Patients' needs in proton therapy: A survey among ten European facilities.

Aims: The number of Proton Therapy (PT) facilities is still limited worldwide, and the access to treatment could be characterized by patients' logistic and economic challenges. Aim of the present survey is to assess the support provided to patients undergoing PT across Europe. Methods: Through a personnel contact, an online questionnaire (62 multiple-choice and open-ended questions) via Microsoft Forms was administered to 10 European PT centers. The questionnaire consisted of 62 questions divided into 6 sections: i) personal data; ii) general information on clinical activity; iii) fractionation, concurrent systemic treatments and technical aspects of PT facility; iv) indication to PT and reimbursement policies; v) economic and/ or logistic support to patients vi) participants agreement on statements related to the possible limitation of access to PT. A qualitative analysis was performed and reported. Results: From March to May 2022 all ten involved centers filled the survey. Nine centers treat from 100 to 500 patients per year. Paediatric patients accounted for 10-30%, 30-50% and 50-70% of the entire cohort for 7, 2 and 1 center, respectively. The most frequent tumours treated in adult population were brain tumours, sarcomas and head and neck carcinomas; in all centers, the mean duration of PT is longer than 3 weeks. In 80% of cases, the treatment reimbursement for PT is supplied by the respective country's Health National System (HNS). HNS also provides economic support to patients in 70% of centers, while logistic and meal support is provided in 20% and 40% of centers, respectively. PT facilities offer economic and/or logistic support in 90% of the cases. Logistic support for parents of pediatric patients is provided by HNS only in one-third of centers. Overall, 70% of respondents agree that geographic challenges could limit a patient's access to proton facilities and 60% believe that additional support should be given to patients referred for PT care. Conclusions: Relevant differences exist among European countries in supporting patients referred to PT in their logistic and economic challenges. Further efforts should be made by HNSs and PT facilities to reduce the risk of inequities in access to cancer care with protons.

Time- and dose-dependent volume decreases in subcortical grey matter structures of glioma patients after radio(chemo)therapy.

Background and purpose: Radiotherapy (RT) is an adjuvant treatment option for glioma patients. Side effects include tissue atrophy, which might be a contributing factor to neurocognitive decline after treatment. The goal of this study was to determine potential atrophy of the hippocampus, amygdala, thalamus, putamen, pallidum and caudate nucleus in glioma patients having undergone magnetic resonance imaging (MRI) before and after RT. Materials and methods: Subcortical volumes were measured using T1-weighted MRI from patients before RT (N = 91) and from longitudinal follow-ups acquired in three-monthly intervals (N = 349). The volumes were normalized to the baseline values, while excluding structures touching the clinical target volume (CTV) or abnormal tissue seen on FLAIR imaging. A multivariate linear effects model was used to determine if time after RT and mean RT dose delivered to the corresponding structures were significant predictors of tissue atrophy. Results: The hippocampus, amygdala, thalamus, putamen, and pallidum showed significant atrophy after RT as function of both time after RT and mean RT dose delivered to the corresponding structure. Only the caudate showed no dose or time dependant atrophy. Conversely, the hippocampus was the structure with the highest atrophy rate of 5.2 % after one year and assuming a mean dose of 30 Gy. Conclusion: The hippocampus showed the highest atrophy rates followed by the thalamus and the amygdala. The subcortical structures here found to decrease in volume indicative of radiosensitivity should be the focus of future studies investigating the relationship between neurocognitive decline and RT.

Overestimation of grey matter atrophy in glioblastoma patients following radio(chemo)therapy.

OBJECTIVE: Brain atrophy has the potential to become a biomarker for severity of radiation-induced side-effects. Particularly brain tumour patients can show great MRI signal changes over time caused by e.g. oedema, tumour progress or necrosis. The goal of this study was to investigate if such changes affect the segmentation accuracy of normal appearing brain and thus influence longitudinal volumetric measurements. MATERIALS AND METHODS: T1-weighted MR images of 52 glioblastoma patients with unilateral tumours acquired before and three months after the end of radio(chemo)therapy were analysed. GM and WM volumes in the contralateral hemisphere were compared between segmenting the whole brain (full) and the contralateral hemisphere only (cl) with SPM and FSL. Relative GM and WM volumes were compared using paired t tests and correlated with the corresponding mean dose in GM and WM, respectively. RESULTS: Mean GM atrophy was significantly higher for full segmentation compared to cl segmentation when using SPM (mean ± std: ΔVGM,full = - 3.1% ± 3.7%, ΔVGM,cl = - 1.6% ± 2.7%; p < 0.001, d = 0.62). GM atrophy was significantly correlated with the mean GM dose with the SPM cl segmentation (r = - 0.4, p = 0.004), FSL full segmentation (r = - 0.4, p = 0.004) and FSL cl segmentation (r = -0.35, p = 0.012) but not with the SPM full segmentation (r = - 0.23, p = 0.1). CONCLUSIONS: For accurate normal tissue volume measurements in brain tumour patients using SPM, abnormal tissue needs to be masked prior to segmentation, however, this is not necessary when using FSL.

Reduced diffusion in white matter after radiotherapy with photons and protons.

BACKGROUND AND PURPOSE: Radio(chemo)therapy is standard in the adjuvant treatment of glioblastoma. Inevitably, brain tissue surrounding the target volume is also irradiated, potentially causing acute and late side-effects. Diffusion imaging has been shown to be a sensitive method to detect early changes in the cerebral white matter (WM) after radiation. The aim of this work was to assess possible changes in the mean diffusivity (MD) of WM after radio(chemo)therapy using Diffusion-weighted imaging (DWI) and to compare these effects between patients treated with proton and photon irradiation. MATERIALS AND METHODS: 70 patients with glioblastoma underwent adjuvant radio(chemo)therapy with protons (n = 20) or photons (n = 50) at the University Hospital Dresden. MRI follow-ups were performed at three-monthly intervals and in this study were evaluated until 33 months after the end of therapy. Relative white matter MD changes between baseline and all follow-up visits were calculated in different dose regions. RESULTS: We observed a significant decrease of MD (p < 0.05) in WM regions receiving more than 20 Gy. MD reduction was progressive with dose and time after radio(chemo)therapy (maximum: -7.9 ± 1.2% after 24 months, ≥50 Gy). In patients treated with photons, significant reductions of MD in the entire WM (p < 0.05) were seen at all time points. Conversely, in proton patients, whole brain MD did not change significantly. CONCLUSIONS: Irradiation leads to measurable MD reduction in white matter, progressing with both increasing dose and time. Treatment with protons reduces this effect most likely due to a lower total dose in the surrounding white matter. Further investigations are needed to assess whether those MD changes correlate with known radiation induced side-effects.

Treatment of brain metastases in small cell lung cancer: Decision-making amongst a multidisciplinary panel of European experts.

BACKGROUND: Brain metastases (BM) are common in patients with small cell lung cancer (SCLC). In recent years, the role of whole brain radiotherapy (WBRT) for brain metastases in lung cancer is being reevaluated, especially in the context of new systemic treatments available for SCLC. With this analysis, we investigate decision-making in SCLC patients with BM among European experts in medical oncology and radiation oncology. METHODS: We analyzed decision-making from 13 medical oncologists (selected by IASLC) and 13 radiation oncologists (selected by ESTRO) specialized in SCLC. Management strategies of individual experts were converted into decision trees and analyzed for consensus. RESULTS AND CONCLUSION: In asymptomatic patients, chemotherapy alone is the most commonly recommended first line treatment. In asymptomatic patients with limited volume of brain metastases, a higher preference for chemotherapy without WBRT among medical oncologists compared to radiation oncologists was observed. For symptomatic patients, WBRT followed by chemotherapy was recommended most commonly. For limited extent of BM in symptomatic patients, some experts chose stereotactic radiotherapy as an alternative to WBRT. Significant variation in clinical decision-making was observed among European SCLC experts for the first line treatment of patients with SCLC and BM.

[Late complications following neo-/adjuvant radiotherapy and surgery for sarcomas of the extremities or pelvis/retroperitoneum : Preventative measures]. / Spätkomplikationen nach neo-/adjuvanter Strahlentherapie und Resektion von Sarkomen der Extremitäten oder des Beckens/Retroperitoneums : Ansätze zur Prävention.

Radiotherapy is one of the pillars in the multimodal therapy of sarcomas of the extremities or pelvis/retroperitoneum. It can be delivered prior to or following surgery. Novel radiation techniques, such as intensity-modulated radiotherapy using high-energy photons or protons, contribute to the reduction of acute and late toxicities. This review article summarizes these concepts.

A Monte Carlo based radiation response modelling framework to assess variability of clinical RBE in proton therapy.

The clinical implementation of a variable relative biological effectiveness (RBE) in proton therapy is currently controversially discussed. Initial clinical evidence indicates a variable proton RBE, which needs to be verified. In this study, a radiation response modelling framework for assessing clinical RBE variability is established. It was applied to four selected glioma patients (grade III) treated with adjuvant radio(chemo)therapy and who developed late morphological image changes on T1-weighted contrast-enhanced (T1w-CE) magnetic resonance (MR) images within approximately two years of recurrence-free follow-up. The image changes were correlated voxelwise with dose and linear energy transfer (LET) values using univariable and multivariable logistic regression analysis. The regression models were evaluated by the area-under-the-curve (AUC) method performing a leave-one-out cross validation. The tolerance dose TD50 at which 50% of patient voxels experienced toxicity was interpolated from the models. A Monte Carlo (MC) model was developed to simulate dose and LET distributions, which includes variance reduction (VR) techniques to decrease computation time. Its reliability and accuracy were evaluated based on dose calculations of the clinical treatment planning system (TPS) as well as absolute dose measurements performed in the patient specific quality assurance. Morphological image changes were related to a combination of dose and LET. The multivariable models revealed cross-validated AUC values of up to 0.88. The interpolated TD50 curves decreased with increasing LET indicating an increase in biological effectiveness. The MC model reliably predicted average TPS dose within the clinical target volume as well as absolute water phantom dose measurements within 2% accuracy using dedicated VR settings. The observed correlation of dose and LET with late brain tissue damage suggests considering RBE variability for predicting chronic radiation-induced brain toxicities. The MC model simulates radiation fields in patients precisely and time-efficiently. Hence, this study encourages and enables in-depth patient evaluation to assess the variability of clinical proton RBE.

Reduced diffusion in normal appearing white matter of glioma patients following radio(chemo)therapy.

BACKGROUND AND PURPOSE: Standard treatment of high grade gliomas includes gross tumour resection followed by radio(chemo)therapy. Radiotherapy inevitably leads to irradiation of normal brain tissue. The goal of this prospective, longitudinal study was to use MRI to quantify normal appearing white and grey matter changes following radiation treatment as a function of dose and time after radiotherapy. MATERIALS AND METHODS: Pre-radiotherapy (proton or photon therapy) MRI and follow-up MRIs collected in 3 monthly intervals thereafter were analysed for 22 glioma patients and included diffusion tensor imaging, quantitative T1, T2* and proton density mapping. Abnormal tissue was excluded from analysis. MR signal changes were quantified within different dose bin regions for grey and white matter and subsequently for whole brain white matter. RESULTS: We found significant reductions in mean diffusivity, radial diffusivity, axial diffusivity and T2* in normal appearing white matter regions receiving a radiation dose as low as 10-20 Gy within the observational period of up to 18 months. The magnitude of these changes increased with the received radiation dose and progressed with time after radiotherapy. Whole brain white matter also showed a significant reduction in radial diffusivity as a function of radiation dose and time after radiotherapy. No significant changes were observed in grey matter. CONCLUSION: Diffusion tensor imaging and T2* imaging revealed normal appearing white matter changes following radiation treatment. The changes were dose dependant and progressed over time. Further work is needed to understand the underlying tissue changes and to correlate the observed diffusion changes with late brain malfunctions.

Combined PET/MRI: Global Warming-Summary Report of the 6th International Workshop on PET/MRI, March 27-29, 2017, Tübingen, Germany.

The 6th annual meeting to address key issues in positron emission tomography (PET)/magnetic resonance imaging (MRI) was held again in Tübingen, Germany, from March 27 to 29, 2017. Over three days of invited plenary lectures, round table discussions and dialogue board deliberations, participants critically assessed the current state of PET/MRI, both clinically and as a research tool, and attempted to chart future directions. The meeting addressed the use of PET/MRI and workflows in oncology, neurosciences, infection, inflammation and chronic pain syndromes, as well as deeper discussions about how best to characterise the tumour microenvironment, optimise the complementary information available from PET and MRI, and how advanced data mining and bioinformatics, as well as information from liquid biomarkers (circulating tumour cells and nucleic acids) and pathology, can be integrated to give a more complete characterisation of disease phenotype. Some issues that have dominated previous meetings, such as the accuracy of MR-based attenuation correction (AC) of the PET scan, were finally put to rest as having been adequately addressed for the majority of clinical situations. Likewise, the ability to standardise PET systems for use in multicentre trials was confirmed, thus removing a perceived barrier to larger clinical imaging trials. The meeting openly questioned whether PET/MRI should, in all cases, be used as a whole-body imaging modality or whether in many circumstances it would best be employed to give an in-depth study of previously identified disease in a single organ or region. The meeting concluded that there is still much work to be done in the integration of data from different fields and in developing a common language for all stakeholders involved. In addition, the participants advocated joint training and education for individuals who engage in routine PET/MRI. It was agreed that PET/MRI can enhance our understanding of normal and disrupted biology, and we are in a position to describe the in vivo nature of disease processes, metabolism, evolution of cancer and the monitoring of response to pharmacological interventions and therapies. As such, PET/MRI is a key to advancing medicine and patient care.

PORTAF - postoperative radiotherapy of non-small cell lung cancer: accelerated versus conventional fractionation - study protocol for a randomized controlled trial.

BACKGROUND: In early-stage non-small cell lung cancer (NSCLC) without affected lymph nodes detected at staging, surgical resection is still the mainstay of treatment. However, in patients with metastatic mediastinal lymph nodes (pN2) or non-radically resected primary tumors (R1/R2), postoperative radiotherapy (possibly combined with chemotherapy) is indicated. So far, investigations about time factors affecting postoperative radiotherapy have only examined the waiting time defined as interval between surgery and start of radiotherapy, but not the overall treatment time (OTT) itself. Conversely, results from trials on primary radio(chemo)therapy in NSCLC show that longer OTT correlates with significantly worse local tumor control and overall survival rates. This time factor of primary radio(chemo)therapy is thought to mainly be based on repopulation of surviving tumor cells between irradiation fractions. It remains to be elucidated if such an effect also occurs when patients with NSCLC are treated with postoperative radiotherapy after surgery (and chemotherapy). Our own retrospective data suggest an advantage of shorter OTT also for postoperative radiotherapy in this patient group. METHODS/DESIGN: This is a multicenter, prospective randomized trial investigating whether an accelerated course of postoperative radiotherapy with photons or protons (7 fractions per week, 2 Gy fractions) improves locoregional tumor control in NSCLC patients in comparison to conventional fractionation (5 fractions per week, 2 Gy fractions). Target volumes and total radiation doses will be stratified in both treatment arms based on individual risk factors. DISCUSSION: For the primary endpoint of the study we postulate an increase in local tumor control from 70% to 85% after 36 months. Secondary endpoints are overall survival of patients; local recurrence-free and distant metastases-free survival after 36 months; acute and late toxicity and quality of life for both treatment methods. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02189967 . Registered on 22 May 2014.

[Melanoma brain metastases : Treatment options]. / Hirnmetastasen des malignen Melanoms : Therapiebesonderheiten.

The majority of patients with metastatic melanoma will develop brain metastases, which are the most common cause of death. Until recently, local therapies (e. g., neurosurgery, radiotherapy) were the only options for brain metastases; however, effective systemic treatment options are now available. Upon suspicion of brain metastases, diagnostic staging with brain MRI and a neurological investigation are indicated. Prognostic factors such as number of cerebral metastases and symptoms, serum lactate dehydrogenase and S­100 levels, extracerebral metastases, and ECOG status are considered during therapeutic planning. Treatment planning and therapeutic interventions should be based on an interdisciplinary and multimodal approach. Established treatments for singular brain metastases are neurosurgical resection and stereotactic radiotherapy, which can prolong survival. In patients with asymptomatic BRAF V600E-mutant brain metastases, the BRAF inhibitors dabrafenib, vemurafenib, and immunotherapy with ipilimumab are used. In the case of multiple symptomatic brain metastases, palliative whole-brain radiotherapy is used for treatment, although it has failed to show an overall survival benefit. Increased intracranial pressure and epileptic seizures are addressed with corticosteroids and anticonvulsants. Current clinical studies for melanoma patients with brain metastases are investigating new treatment options such as PD-1 antibodies, combined ipilimumab and nivolumab, combined BRAF inhibitors and MEK inhibitors, and stereotactic radiation in combination with immunotherapy or targeted therapy.

Time-Resolved Versus Integrated Transit Planar Dosimetry for Volumetric Modulated Arc Therapy: Patient-Specific Dose Differences During Treatment, a Proof of Principle.

PURPOSE: It is desirable that dosimetric deviations during radiation treatments are detected. Integrated transit planar dosimetry is commonly used to evaluate external beam treatments such as volumetric-modulated arc therapy. This work focuses on patient geometry changes which result in differences between the planned and the delivered radiation dose. Integrated transit planar dosimetry will average out some deviations. Novel time-resolved transit planar dosimetry compares the delivered dose of volumetric-modulated arc therapy to the planned dose at various time points. Four patient cases are shown where time-resolved transit planar dosimetry detects patient geometry changes during treatment. METHODS: A control point to control point comparison between the planned dose and the treatment dose of volumetric-modulated arc therapy beams is calculated using the planning computed tomography and the kV cone-beam computed tomography of the day and evaluated with a time-resolved γ function. Results were computed for 4 patients treated with volumetric-modulated arc therapy, each showing an anatomical change: pleural effusion, rectal gas pockets, and tumor regression. RESULTS: In all cases, the geometrical change was detected by time-resolved transit planar dosimetry, whereas integrated transit planar dosimetry showed minor or no indication of the dose discrepancy. Both tumor regression cases were detected earlier in the treatment with time-resolved planar dosimetry in comparison to integrated transit planar dosimetry. The pleural effusion and the gas pocket were detected exclusively with time-resolved transit planar dosimetry. CONCLUSIONS: Clinical cases were presented in this proof-of-principle study in which integrated transit planar dosimetry did not detect dosimetrically relevant deviations to the same extent time-resolved transit planar dosimetry was able to. Time-resolved transit planar dosimetry also provides results that can be presented as a function of arc delivery angle allowing easier interpretation compared to integrated transit planar dosimetry.

Single organ metastatic disease and local disease status, prognostic factors for overall survival in stage IV non-small cell lung cancer: Results from a population-based study.

PURPOSE: To analyse the prognostic impact on overall survival (OS) of single versus multiple organ metastases, organ affected, and local disease status in a population based stage IV non-small cell lung cancer (NSCLC) cohort. METHODS: In this observational study, data were analysed of all histologically confirmed stage IV NSCLC patients diagnosed between 1 January 2006 and 31 December 2012 registered in the Netherlands Cancer Registry. Location of metastases before treatment was registered. Multivariable survival analyses [age, gender, histology, M-status, local disease status, number of involved organs, actual organ affected] were performed for all patients and for an (18)fluorodeoxyglucose-positron emission tomography ((18)FDG-PET)-staged subgroup. RESULTS: 11,094 patients were selected: 60% male, mean age 65 years, 73% adenocarcinoma. Median OS for 1 (N = 5676), 2 (N = 3280), and ⩾ 3 (N = 2138) metastatically affected organs was 6.7, 4.3, 2.8 months, respectively (p < 0.001). Hazard ratio (HR) for 2 versus 1 organ(s) was 1.33 (p < 0.001), for ⩾ 3 versus 1 organ(s) 1.91 (p < 0.001). Results were confirmed in the (18)FDG-PET-staged cohort (N = 1517): patients with single organ versus 2 and ⩾ 3 organ metastases had higher OS (8.6, 5.7, 3.8 months, HR 1.40 and 2.17, respectively, p < 0.001). In single organ metastases, OS for low versus high TN-status was 8.5 versus 6.5 months [HR 1.40 (p < 0 .001)]. (18)FDG-PET-staged single organ metastases patients with low TN-status had a superior OS than those with high TN-status (11.6 versus 8.2 months, HR 1.62, p < 0.001). CONCLUSION: Patients with single organ metastases stage IV NSCLC have a favourable prognosis, especially in combination with low TN status. They have to be regarded as a separate subgroup of stage IV disease.

Validation of functional imaging as a biomarker for radiation treatment response.

Major advances in radiotherapy techniques, increasing knowledge of tumour biology and the ability to translate these advances into new therapeutic approaches are important goals towards more individualized cancer treatment. With the development of non-invasive functional and molecular imaging techniques such as positron emission tomography (PET)-CT scanning and MRI, there is now a need to evaluate potential new biomarkers for tumour response prediction, for treatment individualization is not only based on morphological criteria but also on biological tumour characteristics. The goal of individualization of radiotherapy is to improve treatment outcome and potentially reduce chronic treatment toxicity. This review gives an overview of the molecular and functional imaging modalities of tumour hypoxia and tumour cell metabolism, proliferation and perfusion as predictive biomarkers for radiation treatment response in head and neck tumours and in lung tumours. The current status of knowledge on integration of PET/CT/MRI into treatment management and bioimage-guided adaptive radiotherapy are discussed.

Stereotactic ablative body radiotherapy combined with immunotherapy: present status and future perspectives.

Radiotherapy is along with surgery and chemotherapy one of the prime treatment modalities in cancer. It is applied in the primary, neoadjuvant as well as the adjuvant setting. Radiation techniques have rapidly evolved during the past decade enabling the delivery of high radiation doses, reducing side-effects in tumour-adjacent normal tissues. While increasing local tumour control, current and future efforts ought to deal with microscopic disease at a distance of the primary tumour, ultimately responsible for disease-progression. This review explores the possibility of bimodal treatment combining radiotherapy with immunotherapy.

18F-FLT PET changes during radiotherapy combined with cetuximab in head and neck squamous cell carcinoma patients.

AIM: Early treatment response of head and neck cancer to radiotherapy concomitant with cetuximab was monitored by repetitive PET imaging with the proliferation tracer 18F-FLT. PATIENTS, METHODS: Five head and neck cancer patients, treated with radiotherapy and concomitant cetuximab following cetuximab induction, received four 18F-FLT PET-CT scans before and during treatment. Changes in SUVpeak, SUVmean and CT- and PET-segmented gross tumour volumes were evaluated, as were correlations with immunohistochemical staining for Epidermal Growth Factor Receptor (EGFR) and Ki-67 (proliferation marker) in pre-treatment tumour biopsies. RESULTS: 18F-FLT PET measured tumor responses to the induction dose of cetuximab varied from 43% SUVpeak decrease to 47% increase. After start of radiotherapy 18F-FLT PET parameters decreased significantly in all patients. No associations were found between PET parameters and EGFR or Ki-67 expression levels. CONCLUSION: Proliferation of head and neck carcinomas shows a varying response to cetuximab induction, but consistently decreases after addition of radiotherapy.

Characterization of tumor heterogeneity using dynamic contrast enhanced CT and FDG-PET in non-small cell lung cancer.

PURPOSE: Dynamic contrast-enhanced CT (DCE-CT) quantifies vasculature properties of tumors, whereas static FDG-PET/CT defines metabolic activity. Both imaging modalities are capable of showing intra-tumor heterogeneity. We investigated differences in vasculature properties within primary non-small cell lung cancer (NSCLC) tumors measured by DCE-CT and metabolic activity from FDG-PET/CT. METHODS: Thirty three NSCLC patients were analyzed prior to treatment. FDG-PET/CT and DCE-CT were co-registered. The tumor was delineated and metabolic activity was segmented on the FDG-PET/CT in two regions: low (<50% maximum SUV) and high (≥50% maximum SUV) metabolic uptake. Blood flow, blood volume and permeability were calculated using a maximum slope, deconvolution algorithm and a Patlak model. Correlations were assessed between perfusion parameters for the regions of interest. RESULTS: DCE-CT provided additional information on vasculature and tumor heterogeneity that was not correlated to metabolic tumor activity. There was no significant difference between low and high metabolic active regions for any of the DCE-CT parameters. Furthermore, only moderate correlations between maximum SUV and DCE-CT parameters were observed. CONCLUSIONS: No direct correlation was observed between FDG-uptake and parameters extracted from DCE-CT. DCE-CT may provide complementary information to the characterization of primary NSCLC tumors over FDG-PET/CT imaging.