Compliance of volunteers in a fully-enclosed patient rotation system for MR-guided radiation therapy: a prospective study.

BACKGROUND: Particle therapy makes a noteworthy contribution in the treatment of tumor diseases. In order to be able to irradiate from different angles, usually expensive, complex and large gantries are used. Instead rotating the beam via a gantry, the patient itself might be rotated. Here we present tolerance and compliance of volunteers for a fully-enclosed patient rotation system in a clinical magnetic resonance (MR)-scanner for potential use in MR-guided radiotherapy, conducted within a prospective evaluation study. METHODS: A patient rotation system was used to simulate and perform magnetic resonance imaging (MRI)-examinations with 50 volunteers without an oncological question. For 20 participants, the MR-examination within the bore was simulated by introducing realistic MRI noise, whereas 30 participants received an examination with image acquisition. Initially, body parameters and claustrophobia were assessed. The subjects were then rotated to different angles for simulation (0°, 45°, 90°, 180°) and imaging (0°, 70°, 90°, 110°). At each angle, anxiety and motion sickness were assessed using a 6-item State-Trait-Anxiety-Inventory (STAI-6) and a modified Motion Sickness Assessment Questionnaire (MSAQ). In addition, general areas of discomfort were evaluated. RESULTS: Out of 50 subjects, three (6%) subjects terminated the study prematurely. One subject dropped out during simulation due to nausea while rotating to 45°. During imaging, further two subjects dropped out due to shoulder pain from positioning at 90° and 110°, respectively. The average result for claustrophobia (0 = no claustrophobia to 4 = extreme claustrophobia) was none to light claustrophobia (average score: simulation 0.64 ± 0.33, imaging 0.51 ± 0.39). The mean anxiety scores (0% = no anxiety to 100% = maximal anxiety) were 11.04% (simulation) and 15.82% (imaging). Mean motion sickness scores (0% = no motion sickness to 100% = maximal motion sickness) of 3.5% (simulation) and 6.76% (imaging) were obtained across all participants. CONCLUSION: Our study proves the feasibility of horizontal rotation in a fully-enclosed rotation system within an MR-scanner. Anxiety scores were low and motion sickness was only a minor influence. Both anxiety and motion sickness showed no angular dependency. Further optimizations with regard to immobilization in the rotation device may increase subject comfort.

Effects of Photon versus Carbon-Ion Irradiation in the Rat Cervical Spinal Cord - a Serial T2 and Diffusion-weighted Magnetic Resonance Imaging Study.

Carbon-ion irradiation is increasingly used at the skull base and spine near the radiation-sensitive spinal cord. To better characterize the in vivo radiation response of the cervical spinal cord, radiogenic changes in the high-dose area were measured in rats using magnetic resonance imaging (MRI) diffusion measurements in comparison to conventional photon irradiations. In this longitudinal MRI study, we examined the gray matter (GM) of the cervical spinal cord in 16 female Sprague-Dawley rats after high-dose photon (n = 8) or carbon-ion (12C) irradiation (n = 8) and in 6 sham-exposed rats until myelopathy occurred. The differences in the diffusion pattern of the GM of the cervical spinal cord were examined until the endpoint of the study, occurrence of paresis grade II of both forelimbs was reached. In both radiation techniques, the same order of the occurrence of MR-morphological pathologies was observed - from edema formation to a blood spinal cord barrier (BSCB) disruption to paresis grade II of both forelimbs. However, carbon-ion irradiation showed a significant increase of the mean apparent diffusion coefficient (ADC; P = 0.031) with development of a BSCB disruption in the GM. Animals with paresis grade II as a late radiation response had a highly significant increase in mean ADC (P = 0.0001) after carbon-ion irradiation. At this time, a tendency was observed for higher mean ADC values in the GM after 12C irradiation as compared to photon irradiation (P = 0.059). These findings demonstrated that carbon-ion irradiation leads to greater structural damage to the GM of the rat cervical spinal cord than photon irradiation due to its higher linear energy transfer (LET) value.

Patterns of Temporal Lobe Reaction and Radiation Necrosis after Particle Radiotherapy in Patients with Skull Base Chordoma and Chondrosarcoma-A Single-Center Experience.

BACKGROUND: The current study aims to evaluate the occurrence of temporal lobe reactions and identify possible risk factors for patients who underwent particle therapy of the skull base. METHODS: 244 patients treated for skull base chordoma (n = 144) or chondrosarcoma (n = 100) at the Heidelberg Ion Beam Therapy Center (HIT) using a raster scan technique, were analyzed. Follow-up MRI-scans were matched with the initial planning images. Radiogenic reactions were contoured and analyzed based on volume and dose of treatment. RESULTS: 51 patients with chordoma (35.4%) and 30 patients (30%) with chondrosarcoma experienced at least one temporal lobe reaction within the follow-up period (median 49 months for chondrosarcoma, 62 months for chordoma). Age, irradiated volume, and dose values were significant risk factors for the development of temporal lobe reactions with the highest significance for the value of DMax-7 being defined as the dose maximum in the temporal lobe minus the 7cc with the highest dose (p = 0.000000000019; OR 1.087). CONCLUSION: Temporal lobe reactions are a common side effect after particle therapy of the skull base. We were able to develop a multivariate model, which predicted radiation reactions with a specificity of 99% and a sensitivity of 52.2%.

Management of initial and recurrent radiation-induced contrast enhancements following radiotherapy for brain metastases: Clinical and radiological impact of bevacizumab and corticosteroids.

Purpose: The appearance of radiation-induced contrast enhancements (RICE) after radiotherapy for brain metastases can go along with severe neurological impairments. The aim of our analysis was to evaluate radiological changes, the course and recurrence of RICE and identify associated prognostic factors. Methods: We retrospectively identified patients diagnosed with brain metastases, who were treated with radiotherapy and subsequently developed RICE. Patient demographic and clinical data, radiation-, cancer-, and RICE-treatment, radiological results, and oncological outcomes were reviewed in detail. Results: A total of 95 patients with a median follow-up of 28.8 months were identified. RICE appeared after a median time of 8.0 months after first radiotherapy and 6.4 months after re-irradiation. Bevacizumab in combination with corticosteroids achieved an improvement of clinical symptoms and imaging features in 65.9% and 75.6% of cases, respectively, both significantly superior compared to treatment with corticosteroids only, and further significantly prolonged RICE-progression-free survival to a median of 5.6 months. Recurrence of RICE after initially improved or stable imaging occurred in 63.1% of cases, significantly more often in patients after re-irradiation and was associated with high mortality of 36.6% after the diagnosis of flare-up. Response of recurrence significantly depended on the applied treatment and multiple courses of bevacizumab achieved good response. Conclusion: Our results suggest that bevacizumab in combination with corticosteroids is superior in achieving short-term imaging and symptom improvement of RICE and prolongs the progression-free time compared to corticosteroids alone. Long-term RICE flare-up rates after bevacizumab discontinuation are high, but repeated treatments achieved effective symptomatic control.

Proton and carbon ion beam treatment with active raster scanning method in 147 patients with skull base chordoma at the Heidelberg Ion Beam Therapy Center-a single-center experience.

BACKGROUND: This study aimed to compare the results of irradiation with protons versus irradiation with carbon ions in a raster scan technique in patients with skull base chordomas and to identify risk factors that may compromise treatment results. METHODS: A total of 147 patients (85 men, 62 women) were irradiated with carbon ions (111 patients) or protons (36 patients) with a median dose of 66 Gy (RBE (Relative biological effectiveness); carbon ions) in 4 weeks or 74 Gy (RBE; protons) in 7 weeks at the Heidelberg Ion Beam Therapy Center (HIT) in Heidelberg, Germany. The median follow-up time was 49.3 months. All patients had gross residual disease at the beginning of RT. Compression of the brainstem was present in 38%, contact without compression in 18%, and no contact but less than 3 mm distance in 16%. Local control and overall survival were evaluated using the Kaplan-Meier Method based on scheduled treatment (protons vs. carbon ions) and compared via the log rank test. Subgroup analyses were performed to identify possible prognostic factors. RESULTS: During the follow-up, 41 patients (27.9%) developed a local recurrence. The median follow-up time was 49.3 months (95% CI: 40.8-53.8; reverse Kaplan-Meier median follow-up time 56.3 months, 95% CI: 51.9-60.7). No significant differences between protons and carbon ions were observed regarding LC, OS, or overall toxicity. The 1­year, 3­year, and 5­year LC rates were 97%, 80%, and 61% (protons) and 96%, 80%, and 65% (carbon ions), respectively. The corresponding OS rates were 100%, 92%, and 92% (protons) and 99%, 91%, and 83% (carbon ions). No significant prognostic factors for LC or OS could be determined regarding the whole cohort; however, a significantly improved LC could be observed if the tumor was > 3 mm distant from the brainstem in patients presenting in a primary situation. CONCLUSION: Outcomes of proton and carbon ion treatment of skull base chordomas seem similar regarding tumor control, survival, and toxicity. Close proximity to the brainstem might be a negative prognostic factor, at least in patients presenting in a primary situation.

Particle Therapy in Adult Patients with Pelvic Ewing Sarcoma-Tumor and Treatment Characteristics and Early Clinical Outcomes.

PURPOSE: To report dosimetric characteristics and early clinical outcomes in patients with pelvic Ewing sarcoma undergoing particle therapy. METHODS: Patients ≥ 18 years old with pelvic Ewing sarcoma treated in adjuvant or definitive settings were considered for this retrospective analysis. Proton therapy was carried out with 45-60 Gy (RBE) (1.5-2 Gy (RBE) per fraction) and carbon ion therapy for recurrent disease with 51 Gy (RBE) (3 Gy (RBE) per fraction). Local control (LC), disease control (DC) and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS: For our sample, 21 patients were available, 18 of whom were treated for primary, 3 for locally recurrent and 16 for inoperable disease. The median CTV and PTV were 1215 cm3 and 1630 cm3. Median Dmean values for the PTV, bladder and rectum and median V40 Gy for the bowel for patients undergoing proton therapy were 56 Gy (RBE), 0.6 Gy (RBE), 9 Gy (RBE) and 15 cm3, respectively. At the end of particle therapy, G 1-2 skin reactions (n = 16/21) and fatigue (n = 9/21) were the main reported symptoms. After a median follow-up of 21 months, the 2-year LC, DC and OS were 76%, 56% and 86%, respectively. CONCLUSIONS: Particle therapy in adult pelvic Ewing sarcoma is feasible and provides excellent dosimetric results. First clinical outcomes are promising; however, further long-term follow-up is needed.

Stereotactic radiotherapy of brain metastases: clinical impact of three-dimensional SPACE imaging for 3T-MRI-based treatment planning.

PURPOSE: For planning CyberKnife stereotactic radiosurgery (CK SRS) of brain metastases (BM), it is essential to precisely determine the exact number and location of BM in MRI. Recent MR studies suggest the superiority of contrast-enhanced 3D fast spin echo SPACE (sampling perfection with application-optimized contrast by using different flip angle evolutions) images over 3D gradient echo (GE) T1-weighted MPRAGE (magnetization-prepared rapid gradient echo) images for detecting small BM. The aim of this study is to test the usability of the SPACE sequence for MRI-based radiation treatment planning and its impact on changing treatment. METHODS: For MRI-based radiation treatment planning using 3T MRI in 199 patients with cerebral oligometastases, we compared the detectability of BM in post-gadolinium SPACE images, post-gadolinium MPRAGE images, and post-gadolinium late-phase MPRAGE images. RESULTS: When SPACE images were used for MRI-based radiation treatment planning, 29.8% and 16.9% more BM, respectively, were detected and included in treatment planning than in the post-gadolinium MPRAGE images and the post-gadolinium late-phase MPRAGE images (post-gadolinium MPRAGE imaging: ntotal = 681, mean ± SD 3.4 ± 4.2; post-gadolinium SPACE imaging: ntotal = 884, mean ± SD 4.4 ± 6.0; post-gadolinium late-phase MPRAGE imaging: ntotal = 796, mean ± SD 4.0 ± 5.3; Ppost-gadolinium SPACE imaging versus post-gadolinium MPRAGE imaging < 0.0001, Ppost-gadolinium SPACE imaging versus post-gadolinium late-phase MPRAGE imaging< 0.0001). CONCLUSION: For 3T MRI-based treatment planning of stereotactic radiosurgery of BM, we recommend the use of post-gadolinium SPACE imaging rather than post-gadolinium MPRAGE imaging.

Magnetic resonance guided adaptive stereotactic body radiotherapy for lung tumors in ultracentral location: the MAGELLAN trial (ARO 2021-3).

BACKGROUND: Stereotactic Body Radiotherapy (SBRT) is a standard treatment for inoperable primary and secondary lung tumors. In case of ultracentral tumor location, defined as tumor contact with vulnerable mediastinal structures such as the proximal bronchial tree (PBT) or esophagus, SBRT is associated with an increased risk for severe complications. Magnetic resonance (MR)-guided SBRT can mitigate this risk based on gated dose delivery and daily plan adaptation. The MAGELLAN trial aims to find the maximum tolerated dose (MTD) of MR-guided SBRT of ultracentral lung tumors (ULT). PATIENTS AND METHODS: MAGELLAN is a prospective phase I dose escalation trial. A maximum of 38 patients with primary and secondary ULT with a tumor size ≤ 5 cm will be enrolled. Ultracentral location is defined as an overlap of the planning target volume (PTV) with the PBT or esophagus. Patients are treated at a 0.35 Tesla MR-linac (MRIdian® Linac, ViewRay Inc. ) employing a gating strategy and daily plan adaptation. Dose escalation starts at 10 × 5.5 Gy (biologically effective dose BED3/10: 155.83 Gy/85.25 Gy), may proceed up to 10 × 6.5 Gy (BED3/10: 205.83 Gy/107.25 Gy) and is guided by a customized time-to-event continual reassessment method (TITE CRM) with backup element, which alternately assigns patients to dose escalation and backup cohorts. DISCUSSION: The results of the MAGELLAN trial will guide further research and clinical implementation of MR-guided SBRT as ablative treatment of ULT. Moreover, the combination of MR-guided radiotherapy with TITE-CRM including a backup element may serve as blueprint for future radiation dose escalation studies in critical locations. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT04925583 on 14th June 2021.

DCE-MRI detected vascular permeability changes in the rat spinal cord do not explain shorter latency times for paresis after carbon ions relative to photons.

BACKGROUND AND PURPOSE: Radiation-induced myelopathy, an irreversible complication occurring after a long symptom-free latency time, is preceded by a fixed sequence of magnetic resonance- (MR-) visible morphological alterations. Vascular degradation is assumed the main reason for radiation-induced myelopathy. We used dynamic contrast-enhanced (DCE-) MRI to identify different vascular changes after photon and carbon ion irradiation, which precede or coincide with morphological changes. MATERIALS AND METHODS: The cervical spinal cord of rats was irradiated with iso-effective photon or carbon (12C-)ion doses. Afterwards, animals underwent frequent DCE-MR imaging until they developed symptomatic radiation-induced myelopathy (paresis II). Measurements were performed at certain time points: 1 month, 2 months, 3 months, 4 months, and 6 months after irradiation, and when animals showed morphological (such as edema/syrinx/contrast agent (CA) accumulation) or neurological alterations (such as, paresis I, and paresis II). DCE-MRI data was analyzed using the extended Toft's model. RESULTS: Fit quality improved with gradual disintegration of the blood spinal cord barrier (BSCB) towards paresis II. Vascular permeability increased three months after photon irradiation, and rapidly escalated after animals showed MR-visible morphological changes until paresis II. After 12C-ion irradiation, vascular permeability increased when animals showed morphological alterations and increased further until animals had paresis II. The volume transfer constant and the plasma volume showed no significant changes. CONCLUSION: Only after photon irradiation, DCE-MRI provides a temporal advantage in detecting early physiological signs in radiation-induced myelopathy compared to morphological MRI. As a generally lower level of vascular permeability after 12C-ions led to an earlier development of paresis as compared to photons, we conclude that other mechanisms dominate the development of paresis II.

Longitudinal MRI study after carbon ion and photon irradiation: shorter latency time for myelopathy is not associated with differential morphological changes.

BACKGROUND: Radiation-induced myelopathy is a severe and irreversible complication that occurs after a long symptom-free latency time if the spinal cord was exposed to a significant irradiation dose during tumor treatment. As carbon ions are increasingly investigated for tumor treatment in clinical trials, their effect on normal tissue needs further investigation to assure safety of patient treatments. Magnetic resonance imaging (MRI)-visible morphological alterations could serve as predictive markers for medicinal interventions to avoid severe side effects. Thus, MRI-visible morphological alterations in the rat spinal cord after high dose photon and carbon ion irradiation and their latency times were investigated. METHODS: Rats whose spinal cords were irradiated with iso-effective high photon (n = 8) or carbon ion (n = 8) doses as well as sham-treated control animals (n = 6) underwent frequent MRI measurements until they developed radiation-induced myelopathy (paresis II). MR images were analyzed for morphological alterations and animals were regularly tested for neurological deficits. In addition, histological analysis was performed of animals suffering from paresis II compared to controls. RESULTS: For both beam modalities, first morphological alterations occurred outside the spinal cord (bone marrow conversion, contrast agent accumulation in the musculature ventral and dorsal to the spinal cord) followed by morphological alterations inside the spinal cord (edema, syrinx, contrast agent accumulation) and eventually neurological alterations (paresis I and II). Latency times were significantly shorter after carbon ions as compared to photon irradiation. CONCLUSIONS: Irradiation of the rat spinal cord with photon or carbon ion doses that lead to 100% myelopathy induced a comparable fixed sequence of MRI-visible morphological alterations and neurological distortions. However, at least in the animal model used in this study, the observed MRI-visible morphological alterations in the spinal cord are not suited as predictive markers to identify animals that will develop myelopathy as the time between MRI-visible alterations and the occurrence of myelopathy is too short to intervene with protective or mitigative drugs.

Spinal Stabilization Exercises for Cancer Patients with Spinal Metastases of High Fracture Risk: Feasibility of the DISPO-II Training Program.

Exercise concomitant to radiotherapy for stable spinal metastases was demonstrated to increase bone density and reduce pain. In the DISPO-II study, the feasibility of exercise concomitant to radiotherapy for unstable spinal metastases was investigated. Here, a detailed analysis of the training program is presented. Cancer patients with spinal metastases (Taneichi score ≥ D) were randomly assigned to an intervention group (INT, n = 27, 62 ± 9 years) or control group (CON, n = 29, 61 ± 9 years). INT performed spinal stabilization exercises ("all fours"/"plank"/"swimmer"/"band exercise"), and CON received relaxation, daily concomitant to radiotherapy. Exercise attendance rate was 90% in INT and 80% in CON (p = 0.126). Within INT, exercise dose increased significantly (p < 0.001). 54% of patients could not perform "swimmer" in some or all sessions. 42% could not perform "plank" in some or all sessions. 13 and 25% could not perform "all fours" and "band exercise" in some sessions. "Plank" holding time increased in INT and remained unchanged in CON with different development between groups (p = 0.022). Handgrip strength did not develop differently between groups (p = 0.397). The exercise intervention demonstrated high acceptability but required frequent modifications due to pain, weakness and immobility to be feasible for the majority of participants. It enhanced specific muscle strength. Larger trials should now investigate exercise effects on health.

High-dose carbon-ion based radiotherapy of primary and recurrent sacrococcygeal chordomas: long-term clinical results of a single particle therapy center.

BACKGROUND: This study aimed to analyze the oncological long-term results and late toxicity of carbon ion-based radiotherapy (RT) of patients with sacral chordoma and to identify potential prognostic factors for local control (LC) and overall survival (OS). METHODS: A total of 68 patients with sacral chordoma treated at the Heidelberg Ion Beam Therapy Center were included in this study. Of these 52 patients (77%) received a primary RT and 16 patients (23%) received a RT in a recurrent situation. All patients were treated with carbon ion RT (CIRT), either in combination with photons (n = 22; 32%) or as a monotherapy (n = 46; 68%), with a median radiation dose of 66 Gy RBE (range 60-74 Gy). In 40 patients (59%), RT was performed in the postoperative situation. Postoperative care included regular MRI scans. Local progression was defined as an enlargement of the maximum tumor diameter by 10% or a new tumor growth within the planning target volume (PTV). LC and OS were determined using the Kaplan-Meier method. Furthermore, the relevance of various prognostic factors for LC and OS was assessed by univariate and multivariate analysis. RESULTS: The median follow-up period was 60 months (range 1.3-97.4 months). The 5-year rates for LC, progression-free survival, metastasis-free survival and OS were 53, 53, 52 and 74%, respectively. Local recurrence was observed in 31 patients (46%), occurring after a median follow-up time of 25 months (range 2.5-73.1 months). Only 10% of local recurrences occurred later than 5 years after RT. Statistical analysis showed that RT in the relapse situation corresponded to inferior LC rates compared to the primary situation, while other factors such as the GTV, radiation dose (EQD2) and treatment approach (CIRT alone vs. CIRT combined with photons) were insignificant. For OS after RT, patient age and PTV size proved to be significant predictors. The incidence of late toxicity ≥ III° according to CTCAE v5.0 was 21%. Sacral insufficiency fractures occurred in 49% of patients (maximum III°: 16%) and were thus by far the most frequent late side effect in our analysis. Radiogenic damage to the peripheral nerves, intestinal tract and skin was observed in only 9% (≥ III°: 5%), 3% (all II°) and 9% (all I°) of patients. CONCLUSION: Our analysis showed only moderate long-term LC rates after carbon ion-based RT, with sacral chordomas having a particularly poor prognosis in the recurrent situation. Therefore, future studies should evaluate the safety and effectiveness of further dose escalation and hypofractionation of RT in sacral chordoma and weight potential benefits of dose escalation against side effects.

Paravertebral Muscle Training in Patients with Unstable Spinal Metastases Receiving Palliative Radiotherapy: An Exploratory Randomized Feasibility Trial.

Background: Isometric paravertebral muscle training (IPMT) may improve mobility, pain, and quality of life (QOL) in cancer patients with spinal metastases. However, this regimen remains unproven in patients with unstable spinal metastases (USM), a population at high risk for clinical exacerbation with such interventions. Thus, we conducted this exploratory, non-blinded, randomized controlled trial (NCT02847754) to evaluate the safety/feasibility of IPMT and secondarily assess pain, bone density, pathologic fracture rate, and QOL. Methods: All patients had histologically/radiologically confirmed USM (per Taneichi score) and underwent non-operative management with 5-10 fractions of palliative radiotherapy (RT). Randomization (1:1) groups were IPMT (intervention, INT) or muscle relaxation (control, CON); both lasted 15 min/day and started concurrently with radiotherapy. The primary endpoint was feasibility (completion of training programs three months post-RT). Secondary endpoints were pain response (Visual Analog Scale) and opioid consumption, bone density and pathologic fracture rate, and QOL (European Organization for Research and Treatment of Cancer, EORTC questionnaires). Results: Sixty patients were randomized and 56 received protocol therapy. Mean survival in both groups was 4.4 months. There were no adverse events with either training regimen. Altogether, ≥80% of the planned sessions were completed by 55% (n = 16/29) in CON and 67% (n = 18/27) in INT. Regarding the post-radiotherapy home-based training, ≥80% of planned sessions were completed by 64% (n = 9/14) of the INT cohort. There were no differences in pain scores, opioid consumption, or bone density between arms (p > 0.05 for all). No difference was observed between groups regarding new pathological fractures (INT: n = 1 vs. CON: n = 3) after three months (p = 0.419). There were no QOL differences between arms (all parameters p > 0.05). Conclusions: IPMT is potentially feasible for high-risk USM patients. Future trials adequately powered for relevant endpoints are thus recommended.

Re-irradiation in locally recurrent lung cancer patients.

PURPOSE: Lung cancer remains one of the tumour diagnoses with high lethality, although innovative treatment approaches have yielded improvements in local control and survival rates. There is still no consensus on how to treat local relapse in patients after first-line treatments. Radiotherapy may be considered in this situation; however, data supporting its effectiveness are rare. The purpose of this retrospective analysis was to evaluate outcomes of patients re-irradiated for thoracic tumours in terms of overall survival (OS), local progression-free survival (LPFS), toxicity and dose-volume parameters. PATIENTS AND METHODS: Sixty-two patients with locally recurrent previously irradiated lung cancer were analysed retrospectively (NSCLC n = 52, SCLC n = 10). Target volumes both in lung and mediastinum were re-irradiated with conventional three-dimensional or intensity-modulated radiotherapy techniques. Median overall dose of re-irradiation was 38.5 Gy (range 20-60 Gy) with a median single dose per fraction of 2 Gy (1.8-3.0 Gy). Clinical documents and treatment plans were evaluated. RESULTS: Median follow-up was 8.2 months (range 0-27 months). OS following re-irradiation was 9.3 months (range: 0-27 months) and LPFS was 6.5 months (range: 0-24 months). OS and LPFS were not affected by histology, total dose or patient age and gender. OS was improved in patients whose re-irradiation volumes included less than two mediastinal lymph node stations (p = 0.016). Twelve patients suffered from pneumonitis ≥grade II (19%) and two from pneumonitis grade III. One patient presumably died from pneumonitis grade V. A slight decline in forced expiratory volume (FEV1) was detected in post-re-irradiation lung function testing. CONCLUSIONS: Re-irradiation is an option for patients with tumour recurrence to control local progression and lower the symptom burden. Oncological outcome appears to be affected by size, location of mediastinal target volumes and lung function. Prospective clinical trials are warranted to substantiate the role of re-irradiation in recurrent lung cancer.

Robotic Radiosurgery for Brain Metastases Diagnosed With Either SPACE or MPRAGE Sequence (CYBER-SPACE)-A Single-Center Prospective Randomized Trial.

BACKGROUND: Stereotactic radiosurgery (SRS) of brain metastases (BM) is recommended in oligometastatic scenarios as a less toxic treatment alternative to whole-brain radiotherapy. Recent findings support SRS for patients with multiple (>3) BM. Furthermore, advances in MR imaging have facilitated the detection of very small BM, as advances in SRS technology have facilitated the highly conformal and simultaneous treatment of multiple target lesions. OBJECTIVE: To compare efficacy and toxicity of repeated frameless robotic SRS of up to 10 simultaneous BM through a single-center prospective randomized trial. METHODS: Two hundred patients will be randomized and receive imaging and treatment based on either the highly sensitive SPACE (sampling perfection with application optimized contrasts using different flip angle evolution) or the MPRAGE (magnetization-prepared rapid gradient-echo) magnetic resonance imaging sequence. If during follow-up new metastases are detected, treatment is repeated. The primary endpoint is reached when a patient develops more than 10 simultaneous new BM and is thus deemed unsuitable for further SRS. Overall survival will be assessed as secondary endpoint. Quality of life and neurocognition will be evaluated every 3 mo using CANTAB tests and EORTC (European Organisation for Research and Treatment of Cancer) questionnaires. EXPECTED OUTCOMES: We expect to show that repeated SRS based on sensitive imaging can delay intracranial dissemination while preserving neurocognitive function and quality of life. DISCUSSION: The present study is the first to prospectively assess the benefit of sensitive imaging and repeated stereotactic irradiation in the treatment of patients with multiple BM. It represents a novel approach, where in a palliative setting advanced technology in treatment and diagnostics is employed to improve tumor control while also reducing toxicity and preserving quality of life.

Bone density and pain response following intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy for vertebral metastases - secondary results of a randomized trial.

BACKGROUND: This was a prespecified secondary analysis of a randomized trial that analyzed bone density and pain response following fractionated intensity-modulated radiotherapy (IMRT) versus three-dimensional conformal radiotherapy (3DCRT) for palliative management of spinal metastases. METHODS/MATERIALS: Sixty patients were enrolled in the single-institutional randomized exploratory trial, randomly assigned to receive IMRT or 3DCRT (30 Gy in 10 fractions). Along with pain response (measured by the Visual Analog Scale (VAS) and Chow criteria), quantitative bone density was evaluated at baseline, 3, and 6 months in both irradiated and unirradiated spinal bodies, along with rates of pathologic fractures and vertebral compression fractures. RESULTS: Relative to baseline, bone density increased at 3 and 6 months following IMRT by a median of 24.8% and 33.8%, respectively (p < 0.01 and p = 0.048). These figures in the 3DCRT cohort were 18.5% and 48.4%, respectively (p < 0.01 for both). There were no statistical differences in bone density between IMRT and 3DCRT at 3 (p = 0.723) or 6 months (p = 0.341). Subgroup analysis of osteolytic and osteoblastic metastases showed no differences between groups; however, mixed metastases showed an increase in bone density over baseline in the IMRT (but not 3DCRT) arm. The 3-month rate of the pathological fractures was 15.0% in the IMRT arm vs. 10.5% in the 3DCRT arm. There were no differences in pathological fractures at 3 (p = 0.676) and 6 (p = 1.000) months. The IMRT arm showed improved VAS scores at 3 (p = 0.037) but not 6 months (p = 0.430). Using Chow criteria, pain response was similar at both 3 (p = 0.395) and 6 (p = 0.732) months. CONCLUSIONS: This the first prospective investigation evaluating the impact of IMRT vs. 3DCRT on bone density. Along with pain response and pathologic fracture rates, significant rises in bone density after 3 and 6 months were similar in both cohorts. Future randomized investigations with larger sample sizes are recommended. TRIAL REGISTRATION: NCT, NCT02832830 . Registered 14 July 2016.

Local response and pathologic fractures following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy for spinal metastases - a randomized controlled trial.

BACKGROUND: This was a prespecified secondary analysis of a randomized trial, which analyzed bone density following stereotactic body radiotherapy (SBRT) versus conventional three-dimensional conformal radiotherapy (3DCRT) as part of palliative management of painful spinal metastases. METHODS: Fifty-five patients were enrolled in this single-institutional randomized exploratory trial (NCT02358720). Participants were randomly assigned to receive SBRT (single-fraction 24 Gy) or 3DCRT (30 Gy/10 fractions). Quantitative bone density was evaluated at baseline, 3 and 6 months in both irradiated and unirradiated spinal bodies, along with rates of pathologic fractures and vertebral compression fractures. RESULTS: As compared to baseline, bone density became significantly higher at 3 and 6 months following SBRT by a median of 33.8% and 72.1%, respectively (p < 0.01 for both). These figures in the 3DCRT cohort were 32.9% and 41.2%, respectively (p < 0.01 for both). There were no statistical differences in bone density between SBRT and 3DCRT at 3 (p = 0.629) or 6 months (p = 0.327). Subgroup analysis of osteolytic metastases showed an increase in bone density relative to baseline in the SBRT (but not 3DCRT) arm. Bone density in unaffected vertebrae did not show substantial changes in either group. The 3-month incidence of new pathological fractures was 8.7% in the SBRT arm vs. 4.3% in the 3DCRT arm. CONCLUSIONS: Despite high ablative doses in the SBRT arm, the significant increase in bone density after 3 and 6 months was similar to that of 3DCRT. Our trial demonstrated a moderate rate of subsequent pathological fracture after SBRT. Future randomized investigations with larger sample sizes are recommended. TRIAL REGISTRATION: www.clinicaltrials.gov : NCT02358720 on 9nd of February 2015.

Sacral insufficiency fractures after high-dose carbon-ion based radiotherapy of sacral chordomas.

BACKGROUND: This study aimed to analyse the frequency and clinical relevance of sacral insufficiency fractures (SIFs) after high-dose carbon-ion based irradiation of sacral chordomas. METHODS: A total of 56 patients were included in this retrospective study. Twenty one patients (37%) were treated with definitive radiotherapy (RT), and 35 patients (63%) received postoperative RT using carbon ions, either in combination with photons or as single-modality treatment (median radiation dose 66 Gy RBE, range 60-74 Gy). Follow-up examinations including MRI of the pelvis were performed at 3-monthly intervals in the first year and consecutively at 6-monthly intervals. Median follow-up was 35.5 months (range 2-83). RESULTS: SIFs were diagnosed in 29 patients (52%) after a median follow-up of 11 months (range 1-62 months). Most sacral fractures (79%) occurred within 2 years after RT. For the overall study population, the fracture-free survival probability amounted to values of 0.68 (95% CI, 0.53-0.79) after 1 year, 0.46 (95% CI, 0.31-0.60) after 2 years, and 0.31 (95% CI, 0.16-0.47) after 5 years. Statistical analysis showed no significant difference regarding the fracture rates between patients who received an operation and postoperative RT and patients treated with definitive RT. About one third of the patients with SIFs (34%; 10 of 29 patients) had associated clinical symptoms, most notably pain. All patients with symptomatic fractures required strong analgesics and often intensive pain management. CONCLUSIONS: Sacral fractures after high-dose carbon ion-based RT of sacral chordomas were shown to be a considerable radiogenic late effect, affecting about half of the treated patients. However, only one third of these fractures were clinically symptomatic requiring regular medical care and pain therapy. Further hazard factor analysis in the future with larger patient numbers will possibly enable the identification of high-risk patients for developing SIFs with the ultimate goal to prevent symptomatic fractures.

Whole brain radiation therapy alone versus radiosurgery for patients with 1-10 brain metastases from small cell lung cancer (ENCEPHALON Trial): study protocol for a randomized controlled trial.

BACKGROUND: Conventional whole brain radiotherapy (WBRT) has been established as the treatment standard in patients with cerebral metastases from small-cell lung cancer (SCLC), however, it has only modest efficacy and limited prospective data is available for WBRT as well as local treatments such as stereotactic radiosurgery (SRS). METHODS/DESIGN: The present single-center prospective randomized study, conducted at Heidelberg University Hospital, compares neurocognitive function, as objectively measured by significant deterioration in Hopkins Verbal Learning Test - Revised total recall at 3 months. Fifty-six patients will be randomized to receive either SRS of all brain metastases (up to ten lesions) or WBRT. Secondary endpoints include intracranial progression (local tumor progression and number of new cerebral metastases), extracranial progression, overall survival, death due to brain metastases, local (neurological) progression-free survival, progression-free survival, changes in other cognitive performance measures, quality of life and toxicity. DISCUSSION: Recent evidence suggests that SRS might be a promising treatment option for SCLC patients with brain metastases. The present trial is the first to prospectively investigate the treatment response, toxicity and neurocognition of WBRT and SRS in SCLC patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT03297788 . Registered September 29, 2017.

Diagnostic accuracy of DW MR imaging in the differentiation of chordomas and chondrosarcomas of the skull base: A 3.0-T MRI study of 105 cases.

PURPOSE: To determine the diagnostic accuracy of DW MR imaging with apparent diffusion coefficient (ADC) mapping for the distinction of skull base chordoma from skull base chondrosarcoma. PATIENTS AND METHODS: From October 2009 to April 2014, 105 consecutive patients (chordomas (n = 70), and chondrosarcomas (n = 35) who were planned to receive proton or heavy-ion beam therapy underwent DW MR imaging on a 3.0 T. MR images were assessed by means of consensus of three experienced radiologists who were blinded to pathologic and clinical information. ADC values (mean, minimum, maximum, and normalized) of the solid tumor component were evaluated. Group means and cut-off points were established to separate skull base chordoma from skull base chondrosarcoma, and statistical significances were calculated by Student's t or Mann-Whitney-U tests, and receiver operating characteristic (ROC) curve analyses. The prospective study was approved by the institutional ethics committee. RESULTS: For solid tumor component, there were higher mean, minimum, maximum, and normalized ADC values in chondrosarcomas compared with those in chordomas (all p < 0.001). ROC analysis revealed areas under the curve for mean, minimum, maximum, and normalized ADC values between 0.79 and 0.93. The mean ADC value of the solid tumor components had the best AUC, with a cut-off point of 1585 × 10(-6) mm (2)/s and sensitivity and specificity of 94.3% and 98.6%, respectively. CONCLUSION: Skull base Chondrosarcomas generally have higher mean, minimum, maximum, and normalized ADC values than skull base chordomas, with the mean ADC value of the solid tumor component offering the highest accuracy for characterization.