Publications by authors named "Beate Timmermann"

109 Publications

The effect of adjuvant therapies on long-term outcome for primary resected synovial sarcoma in a series of mainly children and adolescents.

J Cancer Res Clin Oncol 2021 Jul 17. Epub 2021 Jul 17.

Hospital for Children and Adolescents, Goethe-University Frankfurt (Main), Frankfurt, Germany.

Background: The benefit of adjuvant therapy in synovial sarcoma (SS) treatment is under debate. Long-term follow-up data are missing.

Methods: SS patients treated in the consecutive trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P, and the SoTiSaR-registry till 2013 were analyzed.

Results: Median age of 185 patients was 13.9 years (0.1-56)-with median follow-up of 7.4 years for 163 survivors. Most tumors (76%) were located in extremities. Size was < 3 cm in 58 (31%), 3-5 cm in 59 (32%), 5-10 cm in 42 (23%), and > 10 cm in 13 (7%) (13 missing). In 84 (45%) tumors, first excision was complete (R0 corresponding to IRS-I-group) and in 101 (55%) marginal (R1 corresponding to IRS-II-group). In a subsequent surgical intervention during chemotherapy, R0-status was accomplished in 23 additional IRS-II-group patients with secondary surgery. Radiotherapy was administered to 135 (73%), thereof 62 with R0-status and 67 R1-status (6 missing information). Adjuvant chemotherapy was administered to all but six patients. 5-year event-free (EFS) and overall survival (OS) was 82.9% ± 5.7 (95%CI) and 92.5% ± 3.9. Local and metastatic relapse-free survival was 91.3% ± 4.3 and 92.3% ± 4.1 at 5 years, respectively. In the multivariate analysis, tumor size and no chemotherapy were independently associated with EFS. Size and site were associated with OS. In a detailed analysis of local and metastatic events, tumor size was associated with an independent risk for developing metastases. No independent factor for suffering local recurrence could be identified.

Discussion: Omission of chemotherapy in a non-stratified way seems not justified. Size governs survival due to high linear association with risk of suffering metastatic recurrence in a granular classification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-021-03614-6DOI Listing
July 2021

Evaluation of treatment-associated eye toxicity after irradiation in childhood and adolescence-results from the Registry of the Evaluation of Side Effects after Radiotherapy in Childhood and Adolescence (RiSK).

Strahlenther Onkol 2021 Aug 7;197(8):700-710. Epub 2021 Jun 7.

Department of Radiotherapy, Medical School Hannover, Hannover, Germany.

Purpose: The aim of the study is to evaluate treatment-related acute and late eye toxicity associated with radiation therapy in childhood and adolescence as correlated with RT (radiotherapy) doses.

Methods: From 2001 to 2016, a total of 1725 children and adolescents undergoing radiation therapy were prospectively documented in the Registry of the Evaluation of Side Effects after Radiotherapy in Childhood and Adolescence (RiSK). The RTOG/EORTC criteria were used to classify ocular acute and late effects. Uni- and multivariate analyses were carried out to evaluate the impact of patient age, pre-existing impairments, and radiation dose on ocular toxicity.

Results: Of all documented patients, 593 received dose to the eye and formed the basis of this analysis. In 435 patients, information on acute reaction was available and graded 1, 2, 3, and 4 in 49, 17, 0, and 2 patients, respectively. Information on late toxicity was available in 268 patients and graded 1, 2, 3, and 4 in 15, 11, 11, and 5 patients, respectively. The acute toxicity rate was significantly higher in children who received a maximum dose > 50 Gy to the eye (p < 0.001) and who had a pre-existing eye impairment (p < 0.001 in multivariate analysis). The development of late toxicity was significantly higher for patients experiencing acute toxicity and having received a radiation dose > 50 Gy.

Conclusion: Acute and late toxicity both correlate with high radiation dose to the eye (> 50 Gy) and acute toxicity additionally with pre-existing eye impairments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00066-021-01793-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292243PMC
August 2021

Clinical Implementation of Proton Therapy Using Pencil-Beam Scanning Delivery Combined With Static Apertures.

Front Oncol 2021 12;11:599018. Epub 2021 May 12.

West German Proton Therapy Centre Essen, Essen, Germany.

Proton therapy makes use of the favorable depth-dose distribution with its characteristic Bragg peak to spare normal tissue distal of the target volume. A steep dose gradient would be desired in lateral dimensions, too. The widespread spot scanning delivery technique is based, however, on pencil-beams with in-air spot full-widths-at-half-maximum of typically 1 cm or more. This hampers the sparing of organs-at-risk if small-scale structures adjacent to the target volume are concerned. The trimming of spot scanning fields with collimating apertures constitutes a simple measure to increase the transversal dose gradient. The current study describes the clinical implementation of brass apertures in conjunction with the pencil-beam scanning delivery mode at a horizontal, clinical treatment head based on commercial hardware and software components. Furthermore, clinical cases, which comprised craniopharyngiomas, re-irradiations and ocular tumors, were evaluated. The dosimetric benefits of 31 treatment plans using apertures were compared to the corresponding plans without aperture. Furthermore, an overview of the radiation protection aspects is given. Regarding the results, robust optimization considering range and setup uncertainties was combined with apertures. The treatment plan optimizations followed a single-field uniform dose or a restricted multi-field optimization approach. Robustness evaluation was expanded to account for possible deviations of the center of the pencil-beam delivery and the mechanical center of the aperture holder. Supplementary apertures improved the conformity index on average by 15.3%. The volume of the dose gradient surrounding the PTV (evaluated between 80 and 20% dose levels) was decreased on average by 17.6%. The mean dose of the hippocampi could be reduced on average by 2.9 GyRBE. In particular cases the apertures facilitated a sparing of an organ-at-risk, e.g. the eye lens or the brainstem. For six craniopharyngioma cases the inclusion of apertures led to a reduction of the mean dose of 1.5 GyRBE (13%) for the brain and 3.1 GyRBE (16%) for the hippocampi.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.599018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149965PMC
May 2021

Update of the EPTN atlas for CT- and MR-based contouring in Neuro-Oncology.

Radiother Oncol 2021 07 18;160:259-265. Epub 2021 May 18.

Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf Dresden, Germany; German Cancer Consortium (DKTK), partnersite Dresden and German Cancer Research Center (DKFZ), Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresde, Germany; Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR)., Germany.

Background And Purpose: To update the digital online atlas for organs at risk (OARs) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging with new OARs.

Materials And Methods: In this planned update of the neurological contouring atlas published in 2018, ten new clinically relevant OARs were included, after thorough discussion between experienced neuro-radiation oncologists (RTOs) representing 30 European radiotherapy-oncology institutes. Inclusion was based on daily practice and research requirements. Consensus was reached for the delineation after critical review. Contouring was performed on registered CT with intravenous (IV) contrast (soft tissue & bone window setting) and 3 Tesla (T) MRI (T1 with gadolinium & T2 FLAIR) images of one patient (1 mm slices). For illustration purposes, delineation on a 7 T MRI without IV contrast from a healthy volunteer was added. OARs were delineated by three experienced RTOs and a neuroradiologist based on the relevant literature.

Results: The presented update of the neurological contouring atlas was reviewed and approved by 28 experts in the field. The atlas is available online and includes in total 25 OARs relevant to neuro-oncology, contoured on CT and MRI T1 and FLAIR (3 T & 7 T). Three-dimensional (3D) rendered films are also available online.

Conclusion: In order to further decrease inter- and intra-observer OAR delineation variability in the field of neuro-oncology, we propose the use of this contouring atlas in photon and particle therapy, in clinical practice and in the research setting. The updated atlas is freely available on www.cancerdata.org.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2021.05.013DOI Listing
July 2021

Pediatric ependymoma: an overview of a complex disease.

Childs Nerv Syst 2021 May 18. Epub 2021 May 18.

Department of Neuropathology, DGNN Brain Tumor Reference Centre, University of Bonn Medical Centre, Bonn, Germany.

Pediatric ependymomas comprise biologically distinct tumor entities with different (epi)genetics, age distribution and localization, as well as a different prognosis. Regarding risk stratification within these biologically defined entities, histopathological features still seem to be relevant. The mainstay of treatment is gross total resection (GTR) if possible, achieved with intraoperative monitoring and neuronavigation-and if necessary second surgery-followed by adjuvant radiation therapy. However, there is growing evidence that some ependymal tumors may be cured by surgery alone, while others relapse despite adjuvant treatment. To date, the role of chemotherapy is not clear. Current therapy achieves reasonable survival rates for the majority of ependymoma patients. The next challenge is to go beyond initial tumor control and use risk-adapted therapy to reduce secondary effect and therapy-induced morbidity for low-risk patients and to intensify treatment for high-risk patients. With identification of specific alterations, targeted therapy may represent an option for individualized treatment modalities in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00381-021-05207-7DOI Listing
May 2021

Doubling Recruitment of Pediatric Low-grade Glioma within Two Decades does not change Outcome - Report from the German LGG Studies.

Klin Padiatr 2021 May 10;233(3):107-122. Epub 2021 May 10.

Division of Childhood Cancer Epidemiology, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany.

Background: Successive multicenter studies for pediatric low-grade glioma (LGG) in Germany were accompanied by a doubling of annual recruitment over 2 decades. We investigated whether this increase conveyed a change of epidemiologic characteristics or survival.

Methods And Results: Participating centers reported 4634 patients with the radiologic/histologic diagnosis of LGG (1996-2018), rising from 109 to 278/year. Relating these numbers to all pediatric CNS tumors registered at the German Childhood Cancer Registry, the LGG fraction and annual crude incidence rates increased (32% to 51%; 0.94 to 2.12/100,000 children/adolescents<15 years). The consecutive LGG studies recruited 899 (HIT-LGG 1996), 1592 (SIOP-LGG 2004), and 1836 (LGG-registry) patients with similar distribution of tumor-sites, histology, and dissemination. 5-year overall survival was 96%-98% at median observation time of 8.1 years. Acknowledging unequal follow-up periods, 589/899 (66%), 1089/1582 (69%), and 1387/1836 (76%) patients remained under observation, while 1252/4317 received adjuvant treatment with decreasing frequency of front-line radiotherapy from 16% to 5%.

Conclusion: Pediatric LGG incidence rates in Germany are now comparable to other European countries. The rise in patient numbers followed implementation of standard-of-care treatment protocols, but did not result in relevant changes of epidemiologic or clinical parameters or survival. Shifts in patient distribution between treatment arms reflect growing acceptance of the LGG therapy algorithm.

Hintergrund: In den vergangenen 20 Jahren hat sich die jährliche Patientenrekrutierung in den aufeinanderfolgenden multizentrischen Studien für pädiatrische niedrig-gradige Gliome (LGG) in Deutschland verdoppelt. Wir haben untersucht, ob sich mit dieser Zunahme auch epidemiologische Merkmale oder das Überleben verändert haben.

Methodik Und Ergebnisse: Zwischen 1996 und 2018 meldeten die teilnehmenden Zentren insgesamt 4634 Patienten mit der radiologischen/histologischen Diagnose eines LGG. Die Zahl stieg von anfangs 109 bis 278 Patienten pro Jahr. Gleichzeitig stieg der Anteil der LGGs an allen am Deutschen Kinderkrebsregister gemeldeten pädiatrischen Hirntumoren von 32 auf 51%, die jährliche Inzidenz erhöhte sich von 0,94 auf 2,12/100 000 Kinder/Jugendliche<15 Jahre. Die aufeinanderfolgenden LGG-Studien rekrutierten 899 (HIT-LGG 1996), 1592 (SIOP-LGG 2004) und 1836 (LGG-Register) Patienten mit vergleichbarer Verteilung von Tumorsitz, Histologie und Disseminierung. Das 5-Jahres-Überleben lag bei einer medianen Nachbeobachtungszeit von 8,1 Jahren zwischen 96 und 98%. Unter Berücksichtigung der ungleich langen Follow-up-Zeit wurden 589/899 (65,5%), 1089/1582 (68,8%) und 1387/1836 (75,5%) Patienten bislang beobachtet, während 1252/4317 eine adjuvante Therapie erhielten. Dabei sank der Anteil der primären Radiotherapie von 16 auf 5%.

Schlussfolgerung: Die Rekrutierung pädiatrischer LGG ist dank Implementierung verbindlicher Therapiestandards in Deutschland gestiegen, ohne zu relevanten Veränderungen epidemiologischer oder klinischer Merkmale oder des Überlebens zu führen. Die Inzidenz ist mit anderen europäischen Ländern vergleichbar. Verschiebungen der Patientenzuteilung zwischen den Therapiearmen spiegeln die zunehmende Akzeptanz des LGG-Therapie-Algorithmus wider.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1471-5897DOI Listing
May 2021

Feasibility of Proton Beam Therapy as a Rescue Therapy in Heavily Pre-Treated Retinoblastoma Eyes.

Cancers (Basel) 2021 Apr 13;13(8). Epub 2021 Apr 13.

Department of Ophthalmology, University Hospital Essen, University Duisburg Essen, 45122 Essen, Germany.

Despite the increased risk of subsequent primary tumors (SPTs) external beam radiation (EBRT) may be the only therapeutic option to preserve a retinoblastoma eye. Due to their physical properties, proton beam therapy (PBT) offers the possibility to use the effectiveness of EBRT in tumor treatment and to decisively reduce the treatment-related morbidity. We report our experiences of PBT as rescue therapy in a retrospectively studied cohort of 15 advanced retinoblastoma eyes as final option for eye-preserving therapy. The average age at the initiation of PBT was 35 (14-97) months, mean follow-up was 22 (2-46) months. Prior to PBT, all eyes were treated with systemic chemotherapy and a mean number of 7.1 additional treatments. Indication for PBT was non-feasibility of intra-arterial chemotherapy (IAC) in 10 eyes, tumor recurrence after IAC in another 3 eyes and diffuse infiltrating retinoblastoma in 2 eyes. Six eyes (40%) were enucleated after a mean time interval of 4.8 (1-8) months. Cataract formation was the most common complication affecting 44.4% of the preserved eyes, yet 77.8% achieved a visual acuity of >20/200. Two of the 15 children treated developed metastatic disease during follow-up, resulting in a 13.3% metastasis rate. PBT is a useful treatment modality as a rescue therapy in retinoblastoma eyes with an eye-preserving rate of 60%. As patients are at lifetime risk of SPTs consistent monitoring is mandatory.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13081862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069965PMC
April 2021

Ewing Sarcoma-Diagnosis, Treatment, Clinical Challenges and Future Perspectives.

J Clin Med 2021 Apr 14;10(8). Epub 2021 Apr 14.

Pediatrics III, University Hospital Essen, 45147 Essen, Germany.

Ewing sarcoma, a highly aggressive bone and soft-tissue cancer, is considered a prime example of the paradigms of a translocation-positive sarcoma: a genetically rather simple disease with a specific and neomorphic-potential therapeutic target, whose oncogenic role was irrefutably defined decades ago. This is a disease that by definition has micrometastatic disease at diagnosis and a dismal prognosis for patients with macrometastatic or recurrent disease. International collaborations have defined the current standard of care in prospective studies, delivering multiple cycles of systemic therapy combined with local treatment; both are associated with significant morbidity that may result in strong psychological and physical burden for survivors. Nevertheless, the combination of non-directed chemotherapeutics and ever-evolving local modalities nowadays achieve a realistic chance of cure for the majority of patients with Ewing sarcoma. In this review, we focus on the current standard of diagnosis and treatment while attempting to answer some of the most pressing questions in clinical practice. In addition, this review provides scientific answers to clinical phenomena and occasionally defines the resulting translational studies needed to overcome the hurdle of treatment-associated morbidities and, most importantly, non-survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10081685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071040PMC
April 2021

Eye Tumors in Childhood as First Sign of Tumor Predisposition Syndromes: Insights from an Observational Study Conducted in Germany and Austria.

Cancers (Basel) 2021 Apr 14;13(8). Epub 2021 Apr 14.

Institute of Human Genetics, Medical Faculty, University Duisburg-Essen, 45122 Essen, Germany.

Retinoblastoma and other eye tumors in childhood are rare diseases. Many eye tumors are the first signs of a genetic tumor predisposition syndrome and the affected children carry a higher risk of developing other cancers later in life. Clinical and genetic data of all children with eye tumors diagnosed between 2013-2018 in Germany and Austria were collected in a multicenter prospective observational study. In five years, 300 children were recruited into the study: 287 with retinoblastoma, 7 uveal melanoma, 3 ciliary body medulloepithelioma, 2 retinal astrocytoma, 1 meningioma of the optic nerve extending into the eye. Heritable retinoblastoma was diagnosed in 44% of children with retinoblastoma. One child with meningioma of the optic nerve extending into the eye was diagnosed with neurofibromatosis 2. No pathogenic constitutional variant in was detected in a child with medulloepithelioma while two children did not receive genetic analysis. Because of the known association with tumor predisposition syndromes, genetic counseling should be offered to all children with eye tumors. Children with a genetic predisposition to cancer should receive a tailored surveillance including detailed history, physical examinations and, if indicated, imaging to screen for other cancer. Early detection of cancers may reduce mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13081876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070790PMC
April 2021

Treatment of Embryonal Tumours with Multilayered Rosettes with Carboplatin/Etoposide Induction and High-dose Chemotherapy within the Prospective P-HIT Trial.

Neuro Oncol 2021 Apr 28. Epub 2021 Apr 28.

Division of Oncology and Haematology, Department of Paediatrics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany.

Background: Embryonal tumours with multilayered rosettes (ETMR) are highly aggressive tumours occurring in early childhood. Published clinical data refer to retrospective, heterogeneously treated cohorts. Here, we describe the outcome of patients treated according to the prospective P-HIT trial and subsequent HIT2000-interim-registry.

Patients And Methods: Age-stratified treatment included carboplatin/etoposide-induction, tandem-high-dose chemotherapy ("CARBO/ETO+HDCT") and response-stratified radiotherapy. Patients with centrally reviewed neuropathological and molecularly confirmed diagnosis of ETMR recruited within the P-HIT trial (2001-2011; n=19), the HIT2000-interim-registry (2012-2014; n=12) and earlier HIT-trials (n=4) were selected for analysis.

Results: Age-adjusted incidence rate was 1.35 per 1 million children (aged 1-4 years) in the years 2012-2014. Median age at diagnosis for 35 patients was 2.9 years. Metastases at diagnosis were detected in 9 patients. One patient died due to postoperative complications. For 30 patients with non-brainstem tumour location, 5-year progression-free (PFS) and overall survival (OS) were 35% and 47% after treatment with CARBO/ETO+HDCT (n=17), compared to 0% and 8% with other treatments (n=13, p[OS]=0.011). All 4 patients with brainstem tumour died within 10 months after diagnosis. By multivariable analysis, supratentorial location: (HR[PFS]:0.07 [95%CI:0.01-0.38], p=0.003), localised disease (M0): (HR[OS] M0, no residual tumor:0.30 [95%CI:0.009-1.09], p=0.068; M0, residual tumor:0.18 [95%CI: 0.04-0.76], p=0.020) and CARBO/ETO+HDCT treatment (HR[OS]:0.16 [95%CI:0.05-054], p=0.003) were identified as independent prognostic factors. Of 9 survivors, 6 were treated with radiotherapy (craniospinal 4; local 2).

Conclusions: Our data indicate improved survival with intensified chemotherapy (CARBO/ETO+HDCT). However, despite intensive treatment, the outcome was poor. Thus, innovative therapies need to be evaluated urgently in an upfront setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noab100DOI Listing
April 2021

Identification of patient benefit from proton beam therapy in brain tumour patients based on dosimetric and NTCP analyses.

Radiother Oncol 2021 07 17;160:69-77. Epub 2021 Apr 17.

OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. Electronic address:

Background: The limited availability of proton beam therapy (PBT) requires individual treatment selection strategies, such as the model-based approach. In this study, we assessed the dosimetric benefit of PBT compared to photon therapy (XRT), analysed the corresponding changes in normal tissue complication probability (NTCP) on a variety of available models, and illustrated model-based patient selection in an in-silico study for patients with brain tumours.

Methods: For 92 patients treated at two PBT centres, volumetric modulated arc therapy treatment plans were retrospectively created for comparison with the clinically applied PBT plans. Several dosimetric parameters for the brain excluding tumour and margins, cerebellum, brain stem, frontal and temporal lobes, hippocampi, cochleae, chiasm, optic nerves, lacrimal glands, lenses, pituitary gland, and skin were compared between both modalities using Wilcoxon signed-rank tests. NTCP differences (ΔNTCP) were calculated for 11 models predicting brain necrosis, delayed recall, temporal lobe injury, hearing loss, tinnitus, blindness, ocular toxicity, cataract, endocrine dysfunction, alopecia, and erythema. A patient was assumed to be selected for PBT if ΔNTCP exceeded a threshold of 10 percentage points for at least one of the side-effects.

Results: PBT substantially reduced the dose in almost all investigated OARs, especially in the low and intermediate dose ranges and for contralateral organs. In general, NTCP predictions were significantly lower for PBT compared to XRT, in particular in ipsilateral organs. Considering ΔNTCP of all models, 80 patients (87.0%) would have been selected for PBT in this in-silico study, mainly due to predictions of a model on delayed recall (51 patients).

Conclusion: In this study, substantial dose reductions for PBT were observed, mainly in contralateral organs. However, due to the sigmoidal dose response, NTCP was particularly reduced in ipsilateral organs. This underlines that physical dose-volume parameters alone may not be sufficient to describe the clinical relevance between different treatment techniques and highlights potential benefits of NTCP models. Further NTCP models for different modern treatment techniques are mandatory and existing models have to be externally validated in order to implement the model-based approach in clinical practice for cranial radiotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2021.04.008DOI Listing
July 2021

Experiments and Monte Carlo simulations on multiple Coulomb scattering of protons.

Med Phys 2021 Jun 3;48(6):3186-3199. Epub 2021 May 3.

West German Proton Therapy Centre Essen WPE, Essen, Germany.

Background And Purpose: Monte Carlo simulations as well as analytical computations of proton transport in material media require accurate values of multiple Coulomb scattering (MCS) angles. High-quality experimental data on MCS angles in the energy range for proton therapy are, however, sparse. In this work, MCS modeling in proton transport was evaluated employing an experimental method to measure these angles on a medical proton beamline in clinically relevant materials. Results are compared to Monte Carlo simulations and analytical models.

Materials And Methods: Aluminum, brass, and lucite (PMMA) scatterers of clinically relevant thicknesses were irradiated with protons at 100, 160, and 220 MeV. Resulting spatial distributions of individual pencil beams were measured with a scintillating screen. The MCS angles were determined by deconvolution and a virtual point source approach. Results were compared to those obtained with the Monte Carlo codes PENH, TOPAS, and RayStation Monte Carlo, as well as the analytical models RayStation Pencil Beam Algorithm and the Molière/Fano/Hanson variant of the Molière theory.

Results: Experimental data obtained with the presented methodology agree with previously published results within 6%, with an average deviation of 3%. The combined average uncertainty of the experimental data yielded 1.8%, while the combined maximum uncertainty was below 4%. The obtained Monte Carlo results for PENH, TOPAS, and RayStation deviate on average for all considered energies, materials and thicknesses, by 2.5%, 3.4%, and 2.8% from the experimental data, respectively. For the analytical models, the average deviations amount to 4.5% and 2.9% for the RayStation Pencil Beam Algorithm and the Molière/Fano/Hanson model, respectively.

Conclusion: The experimental method developed for the present work allowed to measure MCS angles in clinical proton facilities with good accuracy. The presented method permits to extend the database on experimental MCS angles which is rather limited. This work further provides benchmark data for lucite in thicknesses relevant for clinical applications. The data may serve to validate dose engines of treatment planning systems and secondary dose check software. The Monte Carlo and analytical algorithms studied are capable of reproducing MCS data within the required accuracy for clinical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mp.14860DOI Listing
June 2021

Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG).

Pediatr Blood Cancer 2021 Jun 15;68(6):e28963. Epub 2021 Mar 15.

The Goldschleger eye institute, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.

Introduction: Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment.

Method: Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication.

Results: Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy.

Conclusion: Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28963DOI Listing
June 2021

Proton Beam Therapy for Children With Neuroblastoma: Experiences From the Prospective KiProReg Registry.

Front Oncol 2020 20;10:617506. Epub 2021 Jan 20.

Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), West German Cancer Center (WTZ), Essen, Germany.

Objective: Radiotherapy (RT) is an integral part of the interdisciplinary treatment of patients with high-risk neuroblastoma (NB). With the continuous improvements of outcome, the interest in local treatment strategies that reduce treatment-related side effects while achieving optimal oncological results is growing. Proton beam therapy (PBT) represents a promising alternative to conventional photon irradiation with regard to the reduction of treatment burden.

Method: Retrospective analysis of children with high or intermediate risk NB receiving PBT of the primary tumor site during first-line therapy between 2015 and 2020 was performed. Data from the prospective in-house registry Standard Protonentherapie WPE - Kinder- (KiProReg) with respect to tumor control and treatment toxicity were analyzed. Adverse events were classified according to CTCAE Version 4 (V4.0) before, during, and after PBT.

Results: In total, 44 patients (24 male, 20 female) with high (n = 39) or intermediate risk NB (n = 5) were included in the analysis. Median age was 3.4 years (range, 1.4-9.9 years). PBT doses ranged from 21.0 to 39.6 Gray (Gy) (median 36.0 Gy). Five patients received PBT to the MIBG-avid residual at the primary tumor site at time of PBT according to the NB-2004 protocol. In 39 patients radiation was given to the pre-operative tumor bed with or without an additional boost in case of residual tumor. After a median follow-up (FU) of 27.6 months, eight patients developed progression, either local recurrence (n = 1) or distant metastases (n = 7). Four patients died due to tumor progression. At three years, the estimated local control, distant metastatic free survival, progression free survival, and overall survival was 97.7, 84.1, 81.8, and 90.9%, respectively. During radiation, seven patients experienced higher-grade (CTCAE ≥ °3) hematologic toxicity. No other higher grade acute toxicity occurred. After PBT, one patient developed transient myelitis while receiving immunotherapy. No higher grade long-term toxicity was observed up to date.

Conclusion: PBT was a well tolerated and effective local treatment in children with high and intermediate risk NB. The role of RT in an intensive multidisciplinary treatment regimen remains to be studied in the future in order to better define timing, doses, target volumes, and general need for RT in a particularly sensitive cohort of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.617506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855697PMC
January 2021

Modelling of late side-effects following cranial proton beam therapy.

Radiother Oncol 2021 04 19;157:15-23. Epub 2021 Jan 19.

OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany; German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. Electronic address:

Background: The limited availability of proton beam therapy (PBT) requires individual treatment selection strategies that can be based on normal tissue complication probability (NTCP) models. We developed and externally validated NTCP models for common late side-effects following PBT in brain tumour patients to optimise patients' quality of life.

Methods: Cohorts from three PBT centres (216 patients) were investigated for several physician-rated endpoints at 12 and 24 months after PBT: alopecia, dry eye syndrome, fatigue, headache, hearing and memory impairment, and optic neuropathy. Dose-volume parameters of associated normal tissues and clinical factors were used for logistic regression modelling in a development cohort. Statistically significant parameters showing high area under the receiver operating characteristic curve (AUC) values in internal cross-validation were externally validated. In addition, analyses of the pooled cohorts and of time-dependent generalised estimating equations including all patient data were performed.

Results: In the validation study, mild alopecia was related to high dose parameters to the skin [e.g. the dose to 2% of the volume (D2%)] at 12 and 24 months after PBT. Mild hearing impairment at 24 months after PBT was associated with the mean dose to the ipsilateral cochlea. Additionally, the pooled analyses revealed dose-response relations between memory impairment and intermediate to high doses to the remaining brain as well as D2% of the hippocampi. Mild fatigue at 24 months after PBT was associated with D2% to the brainstem as well as with concurrent chemotherapy. Moreover, in generalised estimating equations analysis, dry eye syndrome was associated with the mean dose to the ipsilateral lacrimal gland.

Conclusion: We developed and in part validated NTCP models for several common late side-effects following PBT in brain tumour patients. Validation studies are required for further confirmation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2021.01.004DOI Listing
April 2021

Radical radiotherapy for paediatric solid tumour metastases: An overview of current European protocols and outcomes of a SIOPE multicenter survey.

Eur J Cancer 2021 Mar 16;145:121-131. Epub 2021 Jan 16.

Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, The Netherlands; Princess Máxima Center for Paediatric Oncology, Utrecht, The Netherlands.

Purpose/objective: About 20% of children with solid tumours (ST) present with distant metastases (DM). Evidence regarding the use of radical radiotherapy of these DM is sparse and open for personal interpretation. The aim of this survey was to review European protocols and to map current practice regarding the irradiation of DM across SIOPE-affiliated countries.

Materials/methods: Radiotherapy guidelines for metastatic sites (bone, brain, distant lymph nodes, lung and liver) in eight European protocols for rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue sarcoma, Ewing sarcoma, neuroblastoma and renal tumours were reviewed. SIOPE centres irradiating ≥50 children annually were invited to participate in an online survey.

Results: Radiotherapy to at least one metastatic site was recommended in all protocols, except for high-risk neuroblastoma. Per protocol, dose prescription varied per site, and information on delineation and treatment planning/delivery was generally missing. Between July and September 2019, 20/27 centres completed the survey. Around 14% of patients were deemed to have DM from ST at diagnosis, of which half were treated with curative intent. A clear cut-off for a maximum number of DM was not used in half of the centres. Regardless of the tumour type and site, conventional radiotherapy regimens were most commonly used to treat DM. When stereotactic radiotherapy was used, a wide range of fractionation regimens were applied.

Conclusion: Current radiotherapy guidelines for DM do not allow a consistent approach in a multicentre setting. Prospective (randomised) trials are needed to define the role of radical irradiation of DM from paediatric ST.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.12.004DOI Listing
March 2021

Rhabdomyosarcoma of the female genitourinary tract: Primary and relapsed disease in infants and older children. Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

Pediatr Blood Cancer 2021 Apr 12;68(4):e28889. Epub 2021 Jan 12.

Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart - Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Stuttgart, Germany.

Background: Rhabdomyosarcoma (RMS) of the female genitourinary tract (FGU-RMS) located at the vagina or uterus is one of the most favorable RMS sites. Little is known about treatment and outcome in infants and relapsed disease (RD).

Methods: Characteristics, treatment, and outcome of 71 children with FGU-RMS registered within five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry (1981-2019) were evaluated.

Results: FGU-RMS was diagnosed in 67 patients with localized disease (LD) at a median age of 2.89 years (0.09-18.08). Multimodal treatment consisted of chemotherapy (CHT) (n = 66), secondary surgery (n = 32), and radiotherapy (n = 11). Age at diagnosis ≤12 months was the only significant negative prognostic factor influencing the event-free survival (EFS). Ten-year EFS and overall survival (OS) for infants ≤12 months were 50% and 81%, respectively. In contrast, children with LD >1 year and ≤10 years had a 10-year EFS and OS of 78% and 94% (P = .038), and >10 years of 82% and 88%, respectively (P = .53). Metastatic disease was observed in four patients of which three are alive. RD occurred in five of 12 infants ≤1 year and 10/55 children at a median of 1.38 years (0.53-2.97) after initial diagnosis. Treatment of patients with RD consisted of multimodal treatment (n = 13) or resection only (n = 2). Nine patients (60%) were alive in clinical remission at a median of 7.02 years (1.23-16.72) after diagnosis of RD.

Conclusion: Infants with FGU-RMS have a higher relapse rate than older children with FGU-RMS, but prognosis is fair.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28889DOI Listing
April 2021

Technical Note: Investigating interplay effects in pencil beam scanning proton therapy with a 4D XCAT phantom within the RayStation treatment planning system.

Med Phys 2021 Mar 6;48(3):1448-1455. Epub 2021 Feb 6.

West German Proton Therapy Center Essen (WPE), Essen, Germany.

Purpose: Pencil beam scanning (PBS) for moving targets is known to be impacted by interplay effects. Four-dimensional computed tomography (4DCT)-based motion evaluation is crucial for understanding interplay and developing mitigation strategies. Availability of high-quality 4DCTs with variable breathing traces is limited. Purpose of this work is the development of a framework for interplay analysis using 4D-XCAT phantoms in conjunction with time-resolved irradiation patterns in a commercial treatment planning system (TPS). Four-dimensional dynamically accumulated dose distributions (4DDDs) are simulated in an in-silico study for a PBS liver treatment.

Methods: An XCAT phantom with 50 phases, varying linearly in amplitude each by 1 mm, was combined with the RayStation TPS (7.99.10). Deformable registration was used with time-resolved dose calculation, mapping XCAT phases to motion signals. To illustrate the applicability of the method a two-field liver irradiation plan was used. A variety sin type motion signals, varying in amplitude (1-20 mm), period (1.6-5.2 s) and phase (0-2π) were applied. Either single variable variations or random combinations were selected. The interplay effect within a clinical target (5 cm diameter) was characterized in terms of homogeneity index (HI5), with and without five paintings. In total 2092 scenarios were analyzed within RayStation.

Results: A framework is presented for interplay research, allowing for flexibility in determining motion management techniques, increasing reproducibility, and enabling comparisons of different methods. A case study showed the interplay effect was correlated with amplitude and strongly affected by the starting phase, leading to large variance. The average of all scenarios (single fraction) resulted in HI5 of 0.31 (±0.11), while introduction of five times layered repainting reduced this to 0.11(±0.03).

Conclusion: The developed framework, which uses the XCAT phantom and RayStation, allows detailed analysis of motion in context of PBS with comparable results to clinical cases. Flexibility in defining motion patterns for detailed anatomies in combination with time-resolved dose calculation, facilitates investigation of optimal treatment and motion mitigation strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mp.14709DOI Listing
March 2021

Model-based comparison of organ at risk protection between VMAT and robustly optimised IMPT plans.

Z Med Phys 2021 Feb 22;31(1):5-15. Epub 2020 Dec 22.

West German Proton Therapy Centre Essen (WPE), Essen, Germany; West German Cancer Centre (WTZ), Essen, Germany; Department of Particle Therapy, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Germany.

The comparison between intensity-modulated proton therapy (IMPT) and volume-modulated arc therapy (VMAT) plans, based on models of normal tissue complication probabilities (NTCP), can support the choice of radiation modality. IMPT irradiation plans for 50 patients with head and neck tumours originally treated with photon therapy have been robustly optimised against density and setup uncertainties. The dose distribution has been calculated with a Monte Carlo (MC) algorithm. The comparison of the plans was based on dose-volume parameters in organs at risk (OARs) and NTCP-calculations for xerostomia, sticky saliva, dysphagia and tube feeding using Langendijk's model-based approach. While the dose distribution in the target volumes is similar, the IMPT plans show better protection of OARs. Therefore, it is not the high dose confirmation that constitutes the advantage of protons, but it is the reduction of the mid-to-low dose levels compared to photons. This work investigates to what extent the advantages of proton radiation are beneficial for the patient's post-therapeutic quality of life (QoL). As a result, approximately one third of the patients examined benefit significantly from proton therapy with regard to possible late side effects. Clinical data is needed to confirm the model-based calculations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.zemedi.2020.09.003DOI Listing
February 2021

High frequency of disease progression in pediatric spinal cord low-grade glioma (LGG): management strategies and results from the German LGG study group.

Neuro Oncol 2021 Jul;23(7):1148-1162

Swabian Children's Cancer Center, University Hospital Augsburg, Augsburg, Germany.

Background: Knowledge on management of pediatric spinal cord low-grade glioma (LGG) is scarce.

Methods: We analyzed clinical datasets of 128 pediatric patients with spinal LGG followed within the prospective multicenter trials HIT-LGG 1996 (n = 36), SIOP-LGG 2004 (n = 56), and the subsequent LGG-Interim registry (n = 36).

Results: Spinal LGG, predominantly pilocytic astrocytomas (76%), harbored KIAA1549-BRAF fusion in 14/35 patients (40%) and FGFR1-TACC1 fusion in 3/26 patients (12%), as well as BRAFV600E mutation in 2/66 patients (3%). 10-year overall survival (OS) and event-free survival (EFS) was 93% ± 2% and 38% ± 5%, respectively. Disseminated disease (n = 16) was associated with inferior OS and EFS, while age ≥11 years and total resection were favorable factors for EFS. We observed 117 patients following total (n = 24) or subtotal/partial resection (n = 74), biopsy (n = 16), or radiologic diagnosis only (n = 3). Eleven patients were treated first with chemotherapy (n = 9) or irradiation (n = 2). Up to 20.8 years after diagnosis/initial intervention, 73/128 patients experienced one (n = 43) or up to six (n = 30) radiological/clinical disease progressions. Tumor resections were repeated in 36 patients (range, 2-6) and 47 patients required nonsurgical treatment (chemotherapy, n = 20; radiotherapy, n = 10; multiple treatment lines, n = 17). Long-term disease control for a median of 6.5 (range, 0.02-20) years was achieved in 73/77 patients following one (n = 57) or repeated (n = 16) resections, and in 35/47 patients after nonsurgical treatment.

Conclusions: The majority of patients experienced disease progression, even after years. Multiple interventions were required for more than a third, yet multimodal treatment enabled long-term disease control. Molecular testing may reveal therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noaa296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248857PMC
July 2021

Local and systemic therapy of recurrent ependymoma in children and adolescents: short- and long-term results of the E-HIT-REZ 2005 study.

Neuro Oncol 2021 06;23(6):1012-1023

Department of Pediatrics III, University Hospital of Essen, Essen, Germany.

Background: Survival in recurrent ependymomas in children and adolescents mainly depends on the extent of resection. Studies on repeated radiotherapy and chemotherapy at relapse have shown conflicting results.

Methods: Using data from the German multi-center E-HIT-REZ-2005 study, we examined the role of local therapy and the efficacy of chemotherapy with blockwise temozolomide (TMZ) in children and adolescents with recurrent ependymomas.

Results: Fifty-three patients with a median age of 6.9 years (1.25-25.4) at first recurrence and a median follow-up time of 36 months (2-115) were recruited. Gross- and near-total resection (GTR/NTR) were achieved in 34 (64.2%) patients and associated with a markedly improved 5-year overall survival (OS) of 48.7% vs. 5.3% in less than GTR/NTR. Radiotherapy showed no improvement in OS following complete resection (OS: 70 (CI: 19.9-120.1) vs. 95 (CI: 20.7-169.4) months), but an advantage was found in less than GTR/NTR (OS: 22 (CI: 12.7-31.3) vs. 7 (CI: 0-15.8) months). Following the application of TMZ, disease progression was observed in most evaluable cases (18/21). A subsequent change to oral etoposide and trofosfamide showed no improved response. PF-A EPN were most abundant in relapses (n = 27). RELA-positive EPN (n = 5) had a 5-year OS of 0%.

Conclusion: The extent of resection is the most important predictor of survival at relapse. Focal re-irradiation is a useful approach if complete resection cannot be achieved, but no additional benefit was seen after GTR/NTR. Longer-term disease stabilization (>6 months) mediated by TMZ occurred in a small number of cases (14.3%).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noaa276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168820PMC
June 2021

Evaluation of Prognostic Factors and Role of Participation in a Randomized Trial or a Prospective Registry in Pediatric and Adolescent Nonmetastatic Medulloblastoma - A Report From the HIT 2000 Trial.

Adv Radiat Oncol 2020 Nov-Dec;5(6):1158-1169. Epub 2020 Oct 7.

University Children's Hospital of Zurich, Switzerland.

Purpose: We aimed to compare treatment results in and outside of a randomized trial and to confirm factors influencing outcome in a large retrospective cohort of nonmetastatic medulloblastoma treated in Austria, Switzerland and Germany.

Methods And Materials: Patients with nonmetastatic medulloblastoma (n = 382) aged 4 to 21 years and primary neurosurgical resection between 2001 and 2011 were assessed. Between 2001 and 2006, 176 of these patients (46.1%) were included in the randomized HIT SIOP PNET 4 trial. From 2001 to 2011 an additional 206 patients were registered to the HIT 2000 study center and underwent the identical central review program. Three different radiation therapy protocols were applied. Genetically defined tumor entity (former molecular subgroup) was available for 157 patients.

Results: Median follow-up time was 7.3 (range, 0.09-13.86) years. There was no difference between HIT SIOP PNET 4 trial patients and observational patients outside the randomized trial, with 7 years progression-free survival rates (PFS) of 79.5% ± 3.1% versus 78.7% ± 3.1% ( = .62). On univariate analysis, the time interval between surgery and irradiation (≤ 48 days vs ≥ 49 days) showed a strong trend to affect PFS (80.4% ± 2.2% vs 64.6% ± 9.1%; = .052). Furthermore, histologically and genetically defined tumor entities and the extent of postoperative residual tumor influenced PFS. On multivariate analyses, a genetically defined tumor entity wingless-related integration site-activated vs non-wingless-related integration site/non-SHH, group 3 hazard ratio, 5.49; = .014) and time interval between surgery and irradiation (hazard ratio, 2.2; = .018) were confirmed as independent risk factors.

Conclusions: Using a centralized review program and risk-stratified therapy for all patients registered to the study center, outcome was identical for patients with nonmetastatic medulloblastoma treated on and off the randomized HIT SIOP PNET 4 trial. The prognostic values of prolonged time to RT and genetically defined tumor entity were confirmed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.adro.2020.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718550PMC
October 2020

Long-term follow-up of children with neuroblastoma receiving radiotherapy to metastatic lesions within the German Neuroblastoma Trials NB97 and NB 2004.

Strahlenther Onkol 2021 Aug 9;197(8):683-689. Epub 2020 Dec 9.

Department of Particle Therapy, West German Proton Therapy Centre Essen (WPE), West German Cancer Center (WTZ), German Cancer Consortium (DKTK), University Hospital Essen, Essen, Germany.

Purpose: Neuroblastoma (NB) is the most common extracranial solid malignancy during childhood. Despite a multimodal treatment approach, the prognosis of patients with metastatic NB is not satisfactory. Although radiotherapy (RT) has become an integral part of treatment of the primary tumor, the role of RT in osteomedullary lesions is not well defined. A retrospective analysis was conducted to evaluate the impact of RT for metastatic sites in children with high-risk NB.

Methods: All patients with stage 4 NB from the prospective, multicenter NB trials NB97 and NB2004 who received RT to metastatic sites during frontline treatment were included in this retrospective analysis.

Results: A total of 18 children were irradiated with a median dose of 36 Gray (Gy; range 20-45 Gy) to one or more (range 1-3) osteomedullary metastases with or without concomitant RT to the primary tumor site. The median follow-up time was 149 months (range 55-220) in survivors. At 5 years, local relapse-free survival (LRFS) at irradiated metastatic sites and metastases-free survival (MFS) at distant, non-irradiated site rates were 51.4 and 39.9%, respectively. The estimated overall survival (OS) rate at 5 years was 49.4%. No high-grade acute or late toxicity and no secondary malignancy was reported.

Conclusion: RT to metastases is feasible for patients with stage 4 NB. However, an impact of RT to residual metastatic sites on outcome was not found. Studies with larger cohorts or prospective trials would be desirable in order to elucidate the role of RT for metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00066-020-01718-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292260PMC
August 2021

Pretreatment central quality control for craniospinal irradiation in non-metastatic medulloblastoma : First experiences of the German radiotherapy quality control panel in the SIOP PNET5 MB trial.

Strahlenther Onkol 2021 Aug 23;197(8):674-682. Epub 2020 Nov 23.

Department for Radiation Oncology, University of Leipzig Medical Center, Stephanstr. 9a, 04103, Leipzig, Germany.

Purpose: Several studies have demonstrated the negative impact of radiotherapy protocol deviations on tumor control in medulloblastoma. In the SIOP PNET5 MB trial, a pretreatment radiotherapy quality control (RT-QC) program was introduced. A first analysis for patients enrolled in Germany, Switzerland and Austria with focus on types of deviations in the initial plan proposals and review criteria for modern radiation technologies was performed.

Methods And Patients: Sixty-nine craniospinal irradiation (CSI) plans were available for detailed analyses. RT-QC was performed according to protocol definitions on dose uniformity. Because of the lack of definitions for high-precision 3D conformal radiotherapy within the protocol, additional criteria for RT-QC on delineation and coverage of clinical target volume (CTV) and planning target volume (PTV) were defined and evaluated.

Results: Target volume (CTV/PTV) deviations occurred in 49.3% of initial CSI plan proposals (33.3% minor, 15.9% major). Dose uniformity deviations were less frequent (43.5%). Modification of the RT plan was recommended in 43.5% of CSI plans. Unacceptable RT plans were predominantly related to incorrect target delineation rather than dose uniformity. Unacceptable plans were negatively correlated to the number of enrolled patients per institution with a cutoff of 5 patients (p = 0.001).

Conclusion: This prospective pretreatment individual case review study revealed a high rate of deviations and emphasizes the strong need of pretreatment RT-QC in clinical trials for medulloblastoma. Furthermore, the experiences point out the necessity of new RT-QC criteria for high-precision CSI techniques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00066-020-01707-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292275PMC
August 2021

Single pencil beam benchmark of a module for Monte Carlo simulation of proton transport in the PENELOPE code.

Med Phys 2021 Jan 10;48(1):456-476. Epub 2020 Dec 10.

West German Proton Therapy Centre Essen WPE, Essen, Germany.

Background And Purpose: PENH is a recently coded module for simulation of proton transport in conjunction with the Monte Carlo code PENELOPE. PENELOPE applies class II simulation to all type of interactions, in particular, to elastic collisions. PENH uses calculated differential cross sections for proton elastic collisions that include electron screening effects as well as nuclear structure effects. Proton-induced nuclear reactions are simulated from information in the ENDF-6 database or from alternative nuclear databases in ENDF format. The purpose of this work is to benchmark this module by simulating absorbed dose distributions from a single finite spot size proton pencil beam in water.

Materials And Methods: Monte Carlo simulations with PENH are compared with simulation results from TOPAS Monte Carlo (v3.1p2) and RayStation Monte Carlo (v6). Different beam models are examined in terms of mean energy and energy spread to match the measured profiles. The phase-space file is derived from experimental measurements. Simulated absorbed dose distributions are compared to experimental data obtained with the ionization chamber array MatriXX 2D detector (IBA Dosimetry) in a water tank. The experiments were conducted with a clinical IBA pencil beam scanning dedicated nozzle. In all simulations a Fermi-Eyges phase-space representation of a single finite spot size proton pencil beam is used.

Results: In general, there is a good agreement between simulated results and experimental data up to a distance of 3 cm from the central axis. In the core region (region where the dose is more than 10% of the maximum dose) PENH shows, overall, the smallest deviations from experimental data, with the largest radial rms (root mean square) smaller than 0.2. The results achieved by TOPAS and RayStation in that region are very close to those of PENH. For the halo region, that is the area of the dose distribution outside the core region reaching down to 0.01% of the maximum intensity, the largest rms achieved by TOPAS is always smaller than 0.5, yielding better results than the rest of the codes.

Conclusion: The physics modeling of the PENELOPE/PENH code yields results consistent with measurements in the dose range relevant for proton therapy. The discrepancies between PENH appearing at distances larger than 3 cm from the central-beam axis are accountable to the lack of neutron simulation in this code. In contradistinction, TOPAS has a better agreement with experimental data at large distances from the central-beam axis because of the simulation of neutrons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mp.14598DOI Listing
January 2021

Mitigation of motion effects in pencil-beam scanning - Impact of repainting on 4D robustly optimized proton treatment plans for hepatocellular carcinoma.

Z Med Phys 2020 Oct 29. Epub 2020 Oct 29.

West German Proton Therapy Centre Essen, Am Mühlenbach 1, 45147 Essen, Germany; University Hospital Essen, Hufelandstr. 55, Essen, Germany; West German Cancer Center (WTZ), Hufelandstr. 55, Essen, Germany.

Proton fields delivered by the active scanning technique can be interfered with the intrafractional motion. This in-silico study seeks to mitigate the dosimetric impacts of motion artifacts, especially its interplay with the time-modulated dose delivery. Here four-dimensional (4d) robust optimization and dose repainting, which is the multiple application of the same field with reduced fluence, were combined. Two types of repainting were considered: layered and volumetric repainting. The time-resolved dose calculation, which is necessary to quantify the interplay effect, was integrated into the treatment planning system and validated. Nine clinical cases of hepatocellular carcinoma (HCC) showing motion in the range of 0.4-1.5cm were studied. It was found that the repainted delivery of 4D robustly optimized plans reduced the impact of interplay effect as quantified by the homogeneity index within the clinical target volume (CTV) to a tolerable level. Similarly, the fractional over- and underdosage was reduced sufficiently for some HCC cases to achieve the purpose of motion management. This holds true for both investigated types of repainting with small dosimetric advantages of volume repainting over layered repainting. Volume repainting, however, cannot be applied clinically in proton centers with slow energy changes. Thus, it served as a reference in the in-silico evaluation. It is recommended to perform the dynamic dose calculation for individual cases to judge if robust optimization in conjunction with repainting is sufficient to keep the interplay effect within bounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.zemedi.2020.08.001DOI Listing
October 2020

Monte Carlo Computation of Dose-Volume Histograms in Structures at Risk of an Eye Irradiated with Heterogeneous Ruthenium-106 Plaques.

Ocul Oncol Pathol 2020 Oct 20;6(5):353-359. Epub 2020 Jul 20.

West German Proton Therapy Center Essen (WPE), Essen, Germany.

Background/aims: The aim of this work is to compare Monte Carlo simulated absorbed dose distributions obtained from 106Ru eye plaques, whose heterogeneous emitter distribution is known, with the common homogeneous approximation. The effect of these heterogeneities on segmented structures at risk is analyzed using an anthropomorphic phantom.

Methods: The generic CCA and CCB, with a homogeneous emitter map, and the specific CCA1364 and CCB1256 106Ru eye plaques are modeled with the Monte Carlo code PENELOPE. To compare the effect of the heterogeneities in the segmented volumes, cumulative dose-volume histograms are calculated for different rotations of the aforementioned plaques.

Results: For the cornea, the CCA with the equatorial placement yields the lowest absorbed dose rate while for the CCA1364 in the same placement the absorbed dose rate is 33% higher. The CCB1256 with the hot spot oriented towards the cornea yields the maximum dose rate per unit of activity while it is 44% lower for the CCB.

Conclusions: Dose calculations based on a homogeneous distribution of the emitter substance yield the lowest absorbed dose in the analyzed structures for all plaque placements. Treatment planning based on such calculations may result in an overdose of the structures at risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000508113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574611PMC
October 2020

[Proton therapy-a chance in the treatment of tumors of the head and neck and base of skull].

Authors:
Beate Timmermann

Radiologe 2020 Nov;60(11):1058-1065

Klinik für Partikeltherapie, Westdeutsches Protonentherapiezentrum Essen, Universitätsklinikum Essen, Hufelandstr. 55, 45147, Essen, Deutschland.

Background: Radiotherapy (RT) is an integral part of the treatment of many tumors located in the vicinity of sensitive organs and structures, including tumors of the head and neck and base of skull in particular. Due to the risk of side effects associated with RT, the use of highly conformal RT techniques is favored. For many indications, proton therapy (PT) is therefore already part of the modern treatment standard.

Objective: This article presents an overview of current indications for PT with emphasis on tumors in the head and neck region and the base of skull. Furthermore, a summary and discussion of relevant results and current developments are included.

Materials And Methods: The work comprises an evaluation of relevant studies and an overview of current issues related to PT of tumors in the areas of the head, neck, and base of skull.

Results: Overall, the studies on PT show promising results. In addition to dosimetric studies, clinical studies also point to advantages of PT, especially with regard to the reduction of side effects.

Discussion: Currently, use of the model-based approach is being discussed. This is intended to identify those patients who benefit most from PT based on the normal tissue complication probability (NTCP). PT for re-RT is also discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00117-020-00762-7DOI Listing
November 2020

Long-term cognitive deficits in pediatric low-grade glioma (LGG) survivors reflect pretreatment conditions-report from the German LGG studies.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa094. Epub 2020 Aug 8.

Paediatrics and Adolescent Medicine, Medical Faculty, University of Augsburg, Augsburg, Germany.

Background: Disease and treatment contribute to cognitive late effects following pediatric low-grade glioma (LGG). We analyzed prospectively collected neuropsychological data of German pediatric LGG survivors and focused on the impact of hydrocephalus at diagnosis, neurofibromatosis type 1 (NF1) status, and extent of surgery.

Methods: We used the Neuropsychological Basic Diagnostic screening tool based on the Cattell-Horn-Carroll model for intelligence and the concept of cross-battery assessment at 2 and 5 years from diagnosis for 316 patients from the German pediatric LGG study and LGG registry (7.1 years median age; 45 NF1; cerebral hemispheres 16%, supratentorial midline 39%, infratentorial 45%). Hydrocephalus was classified radiologically in 137 non-NF1 patients with infratentorial tumors (95/137 complete/subtotal resection).

Results: Patients with NF1 versus non-NF1 exhibited inferior verbal short-term memory and visual processing ( < .001-.021). In non-NF1 patients, infratentorial tumor site and complete/subtotal resection were associated with sequelae in visual processing, psychomotor speed, and processing speed ( < .001-.008). Non-NF1 patients without surgical tumor reduction and/or nonsurgical treatment experienced similar deficits. Degree of hydrocephalus at diagnosis had no further impact. Psychomotor and processing speed were impaired comparably following chemo-/radiotherapy ( < .001-.021). Pretreatment factors such as NF1 or tumor site were relevant at multivariate analysis.

Conclusions: All pediatric LGG survivors are at risk to experience long-term cognitive impairments in various domains. Even surgical only management of cerebellar LGG or no treatment at all, that is, biopsy only/radiological diagnosis did not protect cognitive function. Since pattern and extent of deficits are crucial to tailor rehabilitation, neuropsychological and quality of survival assessments should be mandatory in future LGG trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/noajnl/vdaa094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497816PMC
August 2020

Clinical outcomes and quality of life in children and adolescents with primary brain tumors treated with pencil beam scanning proton therapy.

Pediatr Blood Cancer 2020 12 9;67(12):e28465. Epub 2020 Sep 9.

Department of Radiation Oncology, Inselspital, University Hospital Bern, Bern, Switzerland.

Background: Long-term treatment-related toxicity may substantially impact well-being, quality of life (QoL), and health of children/adolescents with brain tumors (CBTs). Strategies to reduce toxicity include pencil beam scanning (PBS) proton therapy (PT). This study aims to report clinical outcomes and QoL in PBS-treated CBTs.

Procedure: We retrospectively reviewed 221 PBS-treated CBTs aged <18 years. Overall-free (OS), disease-free (DFS), and late-toxicity-free survivals (TFS), local control (LC) and distant (DC) brain/spinal control were calculated using Kaplan-Meier estimates. Prospective QoL reports from 206 patients (proxies only ≤4 years old [yo], proxies and patients ≥5 yo) were descriptively analyzed. Median follow-up was 51 months (range, 4-222).

Results: Median age at diagnosis was 3.1 years (range, 0.3-17.7). The main histologies were ependymoma (n = 88; 39.8%), glioma (n = 37; 16.7%), craniopharyngioma (n = 22; 10.0%), atypical teratoid/rhabdoid tumor (ATRT) (n = 21; 9.5%) and medulloblastoma (n = 15; 6.8%). One hundred sixty (72.4%) patients received chemotherapy. Median PT dose was 54 Gy(relative biological effectiveness) (range, 18.0-64.8). The 5-year OS, DFS, LC, and DC (95% CI) were 79.9% (74-85.8), 65.2% (59.8-70.6), 72.1% (65.4-78.8), and 81.8% (76.3-87.3), respectively. Late PT-related ≥G3 toxicity occurred in 19 (8.6%) patients. The 5-year ≥G3 TFS was 91.0% (86.3-95.7). Three (1.4%) secondary malignancies were observed. Patients aged ≤3 years at PT (P = .044) or receiving chemotherapy (P = .043) experienced more ≥G3 toxicity. ATRT histology independently predicted distant brain failure (P = .046) and death (P = .01). Patients aged ≥5 years self-rated QoL higher than their parents (proxy assessment). Both reported lower social functioning and cognition after PT than at baseline, but near-normal long-term global well-being. QoL was well below normal before and after PT in children ≤4 years.

Conclusions: The outcome of CBTs was excellent after PBS. Few patients had late ≥G3 toxicity. Patients aged <5 years showed worse QoL and toxicity outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28465DOI Listing
December 2020
-->