Akute kognitive Veränderungen unter zerebraler Strahlentherapie bei erwachsenen Tumorpatienten

Kognitive Einschränkungen bei Tumorpatienten im Erwachsenenalter stellen ein häufiges Problem dar. Vorhandene Studien zu diesem Thema fokussieren meist auf die Spät- und Langzeiteffekte von Chemo- oder zerebraler Strahlentherapie. Akute Therapieeffekte stehen nur selten im Forschungsfokus. Vor diesem Hintergrund war es das Ziel der vorliegenden Arbeit, Ausmaß, Verlauf und potentielle Risikofaktoren kognitiver Veränderungen in der akuten Phase der Strahlenreaktion zu untersuchen. Für die Studie wurden erwachsene Tumorpatienten, die eine zerebrale Radiochirurgie, Teilhirn- oder Ganzhirnbestrahlung erhalten sollten (n=150), mit zwei Kontrollgruppen (n=21 alleinig extrakraniell bestrahlte Patienten und n=22 kombiniert radiochemotherapierte Patienten) prospektiv vor Beginn der Radiotherapieserie, an den ersten 1 bis 3 Behandlungstagen und zum Abschluß der Radiotherapieserie verglichen. Mit standardisierten, international etablierten, reliablen und validen Testverfahren wurden die Bereiche Gedächtnis, visuell-räumliche Konstruktion und Aufmerksamkeit untersucht. Zusätzlich wurden das prämorbide Intelligenzniveau und das psychische Allgemeinbefinden der Patienten sowie weitere potentielle Determinanten für das Auftreten kognitiver Veränderungen kontrolliert und explorativ analysiert. Die Ergebnisse geben Hinweise darauf, daß subtile kognitive Veränderungen bei Patienten, die eine Bestrahlung des Gehirns erhalten, in der akuten Phase der Strahlenreaktion auftreten, auch wenn die Patienten unter einem klinischen Blick kognitiv weitgehend unverändert erscheinen. Hauptrisikofaktor für eine kognitive Verschlechterung unter Bestrahlung scheint ein hohes kognitives Leistungsniveau vor Bestrahlungsbeginn zu sein. Als weitere potentielle Risikofaktoren können ein zerebraler Befall, die Ganzhirnbestrahlung und infratentorielle Strukturen im Bestrahlungsvolumen identifiziert werden

INTRAGO: intraoperative radiotherapy in glioblastoma multiforme – a Phase I/II dose escalation study

Background: Glioblastoma multiforme (GBM) is the most frequent primary malignant brain tumor in adults. Despite multimodal therapies, almost all GBM recur within a narrow margin around the initial resected lesion. Thus, novel therapeutic intensification strategies must target both, the population of dispersed tumor cells around the cavity and the postoperative microenvironment. Intraoperative radiotherapy (IORT) is a pragmatic and effective approach to sterilize the margins from persistent tumor cells, abrogate post-injury proliferative stimuli and to bridge the therapeutic gap between surgery and radiochemotherapy. Therefore, we have set up INTRAGO, a phase I/II dose-escalation study to evaluate the safety and tolerability of IORT added to standard therapy in newly diagnosed GBM. In contrast to previous approaches, the study involves the application of isotropic low-energy (kV) x-rays delivered by spherical applicators, providing optimal irradiation properties to the resection cavity. Methods/Design: INTRAGO includes patients aged 50 years or older with a Karnofsky performance status of at least 50% and a histologically confirmed (frozen sections) supratentorial GBM. Safety and tolerability (i.e., the maximum tolerated dose, MTD) will be assessed using a classical 3 + 3 dose-escalation design. Dose-limiting toxicities (DLT) are wound healing deficits or infections requiring surgical intervention, IORT-related cerebral bleeding or ischemia, symptomatic brain necrosis requiring surgical intervention and early termination of external beam radiotherapy (before the envisaged dose of 60 Gy) due to radiotoxicity. Secondary end points are progression-free and overall survival. Trial registration: The study is registered with clinicaltrials.gov, number: NCT02104882 (Registration Date: 03/26/2014)

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

The influence of smoking and other risk factors on the outcome after radiochemotherapy for anal cancer

Abstract Background Smoking is an important risk factor for the development of cancer. Smoking during radiochemotherapy therapy may have a negative influence on prognosis. We evaluated the effect of smoking during radiochemotherapy on the outcome for patients with anal cancer. Methods Sixty-eight patients (34 smokers, 34 non-smokers) treated by radiochemotherapy for anal cancer were analysed. The effect of smoking during radiochemotherapy and other risk factors (gender, T- and N category, tumor site, dose, therapy protocol) on disease-specific survival (DSS), local control (LC) and colostomy free survival (CFS) was evaluated. Results There was a significant difference in age and male:female ratio between the two groups. With a median follow up of 22 months (max. 119) DSS, LC, and CFS were 88%, 84% and 84%. A significant difference in local control between smokers (S) and non-smokers (NS) was found (S 74% vs. NS 94%, p = .03). For DSS and CFS a difference in terms of outcome between smokers and non-smokers was seen (DSS: S 82% vs. NS 96%, p = .19, CFS: S 75% vs. 91%, p = .15), which did not reach statistical significance. In multivariate analyses only gender had a significant association with LC and T category with CFS. The other risk factors did not reach statistical significance. Conclusion Even though our evaluation reached statistical significance only in univariate analysis, we suggest, that the role of smoking during radiochemotherapy for anal cancer should not be ignored. The potential negative effect on prognosis should be explained to patients before therapy.</p

Long-term outcome after combined kyphoplasty and intraoperative radiotherapy (Kypho-IORT) for vertebral tumors

Introduction!#!The spine represents the site which is most frequently affected by bone metastases in patients with systemic cancer. Of all local treatment options, combined kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provides both, instantaneous stabilization and immediate pain relief. We here report on the long-term outcomes of the largest cohort treated with Kypho-IORT to date.!##!Methods!#!Between 2009 and 2019 a total of 104 patients underwent Kypho-IORT to vertebral tumors in the thoracic, lumbar, or sacral spine with transpedicular kyphoplasty and intraoperative irradiation with a needle-shaped electronic brachytherapy source at our center. Patients were treated either on trial, within the prospective Kypho-IORT studies (NCT01280032 and NCT02773966), or, after completion of the study, off trial but compliant with the study protocol. Follow-up and imaging with computed tomography (CT) or magnetic resonance imaging was scheduled after 3 and 6 months and then bi-annually.!##!Results!#!A total of 143 vertebrae (89 thoracic spine, 53 lumbar spine, and 1 sacral spine) were treated in 104 patients. The median follow-up was 14.5 months (range 0.4-109). Local progression occurred in 10 patients (10 vertebrae) after a median time of 22.3 months (range 1.5-73) resulting in local control rates of 97.1, 95.9, and 94.2% at 6, 12, and 24 months, respectively. Overall survival was 74.6, 61.7, and 50.3% at 6, 12, and 24 months, respectively. A single serious adverse event was reported.!##!Conclusion!#!In addition to immediate pain reduction and stabilization, Kypho-IORT shows excellent long-term local control with minimal side effects