necrotic BMs and a subset of heterogeneous BMs predicted as being at high-risk of post-SRS progression, in agreement with current radiobiological understanding. Our study's results show that while radiomics-based SRS outcome models out-perform qualitative appearance analysis, qualitative appearance still provides critical insight into ML model operation.

Dual-center validation of using magnetic resonance imaging radiomics to predict stereotactic radiosurgery outcomes.

Background: MRI radiomic features and machine learning have been used to predict brain metastasis (BM) stereotactic radiosurgery (SRS) outcomes. Previous studies used only single-center datasets, representing a significant barrier to clinical translation and further research. This study, therefore, presents the first dual-center validation of these techniques. Methods: SRS datasets were acquired from 2 centers (n = 123 BMs and n = 117 BMs). Each dataset contained 8 clinical features, 107 pretreatment T1w contrast-enhanced MRI radiomic features, and post-SRS BM progression endpoints determined from follow-up MRI. Random decision forest models were used with clinical and/or radiomic features to predict progression. 250 bootstrap repetitions were used for single-center experiments. Results: Training a model with one center's dataset and testing it with the other center's dataset required using a set of features important for outcome prediction at both centers, and achieved area under the receiver operating characteristic curve (AUC) values up to 0.70. A model training methodology developed using the first center's dataset was locked and externally validated with the second center's dataset, achieving a bootstrap-corrected AUC of 0.80. Lastly, models trained on pooled data from both centers offered balanced accuracy across centers with an overall bootstrap-corrected AUC of 0.78. Conclusions: Using the presented validated methodology, radiomic models trained at a single center can be used externally, though they must utilize features important across all centers. These models' accuracies are inferior to those of models trained using each individual center's data. Pooling data across centers shows accurate and balanced performance, though further validation is required.

HYpofractionated, dose-redistributed RAdiotherapy with protons and photons to combat radiation-induced immunosuppression in head and neck squamous cell carcinoma: study protocol of the phase I HYDRA trial.

BACKGROUND: Radiotherapy (RT) is the standard of care for most advanced head and neck squamous cell carcinoma (HNSCC) and results in an unfavorable 5-year overall survival of 40%. Despite strong biological rationale, combining RT with immune checkpoint inhibitors does not result in a survival benefit. Our hypothesis is that the combination of these individually effective treatments fails because of radiation-induced immunosuppression and lymphodepletion. By integrating modern radiobiology and innovative radiotherapy concepts, the patient's immune system could be maximally retained by (1) increasing the dose per fraction so that the total dose and number of fractions can be reduced (HYpofractionation), (2) redistributing the radiation dose towards a higher peak dose within the tumor center and a lowered elective lymphatic field dose (Dose-redistribution), and (3) using RAdiotherapy with protons instead of photons (HYDRA). METHODS: The primary aim of this multicenter study is to determine the safety of HYDRA proton- and photon radiotherapy by conducting two parallel phase I trials. Both HYDRA arms are randomized with the standard of care for longitudinal immune profiling. There will be a specific focus on actionable immune targets and their temporal patterns that can be tested in future hypofractionated immunoradiotherapy trials. The HYDRA dose prescriptions (in 20 fractions) are 40 Gy elective dose and 55 Gy simultaneous integrated boost on the clinical target volume with a 59 Gy focal boost on the tumor center. A total of 100 patients (25 per treatment group) will be recruited, and the final analysis will be performed one year after the last patient has been included. DISCUSSION: In the context of HNSCC, hypofractionation has historically only been reserved for small tumors out of fear for late normal tissue toxicity. To date, hypofractionated radiotherapy may also be safe for larger tumors, as both the radiation dose and volume can be reduced by the combination of advanced imaging for better target definition, novel accelerated repopulation models and high-precision radiation treatment planning and dose delivery. HYDRA's expected immune-sparing effect may lead to improved outcomes by allowing for future effective combination treatment with immunotherapy. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov; NCT05364411 (registered on May 6th, 2022).

Early and late contrast enhancing lesions after photon radiotherapy for IDH mutated grade 2 diffuse glioma.

OBJECTIVE: The interpretation of new enhancing lesions after radiotherapy for diffuse glioma remains a clinical challenge. We sought to characterize and classify new contrast enhancing lesions in a historical multicenter cohort of patients with IDH mutated grade 2 diffuse glioma treated with photon therapy. METHODS: We reviewed all follow-up MRI's of all patients treated with radiotherapy for histologically confirmed, IDH mutated diffuse grade 2 glioma between 1-1-2007 and 31-12-2018 in two tertiary referral centers. Disease progression (PD) was defined in accordance with the RANO criteria for progressive disease in low grade glioma. Pseudoprogression (psPD) was defined as any transient contrast-enhancing lesion between the end of radiotherapy and PD, or any new contrast-enhancing lesion that remained stable over a period of 12 months in patients who did not exhibit PD. RESULTS: A total of 860 MRI's of 106 patients were reviewed. psPD was identified in 24 patients (23%) on 76 MRI's. The cumulative incidence of psPD was 13% at 1 year, 22% at 5 years, and 28% at 10 years. The mean of the observed maximal volume of psPD was 2.4 cc. The median Dmin in psPD lesions was 50.1 Gy. The presence of an 1p/19q codeletion was associated with an increased risk of psPD (subhazard ratio 2.34, p = 0.048). psPD was asymptomatic in 83% of patients. CONCLUSION: The cumulative incidence of psPD in grade 2 diffuse glioma increases over time. Consensus regarding event definition and statistical analysis is needed for comparisons between series investigating psPD.

Performance sensitivity analysis of brain metastasis stereotactic radiosurgery outcome prediction using MRI radiomics.

Recent studies have used T1w contrast-enhanced (T1w-CE) magnetic resonance imaging (MRI) radiomic features and machine learning to predict post-stereotactic radiosurgery (SRS) brain metastasis (BM) progression, but have not examined the effects of combining clinical and radiomic features, BM primary cancer, BM volume effects, and using multiple scanner models. To investigate these effects, a dataset of n = 123 BMs from 99 SRS patients with 12 clinical features, 107 pre-treatment T1w-CE radiomic features, and BM progression determined by follow-up MRI was used with a random decision forest model and 250 bootstrapped repetitions. Repeat experiments assessed the relative accuracy across primary cancer sites, BM volume groups, and scanner model pairings. Correction for accuracy imbalances across volume groups was investigated by removing volume-correlated features. We found that using clinical and radiomic features together produced the most accurate model with a bootstrap-corrected area under the receiver operating characteristic curve of 0.77. Accuracy also varied by primary cancer site, BM volume, and scanner model pairings. The effect of BM volume was eliminated by removing features at a volume-correlation coefficient threshold of 0.25. These results show that feature type, primary cancer, volume, and scanner model are all critical factors in the accuracy of radiomics-based prognostic models for BM SRS that must be characterised and controlled for before clinical translation.

Development and evaluation of an automated EPTN-consensus based organ at risk atlas in the brain on MRI.

BACKGROUND AND PURPOSE: During radiotherapy treatment planning, avoidance of organs at risk (OARs) is important. An international consensus-based delineation guideline was recently published with 34 OARs in the brain. We developed an MR-based OAR autosegmentation atlas and evaluated its performance compared to manual delineation. MATERIALS AND METHODS: Anonymized cerebral T1-weighted MR scans (voxel size 0.9 × 0.9 × 0.9 mm3) were available. OARs were manually delineated according to international consensus. Fifty MR scans were used to develop the autosegmentation atlas in a commercially available treatment planning system (Raystation®). The performance of this atlas was tested on another 40 MR scans by automatically delineating 34 OARs, as defined by the 2018 EPTN consensus. Spatial overlap between manual and automated delineations was determined by calculating the Dice similarity coefficient (DSC). Two radiation oncologists determined the quality of each automatically delineated OAR. The time needed to delineate all OARs manually or to adjust automatically delineated OARs was determined. RESULTS: DSC was ≥ 0.75 in 31 (91 %) out of 34 automated OAR delineations. Delineations were rated by radiation oncologists as excellent or good in 29 (85 %) out 34 OAR delineations, while 4 were rated fair (12 %) and 1 was rated poor (3 %). Interobserver agreement between the radiation oncologists ranged from 77-100 % per OAR. The time to manually delineate all OARs was 88.5 minutes, while the time needed to adjust automatically delineated OARs was 15.8 minutes. CONCLUSION: Autosegmentation of OARs enables high-quality contouring within a limited time. Accurate OAR delineation helps to define OAR constraints to mitigate serious complications and helps with the development of NTCP models.

Pre-treatment visualization of predicted radiation-induced acute alopecia in brain tumour patients.

BACKGROUND AND PURPOSE: Temporary alopecia is a common side-effect in brain tumour patients receiving cranial radiotherapy with a significant psychological burden for the affected patient. The purpose of this study was to generate a method in our treatment planning system (TPS) to visualize the expected radiation-induced alopecia 4 weeks after treatment, in order to inform the patients thereupon before the start of radiotherapy. MATERIAL AND METHODS: A pilot study was conducted in ten patients receiving hypo- (HF) or conventionally fractionated (CF) photon beam Volumetric Modulated Arc Therapy (VMAT) for an intracranial lesion. Dose calculations were correlated to visible alopecia four weeks after the end of treatment to create a structure predictive of alopecia in our TPS. These alopecia structures for both fractionation schedules were validated in two cohorts of 69 HF and 78 CF patients undergoing radiotherapy between 2016 and 2019. RESULTS: In the pilot cohort, a total physical dose of 4 Gy for HF and 12.6 Gy for CF radiotherapy were found to be predictive of alopecia 4 weeks after treatment. Applying these doses to our validation cohort, we found an accurate prediction of alopecia in 59/69 (86%) HF and 73/78 (96%) CF patients. For the total patient group of 147 patients, the predicted amount of alopecia was accurate in 90% of the cases. All inaccurate predictions overestimated the expected extent of alopecia. CONCLUSION: The presented straightforward method to visualize predicted alopecia 4 weeks after treatment has proven to predict the extent alopecia highly accurate in the vast majority of patients. Sharing these results with the patients pre-treatment may result in stress reduction before cranial irradiation.

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.

Quality of life among patients with 4 to 10 brain metastases after treatment with whole-brain radiotherapy vs. stereotactic radiotherapy: a phase III, randomized, Dutch multicenter trial.

BACKGROUND: Stereotactic radiotherapy (SRT) is an attractive treatment option for patients with brain metastases (BM), sparing healthy brain tissue and likely controlling local tumors. Most previous studies have focused on radiological response or survival. Our randomized trial (NCT02353000) investigated whether quality of life (QoL) is better preserved using SRT than whole-brain radiotherapy (WBRT) for patients with multiple BM. Recently, we published our trial's primary endpoints. The current report discusses the study's secondary endpoints. METHODS: Patients with 4 to 10 BM were randomly assigned to a standard-arm WBRT (20 Gy in 5 fractions) or SRT group (1 fraction of 15-24 Gy or 3 fractions of 8 Gy). QoL endpoints-such as EQ5D domains post-treatment, the Barthel index, the European Organisation for Research and Treatment of Cancer (EORTC) questionnaires, and the neurocognitive Hopkins Verbal Learning Test-were evaluated. RESULTS: Due to poor accrual resulting from patients' and referrers' preference for SRT, this study closed prematurely. The other endpoints' results were published recently. Twenty patients were available for analysis (n=10 vs. n=10 for the two groups, respectively). Significant differences were observed 3 months post-treatment for the mobility (P=0.041), self-care (P=0.028), and alopecia (P=0.014) EQ5D domains, favoring SRT. This self-care score also persisted compared to the baseline (P=0.025). Multiple EORTC categories reflected significant differences, favoring SRT-particularly physical functioning and social functioning. CONCLUSIONS: For patients with multiple BM, SRT alone led to persistently higher QoL than treatment with WBRT. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02353000.

Quality of Automated Stereotactic Radiosurgery Plans in Patients with 4 to 10 Brain Metastases.

The purpose was to compare linac-based stereotactic radiosurgery and hypofractionated radiotherapy plan quality of automated planning, intensity modulated radiotherapy (IMRT) and manual dynamic conformal arc (DCA) plans as well as single- and multiple-isocenter techniques for multiple brain metastases (BM). For twelve patients with four to ten BM, seven non-coplanar linac-based plans were created: a manually planned DCA plan with a separate isocenter for each metastasis, a single-isocenter dynamic IMRT plan, an automatically generated single-isocenter volumetric modulated arc radiotherapy (VMAT) plan, four automatically generated single-isocenter DCA plans with three or five couch angles, with high or low sparing of normal tissue. Paddick conformity index, gradient index (GI), mean dose, total V12Gy and V5Gy of uninvolved brain, number of monitor units (MUs), irradiation time and pass rate were compared. The GI was significantly higher for VMAT than for separate-isocenter, IMRT, and all automatically generated plans. The number of MUs was lowest for VMAT, followed by automatically generated DCA and IMRT plans and highest for manual DCA plans. Irradiation time was the shortest for automatically planned DCA plans. Automatically generated linac-based single-isocenter plans for multiple BM reduce the number of MUs and irradiation time with at least comparable GI and V5Gy relative to the reference separate-isocenter DCA plans.

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.

Model based patient pre-selection for intensity-modulated proton therapy (IMPT) using automated treatment planning and machine learning.

BACKGROUND AND PURPOSE: Patient selection for intensity modulated proton therapy (IMPT), using comparative photon therapy planning, is workload-intensive and time-consuming. Pre-selection aims at avoidance of manual IMPT planning for patients that are in the end ineligible. We investigated the use of machine learning together with automated IMPT treatment planning for pre-selection of head and neck cancer patients, and validated the methodology for the Dutch model based selection (MBS) approach. MATERIALS & METHODS: For forty-five head and neck patients with a previous MBS, an IMPT plan was generated with non-clinical, fully-automated planning. Dosimetric differences of these plans with the corresponding previously generated photon plans, and the outcomes of the former MBS, were used to train a Gaussian naïve Bayes classifier for MBS outcome prediction. During training, strong emphasis was placed on avoiding misclassification of IMPT eligible patients (i.e. false negatives). RESULTS: Pre-selection with the classifier resulted in 0 false negatives, 12 (27%) true negatives, 27 (60%) true positives, and only 6 (13%) false positive predictions. Using this pre-selection, the number of formal selection procedures with involved manual IMPT planning that resulted in a negative outcome could be reduced by 67%. CONCLUSION: With pre-selection, using machine learning and automated treatment planning, the percentage of patients with unnecessary manual IMPT planning for MBS could be drastically reduced, thereby saving costs, labor and time. With the developed approach, larger patient populations can be screened, and likely bias in pre-selection of patients can be mitigated by assisting the physician during patient pre-selection.

A Dutch phase III randomized multicenter trial: whole brain radiotherapy versus stereotactic radiotherapy for 4-10 brain metastases.

BACKGROUND: The clinical value of whole brain radiotherapy (WBRT) for brain metastases (BM) is a matter of debate due to the significant side effects involved. Stereotactic radiosurgery (SRS) is an attractive alternative treatment option that may avoid these side effects and improve local tumor control. We initiated a randomized trial (NCT02353000) to investigate whether quality of life is better preserved after SRS compared with WBRT in patients with multiple brain metastases. METHODS: Patients with 4-10 BM were randomized between the standard arm WBRT (total dose 20 Gy in 5 fractions) or SRS (single fraction or 3 fractions). The primary endpoint was the difference in quality of life (QOL) at 3 months post-treatment. RESULTS: The study was prematurely closed due to poor accrual. A total of 29 patients (13%) were randomized, of which 15 patients have been treated with SRS and 14 patients with WBRT. The median number of lesions were 6 (range: 4-9) and the median total treatment volume was 13.0 cc3 (range: 1.8-25.9 cc3). QOL at 3 months decreased in the SRS group by 0.1 (SD = 0.2), compared to 0.2 (SD = 0.2) in the WBRT group (P = .23). The actuarial 1-year survival rates were 57% (SRS) and 31% (WBRT) (P = .52). The actuarial 1-year brain salvage-free survival rates were 50% (SRS) and 78% (WBRT) (P = .22). CONCLUSION: In patients with 4-10 BM, SRS alone resulted in 1-year survival for 57% of patients while maintaining quality of life. Due to the premature closure of the trial, no statistically significant differences could be determined.

Toxicity of L19-Interleukin 2 Combined with Stereotactic Body Radiation Therapy: A Phase 1 Study.

PURPOSE: The immunocytokine L19-IL2 delivers interleukin-2 to the tumor by exploiting the selective L19-dependent binding of extradomain B of fibronectin on tumor blood vessels. In preclinical models, L19-IL2 has been shown to enhance the local and abscopal effects of radiation therapy. The clinical safety of L19-IL2 monotherapy has been established previously. In this study, the safety and tolerability of L19-IL2 after stereotactic body radiation therapy (SBRT) was assessed. METHODS AND MATERIALS: Patients with oligometastatic solid tumors received radical SBRT to all visible metastases. Within 1 week after SBRT, intravenous L19-IL2 using a 3 + 3 dose escalation design was administered. Safety and tolerability were analyzed as the primary endpoint using the Common Terminology Criteria for Adverse Events 4.03 scoring system, with progression-free and overall survival as secondary endpoints. RESULTS: A total of 6 patients in 2 L19-IL2 dose levels were included. The 15 million International Units (Mio IU) dose level was well tolerated with no dose-limiting toxicity. The most frequently reported adverse events were chills, noninfectious fever, fatigue, edema, erythema, pruritus, nausea/vomiting, and cough and dyspnea. Blood analysis revealed abnormalities in liver function tests, anemia, hypoalbuminemia, and hypokalemia. At the second dose level (ie, 22.5 Mio IU), which is the recommended dose for L19-IL2 monotherapy, all 3 included patients experienced dose-limiting toxicity but recovered without sequelae. We documented 2 long-term progression-free responders, both having non-small cell lung cancer as primary tumor. CONCLUSIONS: Based on the results of this phase 1 clinical trial, the recommended phase 2 dose for SBRT combined with L19-IL2 is 15 Mio IU. The therapeutic efficacy of this combination is currently being evaluated in the multicentric EU-funded phase 2 clinical trial, ImmunoSABR.

Practical robustness evaluation in radiotherapy - A photon and proton-proof alternative to PTV-based plan evaluation.

BACKGROUND AND PURPOSE: A planning target volume (PTV) in photon treatments aims to ensure that the clinical target volume (CTV) receives adequate dose despite treatment uncertainties. The underlying static dose cloud approximation (the assumption that the dose distribution is invariant to errors) is problematic in intensity modulated proton treatments where range errors should be taken into account as well. The purpose of this work is to introduce a robustness evaluation method that is applicable to photon and proton treatments and is consistent with (historic) PTV-based treatment plan evaluations. MATERIALS AND METHODS: The limitation of the static dose cloud approximation was solved in a multi-scenario simulation by explicitly calculating doses for various treatment scenarios that describe possible errors in the treatment course. Setup errors were the same as the CTV-PTV margin and the underlying theory of 3D probability density distributions was extended to 4D to include range errors, maintaining a 90% confidence level. Scenario dose distributions were reduced to voxel-wise minimum and maximum dose distributions; the first to evaluate CTV coverage and the second for hot spots. Acceptance criteria for CTV D98 and D2 were calibrated against PTV-based criteria from historic photon treatment plans. RESULTS: CTV D98 in worst case scenario dose and voxel-wise minimum dose showed a very strong correlation with scenario average D98 (R2 > 0.99). The voxel-wise minimum dose visualised CTV dose conformity and coverage in 3D in agreement with PTV-based evaluation in photon therapy. Criteria for CTV D98 and D2 of the voxel-wise minimum and maximum dose showed very strong correlations to PTV D98 and D2 (R2 > 0.99) and on average needed corrections of -0.9% and +2.3%, respectively. CONCLUSIONS: A practical approach to robustness evaluation was provided and clinically implemented for PTV-less photon and proton treatment planning, consistent with PTV evaluations but without its static dose cloud approximation.

LINAC based stereotactic radiosurgery for multiple brain metastases: guidance for clinical implementation.

Introduction: Stereotactic radiosurgery (SRS) is a promising treatment option for patients with multiple brain metastases (BM). Recent technical advances have made LINAC based SRS a patient friendly technique, allowing for accurate patient positioning and a short treatment time. Since SRS is increasingly being used for patients with multiple BM, it remains essential that SRS be performed with the highest achievable quality in order to prevent unnecessary complications such as radionecrosis. The purpose of this article is to provide guidance for high-quality LINAC based SRS for patients with BM, with a focus on single isocenter non-coplanar volumetric modulated arc therapy (VMAT). Methods: The article is based on a consensus statement by the study coordinators and medical physicists of four trials which investigated whether patients with multiple BM are better palliated with SRS instead of whole brain radiotherapy (WBRT): A European trial (NCT02353000), two American trials and a Canadian CCTG lead intergroup trial (CE.7). This manuscript summarizes the quality assurance measures concerning imaging, planning and delivery. Results: To optimize the treatment, the interval between the planning-MRI (gadolinium contrast-enhanced, maximum slice thickness of 1.5 mm) and treatment should be kept as short as possible (< two weeks). The BM are contoured based on the planning-MRI, fused with the planning-CT. GTV-PTV margins are minimized or even avoided when possible. To maximize efficiency, the preferable technique is single isocenter (non-)coplanar VMAT, which delivers high doses to the target with maximal sparing of the organs at risk. The use of flattening filter free photon beams ensures a lower peripheral dose and shortens the treatment time. To bench mark SRS treatment plan quality, it is advisable to compare treatment plans between hospitals. Conclusion: This paper provides guidance for quality assurance and optimization of treatment delivery for LINAC-based radiosurgery for patients with multiple BM.

Stereotactic Radiosurgery for Multiple Brain Metastases.

PURPOSE OF REVIEW: To give an overview on the current evidence for stereotactic radiosurgery of brain metastases with a special focus on multiple brain metastases. RECENT FINDINGS: While the use of stereotactic radiosurgery in patients with limited brain metastases has been clearly defined, its role in patients with multiple lesions (> 4) is still a matter of controversy. Whole-brain radiation therapy (WBRT) has been the standard treatment approach for patients with multiple brain lesions and is still the most commonly used treatment approach worldwide. Although distant brain failure is improved by WBRT, the overall survival is not readily impacted. As WBRT is associated with significant neurocognitive decline compared to stereotactic radiosurgery (SRS), SRS has been explored and increasingly utilized for selected patients with multiple brain metastases. Recent clinical data indicated the feasibility of stereotactic radiosurgery to multiple brain metastases with a similar survival in patients with more than 4 brain metastases versus patients with a maximum of 4 brain metastases. Also, neurocognitive function and quality of life was maintained after stereotactic radiosurgery which is essential in a palliative setting. The application of stereotactic radiosurgery with Gamma Knife, Cyberknife, or LINAC-based equipment has emerged as an effective and widely available treatment option for patients with limited brain metastases. Although not formally proven in prospective studies, SRS may also be considered as a safe and effective treatment option in selected patients with multiple brain metastases. Especially in patients with a favorable prognosis, survival over several years is observed also in the setting of multiple BM. For these patients, avoidance of the neurocognitive damage of WBRT is desirable, and SRS is often a more appropriate treatment in the current multimodality treatment of BM in which systemic treatment is often the cornerstone of the treatment. For patients with an intermediate (3-12 months) and poor prognosis (< 3 months), the application of WBRT becomes more and more controversial, because of its acute side effects, such as hair loss and fatigue and, thereby, detrimental effect on quality of life. For these patients, best supportive care, primary systemic treatment, and even SRS may be preferred over WBRT on an individualized patient basis.

The Prevention of Brain Metastases in Non-Small Cell Lung Cancer by Prophylactic Cranial Irradiation.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients frequently develop brain metastases (BM), even though the initial imaging with brain CT or MRI was negative. Stage III patients have the highest risk to develop BM, with an incidence of approximately 30%. BM can lead to neurocognitive disorders, loss of quality of life (QoL), and they are the most important factors influencing patient's overall survival (OS). Although a radical local treatment of BM may be possible with primary radiosurgery or after resection, the prognosis often remains poor. Preventing the development of BM through prophylactic cranial irradiation (PCI) may improve the outcome of these patients. METHODS: Data from published randomized trials comparing PCI with non-PCI were sought using electronic database (PubMed) searching, hand searching, and by contacting experts. Trials were included if they considered a randomized comparison of PCI and non-PCI, enrolled NSCLC patients, excluded patients with recurrent or metastatic disease, and reported results on BM occurrence. Each randomized controlled trial (RCT) was assessed for methodological quality using the Cochrane collaboration's tool for the assessment of risk of bias. Study estimates were pooled using a fixed effects sample-weighted meta-analysis approach to calculate an overall estimate and 95% confidence interval (CI). Results on PCI-related toxicity, QoL, and OS were only reported descriptively. RESULTS: Seven RCTs were included in the meta-analysis. In total, 1,462 patients were analyzed, including 717 patients who received PCI and 745 patients who did not. The risk of developing BM was significantly decreased through PCI (13% reduction, RR 0.33; 95% CI 0.22-0.45). PCI-related toxicity and QoL data were limited. Acute toxicity mostly included fatigue, skin-related toxicity, and nausea or vomiting. Late toxicities such as headache, dyspnea, lethargy, and low grade cognitive impairments were also reported in some of the included RCTs. Results on OS were inconclusive. CONCLUSION: The risk of developing BM was reduced in patients who received PCI compared to patients who did not. To implement PCI as the standard treatment for patients with NSCLC, the impact of PCI-related toxicity on QoL should be further investigated, as well as long-term OS. A future individual patient data meta-analysis could produce definitive answers to this clinical question.

Stereotactic Radiosurgery in the Management of Patients With Brain Metastases of Non-Small Cell Lung Cancer: Indications, Decision Tools and Future Directions.

Brain metastases (BM) frequently occur in non-small cell lung cancer (NSCLC) patients. Most patients with BM have a limited life expectancy, measured in months. Selected patients may experience a very long progression-free survival, for example, patients with a targetable driver mutation. Traditionally, whole-brain radiotherapy (WBRT) has been the cornerstone of the treatment, but its indication is a matter of debate. A randomized trial has shown that for patients with a poor prognosis, WBRT does not add quality of life (QoL) nor survival over the best supportive care. In recent decades, stereotactic radiosurgery (SRS) has become an attractive non-invasive treatment for patients with BM. Only the BM is irradiated to an ablative dose, sparing healthy brain tissue. Intracranial recurrence rates decrease when WBRT is administered following SRS or resection but does not improve overall survival and comes at the expense of neurocognitive function and QoL. The downside of SRS compared with WBRT is a risk of radionecrosis (RN) and a higher risk of developing new BM during follow-up. Currently, SRS is an established treatment for patients with a maximum of four BM. Several promising strategies are currently being investigated to further improve the indication and outcome of SRS for patients with BM: the effectivity and safety of SRS in patients with more than four BM, combining SRS with systemic therapy such as targeted agents or immunotherapy, shared decision-making with SRS as a treatment option, and individualized isotoxic dose prescription to mitigate the risk of RN and further enhance local control probability of SRS. This review discusses the current indications of SRS and future directions of treatment for patients with BM of NSCLC with focus on the value of SRS.