Meningioma WHO I with involvement of the optical structures-does proton therapy lead to changes in quality of life with regard to subjective visual performance?

BACKGROUND: In addition to local tumor control, the aim of any curative radio-oncological treatment is to maintain quality of life. In the treatment of patients with meningioma with a close relationship to optical structures, the preservation of visual performance is a particular challenge. Use of proton therapy can reduce the dose burden to organs at risk immediately adjacent to the tumor. The aim of this study was to score the subjective assessment of visual performance in patients with meningioma involving the optical structures before and after proton therapy. METHODS: All proton-treated patients with meningioma WHO I whose planning target volumes (PTV) included parts of the optic nerve and/or chiasm were included in this study. Subjective assessment of visual performance was evaluated using the Visual Disorder Scale (VDS) of the EORTC QLQ-BN20 questionnaire. This scale includes values from 0 to 100, whereby high values reflect a high degree of subjective symptom burden and thus subjective visual impairment. The visual acuity in externally performed eye tests at baseline and follow-ups (FU) was also evaluated. The timepoints for testing were before the start of radiotherapy, at the end of treatment, and 3, 6, 12, and 24 months in FU (times t1-t6). All patients with at least the first annual postradiation FU at the time of the evaluation were included. The correlation between VDS changes and potential influencing factors such as previous therapies, dosimetric data, initial tumor volume, and tumor shrinkage 1 year after treatment was assessed. RESULTS: A total of 56 patients (45 female/11 male) aged 24-82 years (mean ± SD = 53.9 ± 13.3) treated between March 2017 and September 2019 were included in the analysis. The prescription dose was 54.0 Gy (RBE) with active scanned proton therapy. The mean/D2% dose ± SD for the optic chiasm and ipsilateral optic nerve was 43.4 ± 8.9 Gy (RBE)/49.9 ± 7.1 Gy (RBE) and 35.6 ± 11.7 Gy (RBE)/51.7 ± 4.8 Gy (RBE); the mean/D2% dose ± SD of the contralateral optic nerve was 18.8 ± 12.1 Gy (RBE)/42.4 ± 14.6 Gy (RBE), respectively. A total of 302 data collections were available (t1/t2/t3/t4/t5/t6: n = 56/56/48/56/52/34). Median observation time was 23.6 months. Mean symptom burden decreased over time (mean VDS: t1 29.8 ± 27.9; t2 25.0 ± 27.9; t3 21.8 ± 26.0; t4 22.2 ± 26.0; t5 21.4 ± 26.2; t6 17.3 ± 23.6) with statistically significant improvement at 3­ and 6­month FU as well as 1 year after proton therapy (p = 0.0205; p = 0.0187; p = 0.0054). Objective eye tests available in 41/52 patients confirm the trend towards improved visual acuity (97.5% stable/improved until 24-month FU). However, no potential predictor for VDS changes was revealed. CONCLUSION: Proton treatment of patients with meningioma WHO I with involvement of optical structures does not impair subjective visual performance. After treatment, there is a significant improvement in perceived visual performance.

The trends and significance of SSTR PET/CT added to MRI in follow-up imaging of low-grade meningioma treated with fractionated proton therapy.

PURPOSE: Overexpression of the somatostatin receptor (SSTR) has led to adoption of SSTR PET/CT for diagnosis and radiotherapy planning in meningioma, but data on SSTR expression during follow-up remain scarce. We investigated PET/CT quantifiers of SSTR tracers in WHO grade I meningioma following fractionated proton beam therapy (PBT) compared to standard response assessment with MRI. METHODS: Twenty-two patients diagnosed with low-grade meningioma treated by PBT were included. Follow-up included clinical visits, MRI, and [68Ga]Ga-DOTATOC PET/CT scans. Radiologic tumor response, MRI and PET volume (VMRI and VPET), maximum and mean standardied uptake value (SUVmax/SUVmean), total lesion activity (TLA), and heterogeneity index (HI) were evaluated. RESULTS: Median follow-up was 35.3 months (range: 6.4-47.9). Nineteen patients (86.4%, p = 0.0009) showed a decrease of SUVmax between baseline and first follow-up PET/CT (median: -24%, range: -53% to +89%) and in 81.8% of all cases, the SUVmax, SUVmean, and TLA at last follow-up were eventually lower than at baseline (p = 0.0043). Ambiguous trends without significance between the timepoints analyzed were observed for VPET. HI increased between baseline and last follow-up in 75% of cases (p = 0.024). All patients remained radiologically and clinically stable. Median VMRI decreased by -9.3% (range 0-32.5%, p < 0.0001) between baseline and last follow-up. CONCLUSION: PET/CT in follow-up of irradiated meningioma showed an early trend towards decreased binding of SSTR-specific tracers following radiation and MRI demonstrated consistently stable or decreasing tumor volume. Translational research is needed to clarify the underlying biology of the subsequent increase in SSTR PET quantifiers.

Harmonization of proton treatment planning for head and neck cancer using pencil beam scanning: first report of the IPACS collaboration group.

Background and purpose: A collaborative network between proton therapy (PT) centres in Trento in Italy, Poland, Austria, Czech Republic and Sweden (IPACS) was founded to implement trials and harmonize PT. This is the first report of IPACS with the aim to show the level of harmonization that can be achieved for proton therapy planning of head and neck (sino-nasal) cancer.Methods: CT-data sets of five patients were included. During several face-to-face and online meetings, a common treatment planning protocol was developed. Each centre used its own treatment planning system (TPS) and planning approach with some restrictions specified in the treatment planning protocol. In addition, volumetric modulated arc therapy (VMAT) photon plans were created.Results: For CTV1, the average Dmedian was 59.3 ± 2.4 Gy(RBE) for protons and 58.8 ± 2.0 Gy(RBE) for VMAT (aim was 56 Gy(RBE)). For CTV2, the average Dmedian was 71.2 ± 1.0 Gy(RBE) for protons and 70.6 ± 0.4 Gy(RBE) for VMAT (aim was 70 Gy(RBE)). The average D2% for the spinal cord was 25.1 ± 8.5 Gy(RBE) for protons and 47.6 ± 1.4 Gy(RBE) for VMAT. The average D2% for chiasm was 46.5 ± 4.4 Gy(RBE) for protons and 50.8 ± 1.4 Gy(RBE) for VMAT, respectively. Robust evaluation was performed and showed the least robust plans for plans with a low number of beams.Discussion: In conclusion, several influences on harmonization were identified: adherence/interpretation to/of the protocol, available technology, experience in treatment planning and use of different beam arrangements. In future, all OARs that should be included in the optimization need to be specified in order to further harmonize treatment planning.

Evaluation of planning aims and dose prescription in image-guided adaptive brachytherapy and radiochemotherapy for cervical cancer: Vienna clinical experience in 225 patients from 1998 to 2008.

BACKGROUND: To assess planning aims (PAs) and dose prescription in image-guided adaptive brachytherapy (IGABT) of cervical cancer and investigate potential impact on clinical outcome. MATERIAL AND METHODS: Our study population consists of 225 consecutive cervical cancer patients (FIGO stages IB-IVA) treated between 1998 and 2008 at the Medical University of Vienna by external beam radiotherapy (EBRT) ± chemotherapy and IGABT. For this retrospective study, patients were stratified into two treatment groups: PA+ group, all dose constraints fulfilled for prescription; PA-, one or more dose constraints not fulfilled for prescription. The following dose constraints (EBRT+ IGABT) were applied: clinical target volume (CTV)HR D90 ≥ 85 Gy, D2cm3 Rectum < 70 Gy, D2cm3 Bladder < 90 Gy. Differences in patient, tumor and treatment characteristics and clinical outcome (event: local failure or grade 3 + 4 toxicity) were compared between Group 1 and 2. Further, the impact of learning period (1998-2000) and protocol period (2001-2008) on the fulfillment of PAs for dose prescription and clinical outcome was analyzed. RESULTS: In the PA+ group there were 77 (34%) and in the PA- group 148 (66%) patients. In the PA- group, CTVHR D90 < 85 Gy was prescribed in 82 patients, D2cm3 bladder > 90 Gy was prescribed in 80 patients and D2cm3 Rectum > 70 Gy in 60 patients. Fulfillment of the PA for dose prescription improved from 4% in the learning period to 48% in the protocol period. The five-year event-free interval was 64% in the learning period and 84% in the protocol period (p = 0.008). CONCLUSION: Fulfillment of all PAs for dose prescription is challenging - especially in patients with more advanced tumors. However, with growing experience fulfillment of PA for dose prescription can be significantly increased (learning and protocol period). Such increase in fulfilling PA for dose prescription is followed by a significant improvement in clinical outcome.

The Value of PET/CT in Particle Therapy Planning of Various Tumors with SSTR2 Receptor Expression: Comparative Interobserver Study.

The overexpression of somatostatin receptor type 2 (SSTR2) is a property of various tumor types. Hybrid imaging utilizing [68Ga]1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra-acetic acid (DOTA) may improve the differentiation between tumor and healthy tissue. We conducted an experimental study on 47 anonymized patient cases including 30 meningiomas, 12 PitNET and 5 SBPGL. Four independent observers were instructed to contour the macroscopic tumor volume on planning MRI and then reassess their volumes with the additional information from DOTA-PET/CT. The conformity between observers and reference volumes was assessed. In total, 46 cases (97.9%) were DOTA-avid and included in the final analysis. In eight cases, PET/CT additional tumor volume was identified that was not detected by MRI; these PET/CT findings were potentially critical for the treatment plan in four cases. For meningiomas, the interobserver and observer to reference volume conformity indices were higher with PET/CT. For PitNET, the volumes had higher conformity between observers with MRI. With regard to SBGDL, no significant trend towards conformity with the addition of PET/CT information was observed. DOTA PET/CT supports accurate tumor recognition in meningioma and PitNET and is recommended in SSTR2-expressing tumors planned for treatment with highly conformal radiation.

Prospective Analysis of Radiation-Induced Contrast Enhancement and Health-Related Quality of Life After Proton Therapy for Central Nervous System and Skull Base Tumors.

PURPOSE: Intracerebral radiation-induced contrast enhancement (RICE) can occur after photon as well as proton beam therapy (PBT). This study evaluated the incidence, characteristics, and risk factors of RICE after PBT delivered to, or in direct proximity to, the brain and its effect on health-related quality of life (HRQoL). METHODS AND MATERIALS: Four hundred twenty-one patients treated with pencil beam scanning PBT between 2017 and 2021 were included. Follow-up included clinical evaluation and contrast-enhanced magnetic resonance imaging at 3, 6, and 12 months after treatment completion and annually thereafter. RICE was graded according to Common Terminology Criteria for Adverse Events version 4, and HRQoL parameters were assessed via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 questionnaires. RESULTS: The median follow-up was 24 months (range, 6-54), and median dose to 1% relative volume of noninvolved central nervous system (D1%CNS) was 54.3 Gy relative biologic effectiveness (RBE; range, 30-76 Gy RBE). The cumulative RICE incidence was 15% (n = 63), of which 10.5% (n = 44) were grade 1, 3.1% (n = 13) were grade 2, and 1.4% (n = 6) were grade 3. No grade 4 or 5 events were observed. Twenty-six of 63 RICE (41.3%) had resolved at the latest follow-up. The median onset after PBT and duration of RICE in patients in whom the lesions resolved were 11.8 and 9.0 months, respectively. On multivariable analysis, D1%CNS > 57.6 Gy RBE, previous in-field radiation, and diabetes mellitus were identified as significant risk factors for RICE development. Previous radiation was the only factor influencing the risk of symptomatic RICE. After PBT, general HRQoL parameters were not compromised. In a matched cohort analysis of 54/50 patients with and without RICE, no differences in global health score or functional and symptom scales were seen. CONCLUSIONS: The overall incidence of clinically relevant RICE after PBT is very low and has no significant negative effect on long-term patient QoL.

Magnetic resonance imaging for assessment of parametrial tumour spread and regression patterns in adaptive cervix cancer radiotherapy.

PURPOSE: To investigate the impact of magnetic resonance imaging (MRI)-morphologic differences in parametrial infiltration on tumour response during primary radiochemotherapy in cervical cancer. MATERIAL AND METHODS: Eighty-five consecutive cervical cancer patients with FIGO stages IIB (n = 59) and IIIB (n = 26), treated by external beam radiotherapy (± chemotherapy) and image-guided adaptive brachytherapy, underwent T2-weighted MRI at the time of diagnosis and at the time of brachytherapy. MRI patterns of parametrial tumour infiltration at the time of diagnosis were assessed with regard to predominant morphology and maximum extent of parametrial tumour infiltration and were stratified into five tumour groups (TG): 1) expansive with spiculae; 2) expansive with spiculae and infiltrating parts; 3) infiltrative into the inner third of the parametrial space (PM); 4) infiltrative into the middle third of the PM; and 5) infiltrative into the outer third of the PM. MRI at the time of brachytherapy was used for identifying presence (residual vs. no residual disease) and signal intensity (high vs. intermediate) of residual disease within the PM. Left and right PM of each patient were evaluated separately at both time points. The impact of the TG on tumour remission status within the PM was analysed using χ(2)-test and logistic regression analysis. RESULTS: In total, 170 PM were analysed. The TG 1, 2, 3, 4, 5 were present in 12%, 11%, 35%, 25% and 12% of the cases, respectively. Five percent of the PM were tumour-free. Residual tumour in the PM was identified in 19%, 68%, 88%, 90% and 85% of the PM for the TG 1, 2, 3, 4, and 5, respectively. The TG 3-5 had significantly higher rates of residual tumour in the PM in comparison to TG 1 + 2 (88% vs. 43%, p < 0.01). CONCLUSION: MRI-morphologic features of PM infiltration appear to allow for prediction of tumour response during external beam radiotherapy and chemotherapy. A predominantly infiltrative tumour spread at the time of diagnosis resulted in a significantly higher rate of residual tumour in the PM at the time of brachytherapy in comparison to a predominantly expansive tumour spread.

Possibilities and challenges when using synthetic computed tomography in an adaptive carbon-ion treatment workflow.

BACKGROUND AND PURPOSE: Anatomical surveillance during ion-beam therapy is the basis for an effective tumor treatment and optimal organ at risk (OAR) sparing. Synthetic computed tomography (sCT) based on magnetic resonance imaging (MRI) can replace the X-ray based planning CT (X-rayCT) in photon radiotherapy and improve the workflow efficiency without additional imaging dose. The extension to carbon-ion radiotherapy is highly challenging; complex patient positioning, unique anatomical situations, distinct horizontal and vertical beam incidence directions, and limited training data are only few problems. This study gives insight into the possibilities and challenges of using sCTs in carbon-ion therapy. MATERIALS AND METHODS: For head and neck patients immobilised with thermoplastic masks 30 clinically applied actively scanned carbon-ion treatment plans on 15 CTs comprising 60 beams were analyzed. Those treatment plans were re-calculated on MRI based sCTs which were created employing a 3D U-Net. Dose differences and carbon-ion spot displacements between sCT and X-rayCT were evaluated on a patient specific basis. RESULTS: Spot displacement analysis showed a peak displacement by 0.2 cm caused by the immobilisation mask not measurable with the MRI. 95.7% of all spot displacements were located within 1 cm. For the clinical target volume (CTV) the median D50% agreed within -0.2% (-1.3 to 1.4%), while the median D0.01cc differed up to 4.2% (-1.3 to 25.3%) comparing the dose distribution on the X-rayCT and the sCT. OAR deviations depended strongly on the position and the dose gradient. For three patients no deterioration of the OAR parameters was observed. Other patients showed large deteriorations, e.g. for one patient D2% of the chiasm differed by 28.1%. CONCLUSION: The usage of sCTs opens several new questions, concluding that we are not ready yet for an MR-only workflow in carbon-ion therapy, as envisaged in photon therapy. Although omitting the X-rayCT seems unfavourable in the case of carbon-ion therapy, an sCT could be advantageous for monitoring, re-planning, and adaptation.

Preservation of Neurocognition after Proton Beam Radiation Therapy for Intracranial Tumors: First Results from REGI-MA-002015.

PURPOSE: Proton beam radiation therapy reduces dose to healthy brain tissue and thereby decreases the risk of treatment-related decline in neurocognition. Considering the paucity of prospective data, this study aimed to evaluate neurocognitive performance in an adult patient population with intracranial tumors. METHODS AND MATERIALS: Between 2017 and 2021, patients enrolled in the MedAustron registry study and irradiated for intracranial tumors were eligible for neurocognitive assessment. Patients with available 1-year follow-up data were included in the analysis. The test battery consisted of a variety of standardized tests commonly used in European Organization for Research and Treatment of Cancer trials. Scores were transformed into z scores to account for demographic effects, and clinically relevant change was defined as a change of ≥1.5 standard deviations. Binary logistic regression analysis and the χ2 test were conducted for clinical parameters and dosimetric hippocampal parameters to evaluate the relationship with overall cognitive decline and changes in memory. RESULTS: One hundred twenty-three patients with mostly nonprogressive, extra-axial tumors and neurocognitive assessment at baseline and treatment end as well as 3, 6, and 12 months after completion of proton beam radiation therapy were analyzed. Overall, 7 test scores revealed stability in neurocognitive function with minimal positive changes 1 year after treatment completion (statistically significant in 6 of 7 tests), whereas the majority had no or minimal baseline deficits. At 1-year follow-up, 89.4% of all patients remained stable in their overall cognitive functioning without clinically relevant deterioration in 2 or more tests. None of them showed disease progression. Of the patients, 8.1% presented with radiation-induced brain lesions and exhibited a higher percentage of overall cognitive deterioration without reaching statistical significance. Multivariate binary logistic regression analysis revealed higher age at baseline as the only independent parameter to be associated with an overall clinically relevant cognitive decline. There was no significant correlation of hippocampal doses and memory functioning. CONCLUSIONS: One year after proton therapy, we observed preservation of cognitive functioning in the vast majority of our patients with intracranial tumors.

Proton or Carbon Ion Therapy for Skull Base Chordoma: Rationale and First Analysis of a Mono-Institutional Experience.

BACKGROUND: Skull base chordomas are radio-resistant tumors that require high-dose, high-precision radiotherapy, as can be delivered by particle therapy (protons and carbon ions). We performed a first clinical outcome analysis of particle therapy based on the initial 4-years of operation. METHODS: Between August 2017 and October 2021, 44 patients were treated with proton (89%) or carbon ion therapy (11%). Prior gross total resection had been performed in 21% of lesions, subtotal resection in 57%, biopsy in 12% and decompression in 10%. The average prescription dose was 75.2 Gy RBE in 37 fractions for protons and 66 Gy RBE in 22 fractions for carbon ions. RESULTS: At a median follow-up of 34.3 months (range: 1-55), 2-, and 3-year actuarial local control rates were 95.5% and 90.9%, respectively. The 2-, and 3-year overall and progression-free survival rates were 97.7%, 93.2%, 95.5% and 90.9%, respectively. The tumor volume at the time of particle therapy was highly predictive of local failure (p < 0.01), and currently, there is 100% local control in patients with tumors < 49 cc. No grade ≥3 toxicities were observed. There was no significant difference in outcome or side effect profile seen for proton versus carbon ion therapy. Five patients (11.4%) experienced transient grade ≤2 radiation-induced brain changes. CONCLUSIONS: The first analysis suggests the safety and efficacy of proton and carbon ion therapy at our center. The excellent control of small to mid-size chordomas underlines the effectiveness of particle therapy and importance of upfront maximum debulking of large lesions.

Organs at risk dose constraints in carbon ion radiotherapy at MedAustron: Translations between LEM and MKM RBE models and preliminary clinical results.

BACKGROUND: Carbon ion radiotherapy (CIRT) treatment planning is based on relative biological effectiveness (RBE) weighted dose calculations. A large amount of clinical evidence for CIRT was collected in Japan with RBE estimated by the modified microdosimetric kinetic model (MKM) while all European centres apply the first version of the local effect model (LEM). Japanese schedules have been used in Europe with adapted prescription dose and organs at risk (OAR) dose constraints. Recently, less conservative adapted LEM constraints have been implemented in clinical practice. The aim of this study was to analyse the new set of LEM dose constraints for brain parenchyma, brainstem and optic system considering both RBE models and evaluating early clinical data. MATERIAL AND METHODS: 31 patients receiving CIRT at MedAustron were analysed using the RayStation v9A planning system by recalculating clinical LEM-based plans in MKM. Dose statistics (D1cm3, D5cm3, D0.1cm3, D0.7cm3, D10%, D20%) were extracted for relevant critical OARs. Curve fitting for those values was performed, resulting in linear quadratic translation models. Clinical and radiological toxicity was evaluated. RESULTS: Based on derived fits, currently applied LEM constraints matched recommended MKM constraints with deviations between -8% and +3.9%. For particular cases, data did not follow the expected LEM vs MKM trends resulting in outliers. Radiological (asymptomatic) toxicity was detected in two outlier cases. CONCLUSION: Respecting LEM constraints does not automatically ensure that MKM constraints are met. Constraints for both RBE models need to be fulfilled for future CIRT patients at MedAustron. Careful selection of planning strategies is essential.

A year of pandemic for European particle radiotherapy: A survey on behalf of EPTN working group.

OBJECTIVES: To provide an overview of the impact of the pandemic on the clinical activity and take a snapshot of the contingent challenges that European particle therapy centers are called to face, we surveyed the members of the European Particle Therapy Network (EPTN). MATERIAL AND METHODS: A 52-question survey was conducted from 4th April 2021 to 30th July 2021 using the Google Forms platform. Three dedicated sections analysed the clinical context of each participating institution, the staff management, and the clinical changes in the oncological workflow. RESULTS: Out of the 23 contacted European hubs of particle radiotherapy, a total of 9 (39%) responded to the survey. The number of in-person first evaluations and follow-up visits decreased, but telemedicine was implemented. Multidisciplinary tumour board discussions continued during the outbreak using web-based solutions. A delay in cancer diagnosis and oncological staging leading to an increment in more advanced diseases at first presentation was generally observed. Even if the total number of treatments (photons and particles) in the responding institutions showed a trend of decrease, there was or a stable situation or slight increase in particle treatments. The clinical treatment choices followed the national and international scientific recommendations and were patient/disease-oriented. Hypofractionation and short-schedule of chemotherapy, when applicable, were preferred. CONCLUSIONS: Our findings show a rapid and effective reaction of European particle RT hubs to manage the healthcare crisis. Considering the new waves and virus variants, the vaccination campaign will hopefully reduce the oncological impacts and consequences of the prolonged outbreak.

Normofractionated and moderately hypofractionated proton therapy: comparison of acute toxicity and early quality of life outcomes.

Aim: Data on the safety of moderately hypofractionated proton beam therapy (PBT) are limited. The aim of this study is to compare the acute toxicity and early quality of life (QoL) outcomes of normofractionated (nPBT) and hypofractionated PBT (hPBT). Material and methods: We prospectively compared acute toxicity and QoL between patients treated with nPBT (dose per fraction 1.8-2.3 Gy, n = 90) and hPBT (dose per fraction 2.5-3.1 Gy, n = 49) in following locations: head and neck (H&N, n = 85), abdomen and pelvis (A&P, n = 43), and other soft tissue (ST, n = 11). The toxicities were grouped into categories-mucosal, skin, and other sites-and evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at baseline, treatment completion, and 3 months after PBT completion. QoL was evaluated with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 scale for all locations and additionally with EORTC QLQ-HN35 for H&N patients. Results: Overall, the highest toxicity grades of G0, G1, G2, and G3 were observed in 7 (5%), 40 (28.8%), 78 (56.1%), and 15 (10.8%) patients, respectively. According to organ and site, no statistically significant differences were detected in the majority of toxicity comparisons (66.7%). For A&P, hPBT showed a more favorable toxicity profile as compared to nPBT with a higher frequency of G0 and G1 and a lower frequency of G2 and G3 events (p = 0.04), more patients with improvement (95.7% vs 70%, p = 0.023), and full resolution of toxicities (87% vs 50%, p = 0.008). Skin toxicity was unanimously milder for hPBT compared to nPBT in A&P and ST locations (p = 0.018 and p = 0.025, respectively). No significant differences in QoL were observed in 97% of comparisons for QLQ-C30 scale except for loss of appetite in H&N patients (+33.3 for nPBT and 0 for hPBT, p = 0.02) and role functioning for A&P patients (0 for nPBT vs +16.7 hPBT, p = 0.003). For QLQ-HN35, 97.9% of comparisons did not reveal significant differences, with pain as the only scale varying between the groups (-8.33 vs -25, p = 0.016). Conclusion: Hypofractionated proton therapy offers non-inferior early safety and QoL as compared to normofractionated irradiation and warrants further clinical investigation.

Current practice in proton therapy delivery in adult cancer patients across Europe.

BACKGROUND AND PURPOSE: Major differences exist among proton therapy (PT) centres regarding PT delivery in adult cancer patient. To obtain insight into current practice in Europe, we performed a survey among European PT centres. MATERIALS AND METHODS: We designed electronic questionnaires for eight tumour sites, focusing on four main topics: 1) indications and patient selection methods; 2) reimbursement; 3) on-going or planned studies, 4) annual number of patients treated with PT. RESULTS: Of 22 centres, 19 (86%) responded. In total, 4233 adult patients are currently treated across Europe annually, of which 46% consists of patients with central nervous system tumours (CNS), 15% head and neck cancer (HNC), 15% prostate, 9% breast, 5% lung, 5% gastrointestinal, 4% lymphoma, 0.3% gynaecological cancers. CNS are treated in all participating centres (n = 19) using PT, HNC in 16 centres, lymphoma in 10 centres, gastrointestinal in 10 centres, breast in 7 centres, prostate in 6 centres, lung in 6 centres, and gynaecological cancers in 3 centres. Reimbursement is provided by national health care systems for the majority of commonly treated tumour sites. Approximately 74% of centres enrol patients for prospective data registration programs. Phase II-III trials are less frequent, due to reimbursement and funding problems. Reasons for not treating certain tumour types with PT are lack of evidence (30%), reimbursement issues (29%) and/or technical limitations (20%). CONCLUSION: Across European PT centres, CNS tumours and HNC are the most frequently treated tumour types. Most centres use indication protocols. Lack of evidence for PT and reimbursement issues are the most reported reasons for not treating specific tumour types with PT.

Carbon Ion Dose Constraints in the Head and Neck and Skull Base: Review of MedAustron Institutional Protocols.

BACKGROUND: Dose constraints are of paramount importance for the outcome of any radiotherapy treatment. In this article, we report dose-volume constraints as well as currently used fractionation schedules for carbon ion radiotherapy as applied in MedAustron (Wiener Neustadt, Austria). MATERIALS AND METHODS: For fractionation schedules, both German and Japanese regimes were used. From the clinical experience of National Institute of Radiological Sciences (Chiba, Japan) and Heidelberg Ion Therapy (Heidelberg, Germany; formerly GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt, Germany) and the work by colleagues in Centro Nazionale Adroterapia Oncologica (Pavia, Italy) recalculating the dose from the microdosimetric kinetic model to the local effect model, we have set the dose constraints for critical organs of the head and neck area. Where no clinical data was available, an educated guess was made, based on data available from photon and proton series. RESULTS: We report the constraints for the optic nerve and chiasm, brainstem, spinal cord, cochlea, brain parenchyma, salivary gland, eye and adnexa, and mandibular/maxillary bone; constraints are grouped based on a fractionation scheme (German versus Japanese) and the risk of toxicity (safe, low to middle, and middle to high). CONCLUSION: We think validation of dose constraints should present a relevant part of the activity of any carbon ion radiotherapy facility, and we anticipate future multicentric, joint evaluations.

Activation of efficient DNA repair mechanisms after photon and proton irradiation of human chondrosarcoma cells.

Although particle therapy with protons has proven to be beneficial in the treatment of chondrosarcoma compared to photon-based (X-ray) radiation therapy, the cellular and molecular mechanisms have not yet been sufficiently investigated. Cell viability and colony forming ability were analyzed after X-ray and proton irradiation (IR). Cell cycle was analyzed using flow cytometry and corresponding regulator genes and key players of the DNA repair mechanisms were measured using next generation sequencing, protein expression and immunofluorescence staining. Changes in metabolic phenotypes were determined with nuclear magnetic resonance spectroscopy. Both X-ray and proton IR resulted in reduced cell survival and a G2/M phase arrest of the cell cycle. Especially 1 h after IR, a significant dose-dependent increase of phosphorylated γH2AX foci was observed. This was accompanied with a reprogramming in cellular metabolism. Interestingly, within 24 h the majority of clearly visible DNA damages were repaired and the metabolic phenotype restored. Involved DNA repair mechanisms are, besides the homology directed repair (HDR) and the non-homologous end-joining (NHEJ), especially the mismatch mediated repair (MMR) pathway with the key players EXO1, MSH3, and PCNA. Chondrosarcoma cells regenerates the majority of DNA damages within 24 h. These molecular mechanisms represent an important basis for an improved therapy.

Sequential [18F]FDG-[18F]FMISO PET and Multiparametric MRI at 3T for Insights into Breast Cancer Heterogeneity and Correlation with Patient Outcomes: First Clinical Experience.

The aim of this study was to assess whether sequential multiparametric 18[F]fluoro-desoxy-glucose (18[F]FDG)/[18F]fluoromisonidazole ([18F]FMISO) PET-MRI in breast cancer patients is possible, facilitates information on tumor heterogeneity, and correlates with prognostic indicators. In this pilot study, IRB-approved, prospective study, nine patients with ten suspicious breast lesions (BIRADS 5) and subsequent breast cancer diagnosis underwent sequential combined [18F]FDG/[18F]FMISO PET-MRI. [18F]FDG was used to assess increased glycolysis, while [18F]FMISO was used to detect tumor hypoxia. MRI protocol included dynamic breast contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI). Qualitative and quantitative multiparametric imaging findings were compared with pathological features (grading, proliferation, and receptor status) and clinical endpoints (recurrence/metastases and disease-specific death) using multiple correlation analysis. Histopathology was the standard of reference. There were several intermediate to strong correlations identified between quantitative bioimaging markers, histopathologic tumor characteristics, and clinical endpoints. Based on correlation analysis, multiparametric criteria provided independent information. The prognostic indicators proliferation rate, death, and presence/development of recurrence/metastasis correlated positively, whereas the prognostic indicator estrogen receptor status correlated negatively with PET parameters. The strongest correlations were found between disease-specific death and [18F]FDGmean (R=0.83, p < 0.01) and between the presence/development of metastasis and [18F]FDGmax (R=0.79, p < 0.01), respectively. This pilot study indicates that multiparametric [18F]FDG/[18F]FMISO PET-MRI might provide complementary quantitative prognostic information on breast tumors including clinical endpoints and thus might be used to tailor treatment for precision medicine in breast cancer.

Changes in Tumor Biology During Chemoradiation of Cervix Cancer Assessed by Multiparametric MRI and Hypoxia PET.

PURPOSE: Imaging biomarkers assessed with magnetic resonance imaging (MRI) and/or positron emission tomography (PET) enable non-invasive tumor characterization in cervix cancer patients. We investigated the spatio-temporal stability of hypoxia, perfusion, and the cell density of tumors over time by repetitive imaging prior to, during, and after radio-chemotherapy. PROCEDURES: Thirteen patients were included in this prospective study. The imaging protocol included the following: [18F]fluoromisonidazole ([18F]FMISO)-PET/x-ray computed tomography (CT) and multiparametric (mp)-MRI at four time-points (TP): baseline (BL); and weeks 2 (TP1), 5 (TP2), and 19 after treatment start (follow-up FU). Complete datasets for six patients could be assessed for tumor volume, enhancement kinetics, diffusivity, and [18F]FMISO-avidity (P1-P6). In addition, two patients completed all PET/CT examinations (P7-P8) but not all MR scans; however, one of them had no hypoxia (P8). Descriptive statistics, correlations, and voxel-by-voxel analysis were performed. For various, independent reasons, five patients could not complete the study according to the protocol with all imaging sequences. RESULTS: Median tumor ADCs (in ×10-3 mm2/s) were 0.99 ± 0.10 at BL, 1.20 ± 0.12 at TP1, 1.33 ± 0.14 at TP2, and 1.38 ± 0.21 at FU. The median TBRpeak (tumor-to-background) was 2.7 ± 0.8 at BL, 1.6 ± 0.2 at TP1, 1.8 ± 0.3 at TP2, and 1.7 ± 0.3 at FU. The voxel-by-voxel analysis of the [18F]FMISO uptake at BL and TP1 showed no correlation. Between TP2 and TP1 and FU and TP2, weak correlations were found for two patients. CONCLUSIONS: Longitudinal mp-MR and PET imaging enables the in vivo tumor characterization over time. While perfusion and cell density decreased, there was a non-uniform change of hypoxia observed during radiotherapy. To assess the potential impact with regard to more personalized treatment approaches, hypoxia imaging-based dose painting for cervix cancer requires further research.

Uncertainties in assessment of the vaginal dose for intracavitary brachytherapy of cervical cancer using a tandem-ring applicator.

PURPOSE: The vagina has not been widely recognized as organ at risk in brachytherapy for cervical cancer. No widely accepted dose parameters are available. This study analyzes the uncertainties in dose reporting for the vaginal wall using tandem-ring applicators. METHODS AND MATERIALS: Organ wall contours were delineated on axial magnetic resonance (MR) slices to perform dose-volume histogram (DVH) analysis. Different DVH parameters were used in a feasibility study based on 40 magnetic resonance imaging (MRI)-based treatment plans of different cervical cancer patients. Dose to the most irradiated, 0.1 cm(3), 1 cm(3), 2 cm(3), and at defined points on the ring surface and at 5-mm tissue depth were reported. Treatment-planning systems allow different methods of dose point definition. Film dosimetry was used to verify the maximum dose at the surface of the ring applicator in an experimental setup. RESULTS: Dose reporting for the vagina is extremely sensitive to geometrical uncertainties with variations of 25% for 1 mm shifts. Accurate delineation of the vaginal wall is limited by the finite pixel size of MRI and available treatment-planning systems. No significant correlation was found between dose-point and dose-volume parameters. The DVH parameters were often related to noncontiguous volumes and were not able to detect very different situations of spatial dose distributions inside the vaginal wall. Deviations between measured and calculated doses were up to 21%. CONCLUSIONS: Reporting either point dose values or DVH parameters for the vaginal wall is based on high inaccuracies because of contouring and geometric positioning. Therefore, the use of prospective dose constraints for individual treatment plans is not to be recommended at present. However, for large patient groups treated within one protocol correlation with vaginal morbidity can be evaluated.

Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer.

BACKGROUND: To investigate the clinical impact of MRI based cervix cancer brachytherapy combined with external beam radiochemotherapy applying dose volume adaptation and dose escalation in a consecutive group of patients with locally advanced cervix cancer. METHODS: In the period 1998-2003, 145 patients with cervix cancer stages IB-IVA were treated with definitive radiotherapy +/- cisplatin chemotherapy. Median age was 60 years. In 67 patients, the tumour size was 2-5 cm, in 78 patients it was >5 cm. In 29 cases the standard intracavitary technique was combined with interstitial brachytherapy. Total prescribed dose was 80-85 Gy (total biologically equivalent dose in 2 Gy fractions). Since 2001, MRI based treatment planning integrated systematic concepts for High Risk Clinical Target Volume (HR CTV) and organs at risk (OAR), biological modelling, Dose-Volume-Histogram analysis, dose-volume-adaptation (D90, D 2 cm(3)), and dose escalation, if appropriate and feasible. FINDINGS: Dose volume adaptation was performed in 130/145 patients. The mean D90 during the whole period was 86 Gy, with a mean D90 of 81 Gy and 90 Gy during the first and second period, respectively (p<<0.01). Median follow-up was 51 months. Complete remission at 3 months was achieved in 138/145 patients (95%). Actuarial continuous complete remission for true pelvis (CCRtp) was 88% at 3 years. For tumours 2-5 cm, CCRtp was 96% both in 1998-2000 and 2001-2003. For tumours >5 cm it was 71% in 1998-2000 and 90% in 2001-2003 (p=0.05). Progression free survival (PFS) for true pelvis (local control) was 85%, PFS for distant metastases was 80%, both at 3 years. Local control for tumours >5 cm was 64% in 1998-2000 and 82% in 2001-2003 (p=0.09) and 100% and 96%, respectively, for tumours 2-5 cm. PFS for distant metastases remained the same during the two treatment periods with 79% and 80%. Overall survival (OS) was 58%, and cancer-specific survival (CSS) was 68% at 3 years. In the two different periods improvement in OS was from 53% to 64% (p=0.03) and in CSS from 62% to 74% (p=0.13). Improvement occurred only in tumours >5 cm: OS 28% versus 58% (p=0.003); CSS 40% versus 62% (p=0.07). Actuarial late morbidity rate (LENT SOMA, grades 3 and 4) at 3 years was gastrointestinal 4%, urinary 4% and vaginal 5% (stage IIA/IIIA). Gastrointestinal and urinary late morbidity (G3,G4) was 10% in 1998-2000 and 2% in 2001-2003. INTERPRETATION: In locally advanced extensive cervix cancer, local control of > or = 85% can be achieved with low treatment related morbidity (G3/G4), when exploiting the potential of MRI based 3D treatment planning including dose volume adaptation and dose escalation and a combined intracavitary/interstitial brachytherapy, if appropriate. A significant impact of this improvement of local control on survival is to be expected. For locally advanced limited disease the MRI based approach will likely result in assuring excellent local control (> or = 95%) and in minimizing treatment related morbidity.