@article{LewitzkiAndratschkeKuhntetal.2015, author = {Lewitzki, Victor and Andratschke, Nicolaus and Kuhnt, Thomas and Hildebrandt, Guido}, title = {Radiation myelitis after hypofractionated radiotherapy with concomitant gefitinib}, series = {Radiation Oncology}, volume = {10}, journal = {Radiation Oncology}, number = {29}, doi = {10.1186/s13014-015-0334-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175443}, year = {2015}, abstract = {We describe the case of a 71-year-old Caucasian female with primary disseminated non-small cell cancer of the lung, presented for palliative radiotherapy of metastatic spread to the 9th and 11th thoracic vertebrae without intramedullary growth. Palliative radiotherapy with daily fractions of 3 Gy and a cumulative dose of 36 Gy to thoracic vertebrae 8-12 was performed. The patient received concomitantly 250 mg gefitinib daily. After a latent period of 16 months, the patient developed symptoms of myelitis. Magnetic resonance imaging (MRI) did not reveal any bony or intraspinal tumor progression, but spinal cord signal alteration. No response to steroids was achieved. The neurological symptoms were progressive in August 2013 with the right leg being completely plegic. The left leg was incompletely paralyzed. Deep and superficial sensitivity was also diminished bilaterally. The patient was completely urinary and anally incontinent. Contrary to the clinical findings, a follow-up MRI (July 2013) showed amelioration of the former signal alterations in the spinal cord. The diagnosis of paraneoplastic myelopathy was refuted by a negative test for autologous antibodies. At the last clinical visit in May 2014, the neurological symptoms were stable. The last tumor-specific treatment the patient is receiving is erlotinib 125 mg/d. We reviewed the literature and found no reported cases of radiation myelopathy after the treatment in such a setting. The calculated probability of such complication after radiotherapy alone is statistically measurable at the level of 0.02\%. We suppose that gefitinib could also play a role in the development of this rare complication.}, language = {en} } @article{LewitzkiKlementKosmalaetal.2019, author = {Lewitzki, Victor and Klement, Rainer J. and Kosmala, Rebekka and Lisowski, Dominik and Flentje, Michael and Polat, B{\"u}lent}, title = {Accelerated hyperfractionated radiochemotherapy with temozolomide is equivalent to normofractionated radiochemotherapy in a retrospective analysis of patients with glioblastoma}, series = {Radiation Oncology}, volume = {14}, journal = {Radiation Oncology}, doi = {10.1186/s13014-019-1427-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202614}, pages = {227}, year = {2019}, abstract = {Background Current standard of treatment for newly diagnosed patients with glioblastoma (GBM) is surgical resection with adjuvant normofractionated radiotherapy (NFRT) combined with temozolomide (TMZ) chemotherapy. Hyperfractionated accelerated radiotherapy (HFRT) which was known as an option from randomized controlled trials before the temozolomide era has not been compared to the standard therapy in a randomized setting combined with TMZ. Methods Data of 152 patients with newly diagnosed GBM treated from 10/2004 until 7/2018 at a single tertiary care institution were extracted from a clinical database and retrospectively analyzed. Thirty-eight patients treated with NFRT of 60 Gy in 30 fractions (34 with simultaneous and 2 with sequential TMZ) were compared to 114 patients treated with HFRT of 54.0 Gy in 30 fraction of 1.8 Gy twice daily (109 with simultaneous and 3 with sequential TMZ). The association between treatment protocol and other variables with overall survival (OS) was assessed using univariable and multivariable Cox regression analysis; the latter was performed using variables selected by the LASSO method. Results Median overall survival (OS) was 20.3 month for the entire cohort. For patients treated with NFRT median OS was 24.4 months compared to 18.5 months in patients treated with HFRT (p = 0.131). In univariable regression analysis the use of dexamethasone during radiotherapy had a significant negative impact on OS in both patient groups, HR 2.21 (95\% CI 1.47-3.31, p = 0.0001). In multivariable analysis adjusted for O6-methylguanine-DNA methyl-transferase (MGMT) promotor methylation status, salvage treatment and secondary GBM, the use of dexamethasone was still a negative prognostic factor, HR 1.95 (95\% CI 1.21-3.13, p = 0.006). Positive MGMT-methylation status and salvage treatment were highly significant positive prognostic factors. There was no strong association between treatment protocol and OS (p = 0.504). Conclusions Our retrospective analysis supports the hypothesis of equivalence between HFRT and the standard protocol of treatment for GBM. For those patients who are willing to obtain the benefit of shortening the course of radiochemotherapy, HFRT may be an alternative with comparable efficacy although it was not yet tested in a large prospective randomized study against the current standard. The positive influence of salvage therapy and negative impact of concomitant use of corticosteroids should be addressed in future prospective trials. To confirm our results, we plan to perform a pooled analysis with other tertiary clinics in order to achieve better statistical reliability.}, language = {en} } @article{KlementPoppKauletal.2022, author = {Klement, Rainer J. and Popp, Ilinca and Kaul, David and Ehret, Felix and Grosu, Anca L. and Polat, B{\"u}lent and Sweeney, Reinhart A. and Lewitzki, Victor}, title = {Accelerated hyper-versus normofractionated radiochemotherapy with temozolomide in patients with glioblastoma: a multicenter retrospective analysis}, series = {Journal of Neuro-Oncology}, volume = {156}, journal = {Journal of Neuro-Oncology}, number = {2}, issn = {1573-7373}, doi = {10.1007/s11060-021-03926-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-269806}, pages = {407-417}, year = {2022}, abstract = {Background and Purpose The standard treatment of glioblastoma patients consists of surgery followed by normofractionated radiotherapy (NFRT) with concomitant and adjuvant temozolomide chemotherapy. Whether accelerated hyperfractionated radiotherapy (HFRT) yields comparable results to NFRT in combination with temozolomide has only sparsely been investigated. The objective of this study was to compare NFRT with HFRT in a multicenter analysis. Materials and Methods A total of 484 glioblastoma patients from four centers were retrospectively pooled and analyzed. Three-hundred-ten and 174 patients had been treated with NFRT (30 × 1.8 Gy or 30 × 2 Gy) and HFRT (37 × 1.6 Gy or 30 × 1.8 Gy twice/day), respectively. The primary outcome of interest was overall survival (OS) which was correlated with patient-, tumor- and treatment-related variables via univariable and multivariable Cox frailty models. For multivariable modeling, missing covariates were imputed using multiple imputation by chained equations, and a sensitivity analysis was performed on the complete-cases-only dataset. Results After a median follow-up of 15.7 months (range 0.8-88.6 months), median OS was 16.9 months (15.0-18.7 months) in the NFRT group and 14.9 months (13.2-17.3 months) in the HFRT group (p = 0.26). In multivariable frailty regression, better performance status, gross-total versus not gross-total resection, MGMT hypermethylation, IDH mutation, smaller planning target volume and salvage therapy were significantly associated with longer OS (all p < 0.01). Treatment differences (HFRT versus NFRT) had no significant effect on OS in either univariable or multivariable analysis. Conclusions Since HFRT with temozolomide was not associated with worse OS, we assume HFRT to be a potential option for patients wishing to shorten their treatment time.}, language = {en} } @article{PollmannToussaintFlentjeetal.2022, author = {Pollmann, Stephan and Toussaint, Andr{\´e} and Flentje, Michael and Wegener, Sonja and Lewitzki, Victor}, title = {Dosimetric evaluation of commercially available flat vs. self-produced 3D-conformal silicone boluses for the head and neck region}, series = {Frontiers in Oncology}, volume = {12}, journal = {Frontiers in Oncology}, issn = {2234-943X}, doi = {10.3389/fonc.2022.881439}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-283156}, year = {2022}, abstract = {Background Boluses are routinely used in radiotherapy to modify surface doses. Nevertheless, considerable dose discrepancies may occur in some cases due to fit inaccuracy of commercially available standard flat boluses. Moreover, due to the simple geometric design of conventional boluses, also surrounding healthy skin areas may be unintentionally covered, resulting in the unwanted dose buildup. With the fused deposition modeling (FDM) technique, there is a simple and possibly cost-effective way to solve these problems in routine clinical practice. This paper presents a procedure of self-manufacturing bespoke patient-specific silicone boluses and the evaluation of buildup and fit accuracy in comparison to standard rectangular commercially available silicone boluses. Methods 3D-conformal silicone boluses were custom-built to cover the surgical scar region of 25 patients who received adjuvant radiotherapy of head and neck cancer at the University Hospital W{\"u}rzburg. During a standard CT-based planning procedure, a 5-mm-thick 3D bolus contour was generated to cover the radiopaque marked surgical scar with an additional safety margin. From these digital contours, molds were 3D printed and poured with silicone. Dose measurements for both types of boluses were performed with radiochromic films (EBT3) at three points per patient—at least one aimed to be in the high-dose area (scar) and one in the lower-dose area (spared healthy skin). Surface-bolus distance, which ideally should not be present, was determined from cone-beam CT performed for positioning control. The dosimetric influence of surface-bolus distance was also determined on slab phantom for different field sizes. The trial was performed with hardware that may be routinely available in every radiotherapy department, with the exception of the 3D printer. The required number of patients was determined based on the results of preparatory measurements with the help of the statistical consultancy of the University of W{\"u}rzburg. The number of measuring points represents the total number of patients. Results In the high-dose area of the scar, there was a significantly better intended dose buildup of 2.45\% (95\%CI 0.0014-0.0477, p = 0.038, N = 30) in favor of a 3D-conformal bolus. Median distances between the body surface and bolus differed significantly between 3D-conformal and commercially available boluses (3.5 vs. 7.9 mm, p = 0.001). The surface dose at the slab phantom did not differ between commercially available and 3D-conformal boluses. Increasing the surface-bolus distance from 5 to 10 mm decreased the surface dose by approximately 2\% and 11\% in the 6 × 6- and 3 × 3-cm2 fields, respectively. In comparison to the commercially available bolus, an unintended dose buildup in the healthy skin areas was reduced by 25.9\% (95\%CI 19.5-32.3, p < 0.01, N = 37) using the 3D-conformal bolus limited to the region surrounding the surgical scar. Conclusions Using 3D-conformal boluses allows a comparison to the commercially available boluses' dose buildup in the covered areas. Smaller field size is prone to a larger surface-bolus distance effect. Higher conformity of 3D-conformal boluses reduces this effect. This may be especially relevant for volumetric modulated arc therapy (VMAT) and intensity-modulated radiotherapy (IMRT) techniques with a huge number of smaller fields. High conformity of 3D-conformal boluses reduces an unintended dose buildup in healthy skin. The limiting factor in the conformity of 3D-conformal boluses in our setting was the immobilization mask, which was produced primarily for the 3D boluses. The mask itself limited tight contact of subsequently produced 3D-conformal boluses to the mask-covered body areas. In this respect, bolus adjustment before mask fabrication will be done in the future setting.}, language = {en} } @article{LisowskiTroemelLutyjetal.2022, author = {Lisowski, Dominik and Tr{\"o}mel, Jannik and Lutyj, Paul and Lewitzki, Victor and Hartrampf, Philipp E. and Polat, B{\"u}lent and Flentje, Michael and Tamihardja, J{\"o}rg}, title = {Health-related quality of life and clinical outcome after radiotherapy of patients with intracranial meningioma}, series = {Scientific Reports}, volume = {12}, journal = {Scientific Reports}, doi = {10.1038/s41598-022-24192-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301233}, year = {2022}, abstract = {This retrospective, single-institutional study investigated long-term outcome, toxicity and health-related quality of life (HRQoL) in meningioma patients after radiotherapy. We analyzed the data of 119 patients who received radiotherapy at our department from 1997 to 2014 for intracranial WHO grade I-III meningioma. Fractionated stereotactic radiotherapy (FSRT), intensity modulated radiotherapy (IMRT) or radiosurgery radiation was applied. The EORTC QLQ-C30 and QLQ-BN20 questionnaires were completed for assessment of HRQoL. Overall survival (OS) for the entire study group was 89.6\% at 5 years and 75.9\% at 10 years. Local control (LC) at 5 and 10 years was 82.4\% and 73.4\%, respectively. Local recurrence was observed in 22 patients (18.5\%). Higher grade acute and chronic toxicities were observed in seven patients (5.9\%) and five patients (4.2\%), respectively. Global health status was rated with a mean of 59.9 points (SD 22.3) on QLQ-C30. In conclusion, radiotherapy resulted in very good long-term survival and tumor control rates with low rates of severe toxicities but with a deterioration of long-term HRQoL.}, language = {en} } @article{PolatWohllebenKosmalaetal.2022, author = {Polat, B{\"u}lent and Wohlleben, Gisela and Kosmala, Rebekka and Lisowski, Dominik and Mantel, Frederick and Lewitzki, Victor and L{\"o}hr, Mario and Blum, Robert and Herud, Petra and Flentje, Michael and Monoranu, Camelia-Maria}, title = {Differences in stem cell marker and osteopontin expression in primary and recurrent glioblastoma}, series = {Cancer Cell International}, volume = {22}, journal = {Cancer Cell International}, issn = {1475-2867}, doi = {10.1186/s12935-022-02510-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301240}, year = {2022}, abstract = {Background Despite of a multimodal approach, recurrences can hardly be prevented in glioblastoma. This may be in part due to so called glioma stem cells. However, there is no established marker to identify these stem cells. Methods Paired samples from glioma patients were analyzed by immunohistochemistry for expression of the following stem cell markers: CD133, Musashi, Nanog, Nestin, octamer-binding transcription factor 4 (Oct4), and sex determining region Y-box 2 (Sox2). In addition, the expression of osteopontin (OPN) was investigated. The relative number of positively stained cells was determined. By means of Kaplan-Meier analysis, a possible association with overall survival by marker expression was investigated. Results Sixty tissue samples from 30 patients (17 male, 13 female) were available for analysis. For Nestin, Musashi and OPN a significant increase was seen. There was also an increase (not significant) for CD133 and Oct4. Patients with mutated Isocitrate Dehydrogenase-1/2 (IDH-1/2) status had a reduced expression for CD133 and Nestin in their recurrent tumors. Significant correlations were seen for CD133 and Nanog between OPN in the primary and recurrent tumor and between CD133 and Nestin in recurrent tumors. By confocal imaging we could demonstrate a co-expression of CD133 and Nestin within recurrent glioma cells. Patients with high CD133 expression had a worse prognosis (22.6 vs 41.1 months, p = 0.013). A similar trend was seen for elevated Nestin levels (24.9 vs 41.1 months, p = 0.08). Conclusions Most of the evaluated markers showed an increased expression in their recurrent tumor. CD133 and Nestin were associated with survival and are candidate markers for further clinical investigation.}, language = {en} } @article{DietzschBraesigkSeideletal.2022, author = {Dietzsch, Stefan and Braesigk, Annett and Seidel, Clemens and Remmele, Julia and Kitzing, Ralf and Schlender, Tina and Mynarek, Martin and Geismar, Dirk and Jablonska, Karolina and Schwarz, Rudolf and Pazos, Montserrat and Weber, Damien C. and Frick, Silke and Gurtner, Kristin and Matuschek, Christiane and Harrabi, Semi Ben and Gl{\"u}ck, Albrecht and Lewitzki, Victor and Dieckmann, Karin and Benesch, Martin and Gerber, Nicolas U. and Obrecht, Denise and Rutkowski, Stefan and Timmermann, Beate and Kortmann, Rolf-Dieter}, title = {Types of deviation and review criteria in pretreatment central quality control of tumor bed boost in medulloblastoma—an analysis of the German Radiotherapy Quality Control Panel in the SIOP PNET5 MB trial}, series = {Strahlentherapie und Onkologie}, volume = {198}, journal = {Strahlentherapie und Onkologie}, number = {3}, issn = {0179-7158}, doi = {10.1007/s00066-021-01822-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307812}, pages = {282-290}, year = {2022}, abstract = {Purpose In Germany, Austria, and Switzerland, pretreatment radiotherapy quality control (RT-QC) for tumor bed boost (TB) in non-metastatic medulloblastoma (MB) was not mandatory but was recommended for patients enrolled in the SIOP PNET5 MB trial between 2014 and 2018. This individual case review (ICR) analysis aimed to evaluate types of deviations in the initial plan proposals and develop uniform review criteria for TB boost. Patients and methods A total of 78 patients were registered in this trial, of whom a subgroup of 65 patients were available for evaluation of the TB treatment plans. Dose uniformity was evaluated according to the definitions of the protocol. Additional RT-QC criteria for standardized review of target contours were elaborated and data evaluated accordingly. Results Of 65 initial TB plan proposals, 27 (41.5\%) revealed deviations of target volume delineation. Deviations according to the dose uniformity criteria were present in 14 (21.5\%) TB plans. In 25 (38.5\%) cases a modification of the RT plan was recommended. Rejection of the TB plans was rather related to unacceptable target volume delineation than to insufficient dose uniformity. Conclusion In this analysis of pretreatment RT-QC, protocol deviations were present in a high proportion of initial TB plan proposals. These findings emphasize the importance of pretreatment RT-QC in clinical trials for MB. Based on these data, a proposal for RT-QC criteria for tumor bed boost in non-metastatic MB was developed.}, language = {en} }