Homogenous dose prescription in Gamma Knife Radiotherapy: Combining the best of both worlds.

PURPOSE: Stereotactic radiosurgery with linear accelerators (LINACs) or Leksell Gamma Knife® (LGK, Elekta AB) is an established treatment option for intracranial tumors. When those are involving/abutting organs at risk (OAR), homogenous and normofractionated treatments outmatch single fraction deliveries. In such situations, it would be desirable to balance LINAC's homogeneity benefits with LGK's dose gradient attributes. In this study, we determined homogeneity and OAR sparing ranges using a non-clinical, homogenous prototype version of LGK Lightning. METHODS: We retrospectively analyzed thirty fractionated LGK Icon in-house patients with acoustic neuromas, pituitary adenomas and meningiomas. Four treatment plans were generated (54 Gy,1.8 Gy/fx) per patient: one LINAC plan, one clinical Lightning plan ("LGK") and two prototype Lightning plans ("LGK Hom" and "LGK OAR"). We analyzed Dmean and D2% for different OAR, Gradient Index (GI), Paddick Conformity Index (PCI), Homogeneity Index (HI) and beam-on-time (BOT). RESULTS: While the LINAC vs. Lightning plans (LGK Hom|LGK OAR|LGK) boast better homogeneity (median: 1.08 vs. 1.18|1.24|1.35) and shorter BOT (median: 137 s vs. 432 s|510 s|510 s), Lightning plans show improved GI (median: 6.68 vs. 3.86|3.50|3.19), similar PCI (median: 0.75 vs. 0.76|0.75|0.82) and significantly reduced OAR doses. For in-tumor OAR, LGK Hom and LINAC plans achieves similar OAR sparing with improved GI for LGK Hom. CONCLUSIONS: This study is a preliminary attempt to combine the dosimetric advantages of LINAC and LGK treatment planning. We observed that LGK plan homogeneity can be improved toward LINAC standards while maintaining the LGK advantage of favorable OAR doses and GI. Additionally, in-tumor OAR hotspots can be considerably reduced.

Modulation of PD­L1 expression by standard therapy in head and neck cancer cell lines and exosomes.

Although checkpoint inhibitors (CPI) have recently extended the treatment options and improved clinical response of advanced stage head and neck squamous cell carcinoma (HNSCC), treatment success remains unpredictable. Programmed cell death ligand­1 (PD­L1) is a key player in immunotherapy. Tumor cells, and exosomes derived therefrom, are carriers of PD­L1 and efficiently suppress immune responses. The aim of the present study was to analyze the influence of established therapies on PD­L1 expression of HNSCC cell lines and their exosomes. The HNSCC cell lines, UM­SCC­11B, UM­SCC­14C and UM­SCC­22C were treated with fractionated radiotherapy (RT; 5x2 Gy), cisplatin (CT) and cetuximab (Cetux) as monotherapy, or combined therapy, chemoradiotherapy (CRT; RT and CT) or radioimmunotherapy (RT and Cetux). The expression of PD­L1 and phosphorylated (p)ERK1/2 as a mediator of radioresistance were assessed using western blotting, immunohistochemistry and an ex vivo vital tissue culture model. Additionally, exosomes were isolated from concentrated supernatants of the (un­)treated HNSCC cell lines by size exclusion chromatography. Exosomal protein expression levels of PD­L1 were detected using western blotting and semi­quantitative levels were calculated. The functional impact of exosomes from the (un­)treated HNSCC cell lines on the proliferation (MTS assay) and apoptosis (Caspase 3/7 assay) of the untreated HNSCC cell lines were measured and compared. The HNSCC cell lines UM­SCC­11B and UM­SCC­22B showed strong expression of pERK1/2 and PD­L1, respectively. RT upregulated the PD­L1 expression in UM­SCC­11B and UM­SCC­14C and in exosomes from all three cell lines. CT alone induced PD­L1 expression in all cell lines. CRT induced the expression of PD­L1 in all HNSCC cell lines and exosomes from UM­SCC­14C and UM­SCC­22B. The data indicated a potential co­regulation of PD­L1 and activated ERK1/2, most evident in UM­SCC­14C. Exosomes from irradiated UM­SCC­14C cells protected the unirradiated cells from apoptosis by Caspase 3/7 downregulation. The present study suggested a tumor cell­mediated regulation of PD­L1 upon platinum­based CRT in HNSCC and in exosomes. A co­regulation of PD­L1 and MAPK signaling response was hypothesized.

Mobile applications in radiation oncology-current choices and future potentials.

PURPOSE: To review existing scientific literature on mobile applications (apps) in the field of radiation oncology and to evaluate characteristics of commercially available apps across different platforms. METHODS: A systematic review of the literature for publications presenting apps in the field of radiation oncology was carried out using the PubMed database, Cochrane library, Google Scholar, and annual meetings of major radiation oncology societies. Additionally, the two major marketplaces for apps, App Store and Play Store, were searched for available radiation oncology apps for patients and health care professionals (HCP). RESULTS: A total of 38 original publications which met the inclusion criteria were identified. Within those publications, 32 apps were developed for patients and 6 for HCP. The vast majority of patient apps focused on documenting electronic patient-reported outcomes (ePROs). In the two major marketplaces, 26 apps were found, mainly supporting HCP with dose calculations. CONCLUSION: Apps used in (and for) scientific research in radiation oncology are rarely available for patients and HCP in common marketplaces.

Dosimetric benefits of daily treatment plan adaptation for prostate cancer stereotactic body radiotherapy.

BACKGROUND: Hypofractionation is increasingly being applied in radiotherapy for prostate cancer, requiring higher accuracy of daily treatment deliveries than in conventional image-guided radiotherapy (IGRT). Different adaptive radiotherapy (ART) strategies were evaluated with regard to dosimetric benefits. METHODS: Treatments plans for 32 patients were retrospectively generated and analyzed according to the PACE-C trial treatment scheme (40 Gy in 5 fractions). Using a previously trained cycle-generative adversarial network algorithm, synthetic CT (sCT) were generated out of five daily cone-beam CT. Dose calculation on sCT was performed for four different adaptation approaches: IGRT without adaptation, adaptation via segment aperture morphing (SAM) and segment weight optimization (ART1) or additional shape optimization (ART2) as well as a full re-optimization (ART3). Dose distributions were evaluated regarding dose-volume parameters and a penalty score. RESULTS: Compared to the IGRT approach, the ART1, ART2 and ART3 approaches substantially reduced the V37Gy(bladder) and V36Gy(rectum) from a mean of 7.4cm3 and 2.0cm3 to (5.9cm3, 6.1cm3, 5.2cm3) as well as to (1.4cm3, 1.4cm3, 1.0cm3), respectively. Plan adaptation required on average 2.6 min for the ART1 approach and yielded doses to the rectum being insignificantly different from the ART2 approach. Based on an accumulation over the total patient collective, a penalty score revealed dosimetric violations reduced by 79.2%, 75.7% and 93.2% through adaptation. CONCLUSION: Treatment plan adaptation was demonstrated to adequately restore relevant dose criteria on a daily basis. While for SAM adaptation approaches dosimetric benefits were realized through ensuring sufficient target coverage, a full re-optimization mainly improved OAR sparing which helps to guide the decision of when to apply which adaptation strategy.

MRI Detection of Changes in Tissue Sodium Concentration in Brain Metastases after Stereotactic Radiosurgery: A Feasibility Study.

BACKGROUND AND PURPOSE: To date, treatment response to stereotactic radiosurgery (SRS) in brain metastases (BM) can only be determined by MRI evaluation of contrast-enhancing lesions in a long-time follow-up. Sodium MRI has been a subject of immense interest in imaging research as the measure of tissue sodium concentration (TSC) can give valuable quantitative information on cell viability. We aimed to analyze the longitudinal changes of TSC in BM measured with 23 Na MRI before and after SRS for assessment of early local tumor effects. METHODS: Seven patients with a total of 12 previously untreated BM underwent SRS with 22 Gy. In addition to a standard MRI protocol including dynamic susceptibility-weighted contrast-enhanced perfusion, a 23 Na MRI was performed at three time points: (I) 2 days before, (II) 5 days, and (III) 40 days after SRS. Nine BMs were evaluated. The absolute TSC in the BM, the respective peritumoral edemas, and the normal-appearing corresponding contralateral brain area were assessed and the relative TSC were correlated to the changes in BM longest axial diameters. RESULTS: TSC was elevated in nine BM at baseline before SRS with a mean of 73.4 ± 12.3 mM. A further increase in TSC was observed 5 days after SRS in all the nine BM with a mean of 86.9 ± 13 mM. Eight of nine BM showed a mean 60.6 ± 13.3% decrease in the longest axial diameter 40 days after SRS; at this time point, the TSC also had decreased to a mean 65.1 ± 7.9 mM. In contrast, one of the nine BM had a 13.4% increase in the largest axial diameter at time point III. The TSC of this BM showed a further TSC increase of 80.1 mM 40 days after SRS. CONCLUSION: Changes in TSC using 23 Na MRI shows the possible capability to detect radiobiological changes in BM after SRS.

Combined kyphoplasty and intraoperative radiotherapy (Kypho-IORT) versus external beam radiotherapy (EBRT) for painful vertebral metastases - a randomized phase III study.

BACKGROUND: The spine is the most frequent location of bone metastases. Local treatment aims at palliation of pain and, given the increased likelihood of long-term cancer survival, at local control. Kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provided instantaneous pain relief in 70% of patients at the first day after the intervention and resulted in local control rates of > 93% at 1 year in a recently conducted phase I/II trial. To assess its clinical value, we designed a phase III trial which tests Kypho-IORT against the most widespread standard-of-care, external beam radiotherapy (EBRT), in patients with painful vertebral metastases. METHODS: This phase III study includes patients ≥50 years of age with up to 4 vertebral metastases and a pain score of at least 3/10 points on the visual/numeric analogy scale (VAS). Patients randomized into the experimental arm (A) will undergo Kypho-IORT (Kyphoplasty plus IORT with 8 Gy prescribed to 13 mm depth). Patients randomized into the control arm (B) will receive EBRT with either 30 Gy in 10 fractions or 8 Gy as a single dose. The primary end point is pain reduction defined as at least - 3 points on the VAS compared to baseline at day 1. Assuming that 40% of patients in the Kypho-IORT arm and 5% of patients in the control arm will achieve this reduction and 20% will drop out, a total of 54 patients will have to be included to reach a power of 0.817 with a two-sided alpha of 0.05. Secondary endpoints are evaluation of the percentage of patients with a pain reduction of at least 3 points at 2 and 6 weeks, local tumor control, frequency of re-intervention, secondary fractures/sintering, complication rates, skin toxicity/wound healing, progression-free survival (PFS), overall survival (OS) and quality of life. DISCUSSION: This trial will generate level 1 evidence on the clinical value of a one-stop procedure which may provide instantaneous pain relief, long-term control and shortened intervals to further adjuvant (systemic) therapies in patients with spinal metastases. TRIAL REGISTRATION: Registered with ClinicalTrials.gov, number: NCT02773966 (Registration date: 05/16/2016).