Publications by authors named "Volker Budach"

204 Publications

Effectiveness and Safety of Robotic Radiosurgery for Optic Nerve Sheath Meningiomas: A Single Institution Series.

Cancers (Basel) 2021 Apr 30;13(9). Epub 2021 Apr 30.

Charité Cyberknife Center, Augustenburger Platz 1, 13353 Berlin, Germany.

The role of robotic radiosurgery (RRS) in the treatment of optic nerve sheath meningiomas (ONSM) remains controversial and it is only performed in specialized institutions due to tight dose constraints. We evaluated the effectiveness and safety of RRS in the management of ONSM. Twenty-five patients with 27 ONSM lesions who underwent RRS using the Cyberknife (CK) system were retrospectively analyzed (median age, 47.9 years; 84.0% women). Multisession RRS was used with 4-5 fractions with a cumulative dose of 20.0-25.0 Gy in 84.0% of patients and a single fraction at a dose of 14.0-15.0 Gy in 16% of patients. Prior to RRS, seven (28%) patients experienced blindness on the lesion side. In those patients with preserved vision prior to radiosurgery, the visual acuity remained the same in 90.0% and improved in 10.0% of the patients. Overall local tumor control was 96.0% (mean follow-up period; 37.4 ± 27.2 months). Neither patient age, previous surgery, or the period from the initial diagnosis to RRS showed a dependency on visual acuity before or after radiosurgery. RRS is a safe and effective treatment for the management of ONSM. Hypofractionation of radiosurgery in patients with preserved vision before CK treatment results in stable or improved vision.
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http://dx.doi.org/10.3390/cancers13092165DOI Listing
April 2021

External application of liver compresses to reduce fatigue in patients with metastatic cancer undergoing radiation therapy, a randomized clinical trial.

Radiat Oncol 2021 Apr 19;16(1):76. Epub 2021 Apr 19.

Division of Oncology and Hematology, Department of Pediatrics, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

Background: Liver compresses are frequently used in integrative medicine as supportive therapy during cancer treatment in order to reduce fatigue. We performed a pilot study to test whether the external application of yarrow liver compresses impacts fatigue in patients with metastatic cancer undergoing radiation therapy.

Methods: A randomized prospective pilot trial was performed including patients with brain metastasis or bone metastasis of solid tumors. Patients underwent either palliative radiation therapy (RT) of the metastatic lesions (control group) over two weeks or the same RT with additional external application of yarrow liver compresses once daily during RT. The primary objective was improvement on the general fatigue subscale of the multidimensional fatigue inventory (MFI-20) at the end of treatment, where a mean difference of two points is considered clinically relevant. Secondary objectives included psychological distress, quality of life and qualitative analysis with self-established visual analogue scales (VAS). Mean differences in general fatigue at the end of treatment compared to baseline were analyzed using the ANCOVA test.

Results: From 09/2017 to 08/2019 a total of 39 patients were randomized. Due to drop outs 24 patients (12 per group) were available for analysis. Patients in the intervention group received a mean number of 10.5 (range, 7-14) applications of yarrow liver compresses. The mean improvement at the end of therapy on the general fatigue subscale of the MFI-20 was 2 points in favor of the intervention group (p = 0.13), and all other MFI-20 subscales showed at least a trend towards improvement in favor of the intervention group. Likewise, psychological distress and VAS data was improved, the latter reaching statistical significance for the symptoms fatigue, tension and lack of drive. Major toxicities were not observed.

Conclusions: External application of liver compresses appears to reduce fatigue within a clinical relevant range in patients with metastatic cancer undergoing radiation therapy.

Trial Registration: ISRCTN, ICTRP DRKS00012999.
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http://dx.doi.org/10.1186/s13014-021-01757-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054395PMC
April 2021

Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.

Lancet Oncol 2021 05 13;22(5):727-736. Epub 2021 Apr 13.

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Background: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other.

Methods: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies).

Findings: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRT) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRT (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (IC-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and IC followed by CLRT (80%).

Interpretation: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or IC-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer.

Fundings: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.
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http://dx.doi.org/10.1016/S1470-2045(21)00076-0DOI Listing
May 2021

PET measured hypoxia and MRI parameters in re-irradiated head and neck squamous cell carcinomas: findings of a prospective pilot study.

F1000Res 2020 19;9:1350. Epub 2020 Nov 19.

Department of Radiation Oncology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Tumor hypoxia measured by dedicated tracers like [ F]fluoromisonidazole (FMISO) is a well-established prognostic factor in head and neck squamous cell carcinomas (HNSCC) treated with definitive chemoradiation (CRT). However, prevalence and characteristics of positron emission tomography (PET) measured hypoxia in patients with relapse after previous irradiation is missing. Here we report imaging findings of a prospective pilot study in HNSCC patients treated with re-irradiation. In 8 patients with recurrent HNSCC, diagnosed at a median of 18 months after initial radiotherapy/CRT, [ F]fluorodeoxyglucose (FDG)-PET/CT (n=8) and FMISO-PET/MRI (n=7) or FMISO-PET/CT (n=1) were performed. Static FMISO-PET was performed after 180 min. MRI sequences in PET/MRI included diffusion-weighted imaging with apparent diffusion coefficient (ADC) values and contrast enhanced T1w imaging (StarVIBE). Lesions (primary tumor recurrence, 4; cervical lymph node, 1; both, 3) were delineated on FDG-PET and FMISO-PET data using a background-adapted threshold-based method. SUV and SUV in FDG- and FMISO-PET were derived, as well as maximum tumor-to-muscle ratio (TMR ) and hypoxic volume with 1.6-fold muscle SUV (HV ) in FMISO-PET. Intensity of lesional contrast enhancement was rated relative to contralateral normal tissue. Average ADC values were derived from a 2D region of interest in the tumor. In FMISO-PET, median TMR was 1.7 (range: 1.1-1.8). Median HV was 0.05 ml (range: 0-7.3 ml). Only in 2/8 patients, HV was ≥1.0 ml. In FDG-PET, median SUV was 9.3 (range: 5.0-20.1). On contrast enhanced imaging four lesions showed decreased and four lesions increased contrast enhancement compared to non-pathologic reference tissue. Median average ADC was 1,060 ×10 mm /s (range: 840-1,400 ×10 mm /s). This pilot study implies that hypoxia detectable by FMISO-PET may not be as prevalent as expected among loco-regional recurrent, HPV negative HNSCC. ADC values were only mildly reduced, and contrast enhancement was variable. The results require confirmation in larger sample sizes.
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http://dx.doi.org/10.12688/f1000research.27303.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970429.2PMC
November 2020

Salvage-Radiation Therapy and Regional Hyperthermia for Biochemically Recurrent Prostate Cancer after Radical Prostatectomy (Results of the Planned Interim Analysis).

Cancers (Basel) 2021 Mar 6;13(5). Epub 2021 Mar 6.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Radiation Oncology, 13353 Berlin, Germany.

Efforts to improve the outcome of prostate cancer (PC) patients after radical prostatectomy (RP) include adjuvant or salvage radiation therapy (SRT), but still up to 50% of patients develop a disease progression after radiotherapy (RT). Regional hyperthermia (HT) is well-known to improve tumor sensitivity to RT in several entities. Here we report on a planned interim analysis of tolerability and feasibility after recruitment of the first 50 patients of a trial combining SRT and HT. We conducted a prospective multicenter non-randomized Phase-II-Trial (HTProstate-NCT04159051) investigating the implementation of combined moderate-dose escalated SRT (70 Gy in 35 fractions) and locoregional deep HT (7-10 HT sessions). The primary endpoints were the rate of acute genitourinary (GU), gastrointestinal (GI), and HT-related toxicities, completed HT sessions (≥7), and SRT applications per protocol (≥95% of patients). The two-step design included a planned interim analysis for acute GU-, GI- and HT-specific toxicities to ensure patients' safety. Between November 2016 and December 2019, 52 patients entered into the trial. After 50 patients completed therapy and three months of follow-up, we performed the planned interim analysis. 10% of patients developed acute grade 2 GU and 4% grade 2 GI toxicities. No grade ≥3 GU or GI toxicities occurred. HT-specific symptoms grade 2 and 3 were observed in 4% and 2% of all patients. Thus, the pre-specified criteria for safety and continuation of recruitment were met. Moreover, ≥7 HT treatments were applicable, indicating the combination of SRT + HT to be feasible. Evaluation of early QoL showed no significant changes. With its observed low rate of GU and GI toxicities, moderate and manageable rates of HT-specific symptoms, and good feasibility, the combined SRT + HT seems to be a promising treatment approach for biochemical recurrence after RP in PC patients.
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http://dx.doi.org/10.3390/cancers13051133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961934PMC
March 2021

Prognostic Factors Predict Oncological Outcome in Older Patients With Head and Neck Cancer Undergoing Chemoradiation Treatment.

Front Oncol 2020 23;10:566318. Epub 2021 Feb 23.

Department of Radiation Oncology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Purpose: Older patients with head and neck cancer (HNC) represent a challenging group, as frailty and comorbidities need to be considered. This study aimed to evaluate the efficacy and side effects of curative and palliative (chemo) radiation ([C]RT) with regard to basic geriatric screening in older patients.

Methods: This study included HNC patients aged ≥70 years who were treated with curative or palliative (C)RT. Clinicopathological data including Charlson Comorbidity Index (CCI), Karnofsky performance status (KPS), and treatment data were analyzed as predictors of overall survival (OS).

Results: A total of 271 patients (median age, 74 years) were enrolled. The majority had UICC stage III/IV (90%) and underwent curative treatment (85.2%). A total of 144 (53.1%) patients received definitive and 87 (32.1%) had adjuvant (C)RT. Overall, 40 patients (14.8%) received palliative (C)RT. Median follow-up duration (curative setting) was 87 months, and the 2- and 5-year OS rates were 57.8 and 35.9%, respectively. Median OS was significantly different for age ≤75 >75 years, CCI <6 ≥6, KPS ≥70 <70%, Tx/T1/T2 v. T3/T4, and adjuvant definitive (C)RT, respectively. Age 70-75 years (p = 0.004), fewer comorbidities when CCI < 6 (p = 0.014), good KPS ≥ 70% (p = 0.001), and adjuvant (C)RT (p = 0.008) independently predicted longer survival. Palliative RT resulted in a median OS of 4 months.

Conclusion: Older age, lower KPS, higher CCI, and definitive (C)RT are indicators of worse survival in older patients with HNC treated curatively. Without a comprehensive geriatric assessment in patients aged >75 years, the KPS and CCI can be useful tools to account for "fitness, vulnerability or frailty" to help in treatment decision-making.
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http://dx.doi.org/10.3389/fonc.2020.566318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942196PMC
February 2021

What is the role of the subventricular zone in radiotherapy of glioblastoma patients?

Radiother Oncol 2021 Feb 23;158:138-145. Epub 2021 Feb 23.

Department of Radiation Oncology Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; German Cancer Consortium (DKTK), partner site Berlin, Germany. Electronic address:

Background And Purpose: Current glioblastoma (GBM) therapies prolong survival, but overall prognosis is still poor. Irradiation of the subventricular zone (SVZ) has recently been discussed as a promising concept as this tissue harbors stem cells which seem to play a role in the initiation and recurrence of GBM. In this study, we retrospectively examined the relationship of SVZ irradiation dose and survival in a large, homogeneous GBM patient cohort.

Materials And Methods: We included 200 GBM patients who had been treated at our institution with trimodal therapy (surgery, radiotherapy and chemotherapy) between 2009 and 2020. The SVZ was delineated, and dose-volume histograms were calculated and extracted. Tumors were classified according to their contact with the SVZ. The Kaplan-Meier method was used for survival analysis, and univariable and multivariable Cox regression (MVA) were used to determine prognostic effects on progression-free survival (PFS) and overall survival (OS).

Results: Median PFS of the study group was 7.2 months; median OS was 15.1 months. In MVA (with mean dose to the ipsilateral SVZ as a continuous covariable), PFS was significantly lower for patients with a Karnofsky performance status (KPS) < 70% and without MGMT promoter methylation. Factors prognostic for shorter OS were old age, lower KPS, unmethylated MGMT status, SVZ contact and biopsy instead of subtotal- or gross total resection. There was no significant correlation between survival and SVZ dose.

Conclusion: In this cohort, an increased mean dose to the ipsilateral or contralateral SVZ did not correlate with improved survival in irradiated GBM patients in MVA. Patients whose tumor directly involved the SVZ showed worse OS in MVA.
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http://dx.doi.org/10.1016/j.radonc.2021.02.017DOI Listing
February 2021

Late Sequelae of Radiotherapy—The Effect of Technical and Conceptual Innovations in Radiation Oncology.

Dtsch Arztebl Int 2021 03 26;118(Forthcoming). Epub 2021 Mar 26.

Background: Approximately half of all patients with tumors need radiotherapy. Long-term survivors may suffer from late sequelae of the treatment. The existing radiotherapeutic techniques are being refined so that radiation can be applied more precisely, with the goal of limiting the radiation exposure of normal tissue and reducing late sequelae.

Methods: This review is based on the findings of a selective search in PubMed for publications on late sequelae of conventional percutaneous radiotherapy, January 2000 to May 2020. Late sequelae affecting the central nervous system, lungs, and heart and the development of second tumors are presented, and radiobiological mechanisms and the relevant technical and conceptual considerations are discussed.

Results: The current standard of treatment involves the use of linear accelerators, intensitymodulated radiotherapy (IMRT), image-guided and respiratory-gated radiotherapy, and the integration of positron emission tomography combined with computed tomography (PET-CT) in radiation treatment planning. Cardiotoxicity has been reduced with regard to the risk of coronary heart disease after radiotherapy for Hodgkin's lymphoma (hazard ratio [HR] 0.44 [0.23; 0.85]). It was also found that the rate of radiation-induced pneumonitis dropped from 7.9% with conformal treatment to 3.5% with IMRT in a phase III lung cancer trial. It is hoped that neurocognitive functional impairment will be reduced by hippocampal avoidance in modern treatment planning: an initial phase III trial yielded a hazard ratio of 0.74 [0.58; 0.94]. It is estimated that 8% of second solid tumors in adults are induced by radiotherapy (3 additional tumors per 1000 patients at 10 years).

Conclusion: Special challenges for research in this field arise from the long latency of radiation sequelae and the need for large-scale, well-documented patient collectives in order to discern dose-effect relationships, and take account of cofactors, when the overall number of events is small. It is hoped that further technical and conceptual advances will be made in the areas of adaptive radiotherapy, proton and heavy-ion therapy, and personalized therapy.
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http://dx.doi.org/10.3238/arztebl.m2021.0024DOI Listing
March 2021

Fever range whole body hyperthermia for re-irradiation of head and neck squamous cell carcinomas: Final results of a prospective study.

Oral Oncol 2021 Feb 21;116:105240. Epub 2021 Feb 21.

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Radiation Oncology, Berlin, Germany.

Objectives: Fever-range whole body hyperthermia (FRWBH) has been shown to improve tumor oxygenation in vivo. A prospective pilot study addressed the question if addition of FRWBH to re-irradiation is feasible in recurrent head and neck squamous cell carcinomas (HNSCC) with unfavorable prognostic features.

Materials And Methods: The study completed accrual with the recruitment of ten patients between April 2018 and March 2020. Re-irradiation was administered using volumetric arc hyperfractionated radiotherapy with bi-daily 1.2 Gray (Gy) single fractions and a total dose of 66 Gy to all macroscopic tumor lesions. Concomitant chemotherapy consisted mostly of cisplatin (7 patients). FRWBH was scheduled weekly during re-irradiation. The study was registered in the clinicaltrials.gov database (NCT03547388).

Results: Only five patients received all cycles of FRWBH. Poor patient compliance, active infections during treatment and study restrictions due to the Covid-19 pandemic were the main reasons for omitting FRWBH. No increase of acute toxicity was observed by FRWBH. Exploratory evaluation of outcome data suggests that FRWBH treatment according to protocol does not seem to have a detrimental effect on tumor control or survival and might even increase treatment efficacy.

Conclusion: FRWBH is difficult to apply concomitant to re-irradiation in HNSCC. No excess toxicity was observed in patients receiving FRWBH and exploratory analyses suggest potential anti-tumor activity and decreased patient-reported depression scores after FRWBH.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105240DOI Listing
February 2021

State of the art treatment for stage I to III anal squamous cell carcinoma: A systematic review and meta-analysis.

Radiother Oncol 2021 04 4;157:188-196. Epub 2021 Feb 4.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Department of Surgery, Berlin, Germany.

Background And Purpose: This systematic review summarised and critically appraised evidence on the efficacy and safety of interventions for anal cancer to support the panel of experts developing the national evidence-based anal cancer guideline in Germany.

Materials And Methods: We conducted a systematic review and meta-analyses of interventions for the treatment of stage I to III anal squamous cell carcinoma (SCCA). We systematically searched several databases and included any randomised controlled trial (RCT) assessing the pre-specified patient populations, regardless of the interventions studied. Non-randomised controlled studies of selected, pre-specified interventions were included if RCTs were not available or contained insufficient information. Where possible, we conducted meta-analyses and critically assessed confidence in the effect estimates using the GRADE approach.

Results: Our searches yielded 10,325 (25 October 2018) and 889 hits (update search on 18 July 2019). Among the 41 studies (47 publications) included, we identified 19 comparisons of interventions for SCCA, and confidence in the effect estimates ranged from very low to high. Most RCTs compared various chemoradiation regimes. For other treatment options, such as local excision in early stages or different radiotherapies, we mostly identified comparative cohort studies.

Conclusion: Our findings indicate that, in most clinical situations, primary chemoradiation based on 5-FU and MMC is still the gold standard. However, treatment options for stage I anal cancer, particularly of the anal margin, as well as newer treatment approaches should be investigated in future RCTs. Overall, our findings may help health care professionals and patients make informed decisions about treatment choices.
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http://dx.doi.org/10.1016/j.radonc.2021.01.031DOI Listing
April 2021

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group.

Radiother Oncol 2021 03 27;156:281-293. Epub 2021 Jan 27.

University of Chicago, IL, USA.

Background And Purpose: The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.

Materials And Methods: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.

Results: For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005).

Conclusion: The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.
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http://dx.doi.org/10.1016/j.radonc.2021.01.013DOI Listing
March 2021

Interdisciplinary Clinical Target Volume Generation for Cardiac Radioablation: Multicenter Benchmarking for the RAdiosurgery for VENtricular TAchycardia (RAVENTA) Trial.

Int J Radiat Oncol Biol Phys 2021 Jan 27. Epub 2021 Jan 27.

I. Medizinische Klinik, Universitätsklinikum Mannheim and German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Mannheim, Germany.

Purpose: Cardiac radioablation is a novel treatment option for therapy-refractory ventricular tachycardia (VT) ineligible for catheter ablation. Three-dimensional clinical target volume (CTV) definition is a key step, and this complex interdisciplinary procedure includes VT-substrate identification based on electroanatomical mapping (EAM) and its transfer to the planning computed tomography (PCT). Benchmarking of this process is necessary for multicenter clinical studies such as the RAVENTA trial.

Methods And Materials: For benchmarking of the RAVENTA trial, patient data (epicrisis, electrocardiogram, high-resolution EAM, contrast-enhanced cardiac computed tomography, PCT) of 3 cases were sent to 5 university centers for independent CTV generation, subsequent structure analysis, and consensus finding. VT substrates were first defined on multiple EAM screenshots/videos and manually transferred to the PCT. The generated structure characteristics were then independently analyzed (volume, localization, surface distance and conformity). After subsequent discussion, consensus structures were defined.

Results: VT substrate on the EAM showed visible variability in extent and localization for cases 1 and 2 and only minor variability for case 3. CTVs ranged from 6.7 to 22.9 cm, 5.9 to 79.9 cm, and 9.4 to 34.3 cm; surface area varied from 1087 to 3285 mm, 1077 to 9500 mm, and 1620 to 4179 mm, with a Hausdorff-distance of 15.7 to 39.5 mm, 23.1 to 43.5 mm, and 15.9 to 43.9 mm for cases 1 to 3, respectively. The absolute 3-dimensional center-of-mass difference was 5.8 to 28.0 mm, 8.4 to 26 mm, and 3.8 to 35.1 mm for cases 1 to 3, respectively. The entire process resulted in CTV structures with a conformity index of 0.2 to 0.83, 0.02 to 0.85, and 0.02 to 0.88 (ideal 1) with the consensus CTV as reference.

Conclusions: Multicenter efficacy endpoint assessment of cardiac radioablation for therapy-refractory VT requires consistent CTV transfer methods from the EAM to the PCT. VT substrate definition and CTVs were comparable with current clinical practice. Remarkable differences regarding the degree of agreement of the CTV definition on the EAM and the PCT were noted, indicating a loss of agreement during the transfer process between EAM and PCT. Cardiac radioablation should be performed under well-defined protocols and in clinical trials with benchmarking and consensus forming.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.028DOI Listing
January 2021

FLASH proton irradiation setup with a modulator wheel for a single mouse eye.

Med Phys 2021 Apr 1;48(4):1839-1845. Epub 2021 Mar 1.

Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Purpose: Recent studies indicate that FLASH irradiation, which involves ultra-high dose rates in a short time window (usually >40 Gy/s in <500 ms), might be equally efficient against tumors but less harmful to healthy tissues, compared to conventional irradiation with the same total dose. Aiming to verify the latter claim for ocular proton radiotherapy, in vivo experiments with mice are being carried out by Charité - Universitätsmedizin Berlin. This work presents the implemented setup for delivering FLASH proton radiation to a single eye of mice at the Helmholtz-Zentrum Berlin für Materialien und Energie (HZB).

Materials And Methods: The HZB cyclotron is tuned to provide a high-intensity 68 MeV focused proton beam. Outside the vacuum beamline, the protons hit a single scatterer, which also serves as range shifter, and a rotating modulator wheel, which produces a flat depth-dose distribution. Two transmission ionization chambers in between, read out by fast electronics, are used as dose monitors for triggering an in-vacuum beam shutter, which blocks the beam once the desired dose has been delivered. A collimating aperture shapes the radiation field at the isocenter, which is measured by a radioluminescent screen and a CCD camera. At the same position, a parallel-plate ionization chamber of type Advanced Markus is used for absolute dosimetry and characterization of the spread-out Bragg peak inside a water phantom. A thin-foil mirror of adjustable tilt in the beam path assists the correct alignment of the target through side illumination. Radiochromic films of type EBT3 are used to supplement the dosimetry and assist the alignment.

Results: A dose rate of 75 Gy/s has been measured, delivering within 200 ms 15 Gy (RBE) with a reproducibility better than ±1%. A depth-dose curve with a range of 5.2 mm in water, 0.9 mm distal fall-off (90%-10%), and ±2.5% ripple has been demonstrated, with a PTV of 6.3 mm diameter, 1.7 mm lateral penumbra (90%-10%), 8% uniformity, and 3% symmetry.

Conclusions: The implemented setup is able to accommodate ocular irradiation of narcotized mice with protons, targeting selectively the left or the right eye, under conventional and FLASH conditions. Switching between these two modes can be done within half an hour, including the calibration of the dose monitors and the verification of the dose delivery. Further upgrades are planned after the completion of the on-going experiment.
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http://dx.doi.org/10.1002/mp.14730DOI Listing
April 2021

Predicting survival in anaplastic astrocytoma patients in a single-center cohort of 108 patients.

Radiat Oncol 2020 Dec 17;15(1):282. Epub 2020 Dec 17.

Department of Radiation Oncology, Charité University Hospital Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

Background: Current guidelines for the treatment of anaplastic astrocytoma (AA) recommend maximal safe resection followed by radiotherapy and chemotherapy. Despite this multimodal treatment approach, patients have a limited life expectancy. In the present study, we identified variables associated with overall survival (OS) and constructed a model score to predict the OS of patients with AA at the time of their primary diagnosis.

Methods: We retrospectively evaluated 108 patients with newly diagnosed AA. The patient and tumor characteristics were analyzed for their impact on OS. Variables significantly associated with OS on multivariable analysis were included in our score. The final algorithm was based on the 36-month survival rates corresponding to each characteristic.

Results: On univariate analysis, age, Karnofsky performance status, isocitrate dehydrogenase status, and extent of resection were significantly associated with OS. On multivariable analysis all four variables remained significant and were consequently incorporated in the score. The total score ranges from 20 to 33 points. We designated three prognostic groups: A (20-25), B (26-29), and C (30-33 points) with 36-month OS rates of 23%, 71%, and 100%, respectively. The OS rate at 5 years was 8% in group A, 61% in group B and 88% in group C.

Conclusions: Our model score predicts the OS of patients newly diagnosed with AA and distinguishes patients with a poor survival prognosis from those with a greater life expectancy. Independent and prospective validation is needed. The upcoming changes of the WHO classification of brain tumors as well as the practice changing results from the CATNON trial will most likely require adaption of the score.
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http://dx.doi.org/10.1186/s13014-020-01728-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745461PMC
December 2020

Shortened Tracer Uptake Time in GA-68-DOTATOC-PET of Meningiomas Does Not Impair Diagnostic Accuracy and PET Volume Definition.

Diagnostics (Basel) 2020 Dec 13;10(12). Epub 2020 Dec 13.

Department of Nuclear Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.

Ga-68-DOTATOC-PET/MRI can affect the planning target volume (PTV) definition of meningiomas before radiosurgery. A shorter tracer uptake time before image acquisition could allow the examination of more patients. The aim of this study was to investigate if shortening uptake time is possible without compromising diagnostic accuracy and PET volume. Fifteen patients ( = 12; mean age 52 years (34-80 years)) with meningiomas were prospectively examined with dynamic [68Ga]Ga-68-labeled [DOTA0-Phe1-Tyr3] octreotide (Ga-68-DOTATOC)-PET/MRI over 70 min before radiosurgery planning. Meningiomas were delineated manually in the PET dataset. PET volumes at each time point were compared to the reference standard 60 min post tracer injection (p.i.) using the Friedman test followed by a Wilcoxon signed-rank test and Bonferroni correction. In all patients, the earliest time point with 100% lesion detection compared to 60 min p.i. was identified. PET volumes did not change significantly from 15 min p.i. ( = 1.0) compared to 60 min p.i. The earliest time point with 100% lesion detection in all patients was 10 min p.i. In patients with meningiomas undergoing Ga-68-DOTATOC-PET, the tracer uptake time can safely be reduced to 15 min p.i. with comparable PET volume and 100% lesion detection compared to 60 min p.i.
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http://dx.doi.org/10.3390/diagnostics10121084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763245PMC
December 2020

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

Surgical versus clinical staging prior to primary chemoradiation in patients with cervical cancer FIGO stages IIB-IVA: oncologic results of a prospective randomized international multicenter (Uterus-11) intergroup study.

Int J Gynecol Cancer 2020 Dec;30(12):1855-1861

Department of Gynecology, University of Cologne, Koln, Germany.

Objective: Revised staging of patients with locally advanced cervical cancer is based on clinical examination, imaging, and potential surgical findings. A known limitation of imaging techniques is an appreciable rate of understaging. In contrast, surgical staging may provide more accurate information on lymph node involvement. The aim of this prospective study was to evaluate the impact of pre-treatment surgical staging, including removal of bulky lymph nodes, on disease-free survival in patients with locally advanced cervical cancer.

Methods: Uterus-11 was a prospective international multicenter study including patients with locally advanced cervical cancer who were randomized 1:1 to surgical staging (experimental arm) or clinical staging (control arm) followed by primary platinum-based chemoradiation. Patients with histologically proven squamous cell carcinoma, adenocarcinoma, or adenosquamous cancer International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IIB-IVA underwent gynecologic examination and pre-treatment imaging including abdominal computed tomography (CT) and/or abdominal magnetic resonance imaging (MRI). Patients had chest imaging (any of the following: X-ray, CT, or PET-CT). The primary endpoint was disease-free survival and the secondary endpoint was overall survival. An ad hoc analysis was performed after trial completion for cancer-specific survival. Randomization was conducted from February 2009 to August 2013.

Results: A total of 255 patients (surgical arm, n=130; clinical arm, n=125) with locally advanced cervical cancer were randomized. Of these, 240 patients were eligible for analysis. The two groups were comparable with respect to patient characteristics. The surgical approach was transperitoneal laparoscopy in most patients (96.6%). Laparoscopic staging led to upstaging in 39 of 120 (33%) patients. After a median follow-up of 90 months (range 1-123) in both arms, there was no difference in disease-free survival between the groups (p=0.084). For patients with FIGO stage IIB, surgical staging is superior to clinical staging with respect to disease-free survival (HR 0.51, 95% CI 0.30 to 0.86, p=0.011). In the post-hoc analysis, surgical staging was associated with better cancer-specific survival (HR 0.61, 95% CI 0.40 to 0.93, p=0.020).

Conclusion: Our study did not show a difference in disease-free survival between surgical and clinical staging in patients with locally advanced cervical cancer. There was a significant benefit in disease-free survival for patients with FIGO stage IIB and, in a post-hoc analysis, a cancer-specific survival benefit in favor of laparoscopic staging. The high risk of distant metastases in both arms emphasizes the need for further evaluation.
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http://dx.doi.org/10.1136/ijgc-2020-001973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788482PMC
December 2020

Development and validation of a novel prognostic score for elderly head-and-neck cancer patients undergoing radiotherapy or chemoradiation.

Radiother Oncol 2021 01 24;154:276-282. Epub 2020 Nov 24.

Department of Radiation Oncology, University of Freiburg - Medical Center, Germany; German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (dkfz), Heidelberg, Germany. Electronic address:

Background And Purpose: To establish a clinically feasible prognostic score and nomogram based on easily accessible clinical data that will aid decision-making in elderly head-and-neck squamous cell carcinoma (HNSCC) patients undergoing (chemo)radiotherapy.

Material And Methods: 284 elderly HNSCC patients (≥65 years) undergoing curative (chemo)radiotherapy were included for the development of a score predicting overall survival (OS) based on the beta regression coefficients from significant parameters in a multivariate Cox regression analysis with p < 0.1 as inclusion criterion. A second, external cohort of 217 elderly HNSCC patients receiving (chemo)radiotherapy was used for validation. Using the aggregated data (n = 501), a nomogram was developed to predict 2- and 4-year OS.

Results: Karnofsky Performance Status (HR = 2.654; p < 0.001), Charlson Comorbidity Index (HR = 2.598; p < 0.001) and baseline C-reactive protein (CRP) level (HR = 1.634; p = 0.068) were prognostic for OS in the multivariate analysis. An OS score based on beta regression coefficients was created, in which reduced performance status, increased comorbidity burden and increased CRP levels were included, leading to 3 distinct survival groups. The median OS for the 3 groups amounted to 107, 28 and 6 months, respectively (p < 0.001). The developed score was able to significantly differentiate between a favorable (median OS = 130 months), intermediate (29 months) and unfavorable prognosis (9 months) also in the external validation cohort (p = 0.005).

Conclusion: We propose a novel, validated prognostic score based on easily accessible clinical data allowing stratification between prognostic groups of elderly HNSCC patients receiving (chemo)radiotherapy. The derived nomogram for the prediction of 2-year and 4-year OS may aid decision-making for this vulnerable population.
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http://dx.doi.org/10.1016/j.radonc.2020.11.023DOI Listing
January 2021

The rationale and development of a CyberKnife© registry for pediatric patients with CNS lesions.

Childs Nerv Syst 2021 Mar 10;37(3):871-878. Epub 2020 Nov 10.

European CyberKnife Center Munich, Max Lebsche Platz 31, 81377, Munich, Germany.

Background: CyberKnife© Radiosurgery (CKRS) is a recognized treatment concept for CNS lesions in adults due to its high precision and efficacy beside a high patient comfort. However, scientific evidence for this treatment modality in pediatric patients is scarce. A dedicated registry was designed to document CyberKnife© procedures in children, aiming to test the hypothesis that it is safe and efficient for the treatment of CNS lesions.

Methods: The CyberKnife© registry is designed as a retrospective and prospective multicenter observational study (German Clinical Trials Register ( https://www.drks.de ), DRKS-ID 00016973). Patient recruitment will be ongoing throughout a 5-year period and includes collection of demographic, treatment, clinical, and imaging data. Follow-up results will be monitored for 10 years. All data will be registered in a centralized electronic database at the Charité-Universitätsmedizin. The primary endpoint is stable disease for benign and vascular lesions at 5 years of follow-up and local tumor control for malign lesions at 1- and 2-year follow-up. Secondary endpoints are radiation toxicity, side effects, and neurocognitive development.

Conclusion: The CyberKnife© registry intends to generate scientific evidence for all treatment- and outcome-related aspects in pediatric patients with treated CNS lesions. The registry may define safety and efficacy of CKRS in children and serve as a basis for future clinical trials, inter-methodological comparisons and changes of treatment algorithms.
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http://dx.doi.org/10.1007/s00381-020-04944-5DOI Listing
March 2021

Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.

Lancet Oncol 2020 12 2;21(12):1602-1610. Epub 2020 Nov 2.

Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.

Background: 10-year results from several studies showed improved disease-free survival and distant metastasis-free survival, reduced breast cancer-related mortality, and variable effects on overall survival with the addition of partial or comprehensive regional lymph node irradiation after surgery in patients with breast cancer. We present the scheduled 15-year analysis of the European Organisation for Research and Treatment of Cancer (EORTC) 22922/10925 trial, which aims to investigate the impact on overall survival of elective internal mammary and medial supraclavicular (IM-MS) irradiation.

Methods: EORTC 22922/10925, a randomised, phase 3 trial done across 46 radiation oncology departments from 13 countries, included women up to 75 years of age with unilateral, histologically confirmed, stage I-III breast adenocarcinoma with involved axillary nodes or a central or medially located primary tumour. Surgery consisted of mastectomy or breast-conserving surgery and axillary staging. Patients were randomly assigned (1:1) centrally using minimisation to receive IM-MS irradiation at 50 Gy in 25 fractions (IM-MS irradiation group) or no IM-MS irradiation (control group). Stratification was done for institution, menopausal status, site of the primary tumour within the breast, type of breast and axillary surgery, and pathological T and N stage. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival analysed according to the intention-to-treat principle. Secondary endpoints were disease-free survival, distant metastasis-free survival, breast cancer mortality, any breast cancer recurrence, and cause of death. Follow-up is ongoing for 20 years after randomisation. This study is registered with ClinicalTrials.gov, NCT00002851.

Findings: Between Aug 5, 1996, and Jan 13, 2004, we enrolled 4004 patients, of whom 2002 were randomly assigned to the IM-MS irradiation group and 2002 to the no IM-MS irradiation group. At a median follow-up of 15·7 years (IQR 14·0-17·6), 554 (27·7%) patients in the IM-MS irradiation group and 569 (28·4%) patients in the control group had died. Overall survival was 73·1% (95% CI 71·0-75·2) in the IM-MS irradiation group and 70·9% (68·6-72·9) in the control group (HR 0·95 [95% CI 0·84-1·06], p=0·36). Any breast cancer recurrence (24·5% [95% CI 22·5-26·6] vs 27·1% [25·1-29·2]; HR 0·87 [95% CI 0·77-0·98], p=0·024) and breast cancer mortality (16·0% [14·3-17·7] vs 19·8% [18·0-21·7]; 0·81 [0·70-0·94], p=0·0055) were lower in the IM-MS irradiation group than in the control group. No significant differences in the IM-MS irradiation group versus the control group were seen for disease-free survival (60·8% [95% CI 58·4-63·2] vs 59·9% [57·5-62·2]; HR 0·93 [95% CI 0·84-1·03], p=0·18), or distant metastasis-free survival (70·0% [67·7-72·2] vs 68·2% [65·9-70·3]; 0·93 [0·83-1·04], p=0·18). Causes of death between groups were similar.

Interpretation: The 15-year results show a significant reduction of breast cancer mortality and any breast cancer recurrence by IM-MS irradiation in stage I-III breast cancer. However, this is not converted to improved overall survival.

Funding: US National Cancer Institute, Ligue Nationale contre le Cancer, and KWF Kankerbestrijding.
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http://dx.doi.org/10.1016/S1470-2045(20)30472-1DOI Listing
December 2020

68Ga-PSMA-PET/CT-based radiosurgery and stereotactic body radiotherapy for oligometastatic prostate cancer.

PLoS One 2020 21;15(10):e0240892. Epub 2020 Oct 21.

Charité -Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Radiation Oncology and Radiotherapy, Berlin, Germany.

Background: Androgen deprivation therapy (ADT) remains the standard therapy for patients with oligometastatic prostate cancer (OMPC). Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT)-based stereotactic body radiotherapy (SBRT) is emerging as an alternative option to postpone starting ADT and its associated side effects including the development of drug resistance. The aim of this study was to determine progression free-survival (PFS) and treatment failure free-survival (TFFS) after PSMA-PET/CT-based SBRT in OMPC patients. The efficacy and safety of single fraction radiosurgery (SFRS) and ADT delay were investigated.

Methods: Patients with ≤5 metastases from OMPC, with/without ADT treated with PSMA-PET/CT-based SBRT were retrospectively analyzed. PFS and TFFS were primary endpoints. Secondary endpoints were local control (LC), overall survival (OS) and ADT-free survival (ADTFS).

Results: Fifty patients with a total of 75 metastases detected by PSMA-PET/CT were analyzed. At the time of SBRT, 70% of patients were castration-sensitive. Overall, 80% of metastases were treated with SFRS (median dose 20 Gy, range: 16-25). After median follow-up of 34 months (range: 5-70) median PFS and TFFS were 12 months (range: 2-63) and 14 months (range: 2-70), respectively. Thirty-two (64%) patients had repeat oligometastatic disease. Twenty-four (48%) patients with progression underwent second SBRT course. Two-year LC after SFRS was 96%. Grade 1 and 2 toxicity occurred in 3 (6%) and 1 (2%) patients, respectively. ADTFS and OS rates at 2-years were 60.5% and 100%, respectively. In multivariate analysis, TFFS significantly improved in patients with time to first metastasis (TTM) >36 months (p = 0.01) and PSA before SBRT ≤1 ng/ml (p = 0.03).

Conclusion: For patients with OMPC, SBRT might be used as an alternative to ADT. This way, the start/escalation of palliative ADT and its side effects can be deferred. Metastases treated with PSMA-PET/CT-based SFRS reached excellent LC with minimal toxicity. Low PSA levels and longer TTM predict elongated TFFS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240892PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577453PMC
December 2020

Reirradiation of High-Grade Gliomas: A Retrospective Analysis of 198 Patients Based on the Charité Data Set.

Adv Radiat Oncol 2020 Sep-Oct;5(5):959-964. Epub 2020 Jun 18.

Department of Radiation Oncology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.

Purpose: There is no standard of care for recurrent high-grade glioma. Treatment strategies include reresection, reirradiation, systemic agents, intratumoral thermotherapy using magnetic iron-oxide nanoparticles ("nanotherapy"), and tumor treating fields. Only a small number of patients are eligible for reresection, and because many patients receive a full course of radiation therapy, there is fear of reirradiation-induced morbidity. Modern radiation techniques have resulted in greater acceptance of reirradiation. In this work we retrospectively analyzed patients who had undergone reirradiation of high-grade glioma at Charité Universitätsmedizin Berlin.

Methods And Materials: All patients treated with reirradiation for recurrent high-grade glioma in our department from January 1997 to February 2014 were analyzed in this study. In total, 198 patients were included. The primary endpoint was overall survival after recurrence.

Results: One hundred ninety-eight patients were identified. Median time from first radiation therapy to reirradiation was 14 months. Median follow-up from the first day of reirradiation to last contact or death was 7 months. Median overall survival after relapse was 7 months for the overall cohort. For glioblastoma, median overall survival after relapse was 6 months and for grade 3 gliomas 14 months. Treatment was generally well tolerated. Common Terminology Criteria for Adverse Events grade 3 toxicity was observed in 5.1% patients and grade 4 toxicity in 2.5%. No patient developed grade 5 toxicity. The likelihood of developing severe toxicity (Common Terminology Criteria for Adverse Events grade 3 or 4) was not significantly higher in the group of patients who received reirradiation in the first 14 months after initial radiation therapy. Patients who received a higher biologically effective dose to the tumor also did not have a significantly higher rate of severe acute toxicity.

Conclusions: The prognosis of recurrent high-grade glioma remains dismal. Reirradiation is often tolerable even after early recurrence (<14 months) and with higher doses (eg, 49.4 Gy/3.8 Gy) in selected patients.
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http://dx.doi.org/10.1016/j.adro.2020.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557122PMC
June 2020

A FDG-PET radiomics signature detects esophageal squamous cell carcinoma patients who do not benefit from chemoradiation.

Sci Rep 2020 10 19;10(1):17671. Epub 2020 Oct 19.

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Radiation Oncology, Augustenburger Platz 1, 13353, Berlin, Germany.

Detection of patients with esophageal squamous cell carcinoma (ESCC) who do not benefit from standard chemoradiation (CRT) is an important medical need. Radiomics using 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a promising approach. In this retrospective study of 184 patients with locally advanced ESCC. 152 patients from one center were grouped into a training cohort (n = 100) and an internal validation cohort (n = 52). External validation was performed with 32 patients treated at a second center. Primary endpoint was disease-free survival (DFS), secondary endpoints were overall survival (OS) and local control (LC). FDG-PET radiomics features were selected by Lasso-Cox regression analyses and a separate radiomics signature was calculated for each endpoint. In the training cohort radiomics signatures containing up to four PET derived features were able to identify non-responders in regard of all endpoints (DFS p < 0.001, LC p = 0.003, OS p = 0.001). After successful internal validation of the cutoff values generated by the training cohort for DFS (p = 0.025) and OS (p = 0.002), external validation using these cutoffs was successful for DFS (p = 0.002) but not for the other investigated endpoints. These results suggest that pre-treatment FDG-PET features may be useful to detect patients who do not respond to CRT and could benefit from alternative treatment.
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http://dx.doi.org/10.1038/s41598-020-74701-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573602PMC
October 2020

Efficacy and safety of CyberKnife radiosurgery in elderly patients with brain metastases: a retrospective clinical evaluation.

Radiat Oncol 2020 Sep 29;15(1):225. Epub 2020 Sep 29.

Charité CyberKnife Center, Augustenburger Platz 1, 13353, Berlin, Germany.

Background: Stereotactic radiosurgery (SRS) has been increasingly applied for up to 10 brain metastases instead of whole brain radiation therapy (WBRT) to achieve local tumor control while reducing neurotoxicity. Furthermore, brain-metastasis incidence is rising due to the increasing survival of patients with cancer. Our aim was to analyze the efficacy and safety of CyberKnife (CK) radiosurgery for elderly patients.

Methods: We retrospectively identified all patients with brain metastases ≥ 65 years old treated with CK-SRS at our institution since 2011 and analyzed data of primary diseases, multimodality treatments, and local therapy effect based on imaging follow-up and treatment safety. Kaplan-Meier analysis for local progression-free interval and overall survival were performed.

Results: We identified 97 patients (233 lesions) fulfilling the criteria at the first CK-SRS. The mean age was 73.2 ± 5.8 (range: 65.0-87.0) years. Overall, 13.4% of the patients were > 80 years old. The three most frequent primary cancers were lung (40.2%), kidney (22.7%), and malignant melanoma (15.5%). In 38.5% (47/122 treatments) multiple brain metastases were treated with the CK-SRS, with up to eight lesions in one session. The median planning target volume (PTV) was 1.05 (range: 0.01-19.80) cm. A single fraction was applied in 92.3% of the lesions with a median prescription dose of 19 (range: 12-21) Gy. The estimated overall survivals at 3-, 6-, and 12 months after SRS were 79, 55, and 23%, respectively. The estimated local tumor progression-free intervals at 6-, 12-, 24-, 36-, and 72 months after SRS were 99.2, 89.0, 67.2, 64.6, and 64.6%, respectively. Older age and female sex were predictive factors of local progression. The Karnofsky performance score remained stable in 97.9% of the patients; only one patient developed a neurological deficit after SRS of a cerebellar lesion (ataxia, CTCAE Grade 2).

Conclusions: SRS is a safe and efficient option for the treatment of elderly patients with brain metastases with good local control rates without the side effects of WBRT. Older age and female sex seem to be predictive factors of local progression. Prospective studies are warranted to clarify the role of SRS treatment for elderly patients.
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http://dx.doi.org/10.1186/s13014-020-01655-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523070PMC
September 2020

Long-term results of robotic radiosurgery for non brachytherapy patients with cervical cancer.

Strahlenther Onkol 2020 Sep 24. Epub 2020 Sep 24.

Faculty of Medicine and University Hospital Cologne, Department of Radiation Oncology and Cyberknife Center, University of Cologne, Kerpener Str. 62, Cologne, 50937, Germany.

Background: Consolidation brachytherapy is a critical treatment component for cervical cancer patients undergoing primary chemoradiation. Some patients are unsuitable for brachytherapy for a variety of reasons. The use of alternatives (LINAC-based stereotactic radiosurgery or external beam boosts) compromise oncologic results in cervical cancer patients. Thus, we evaluated the value of brachytherapy-like doses prescriptions using robotic radiosurgery (CyberKnife®, CR, Acuuray, Sunnyvale, CA, USA).

Methods: From 06/2011 to 06/2015, 31 patients (median age 53 years; range 30-77 years) with histologically proven FIGO stages IB-IVB cervical cancer underwent primary chemoradiation. All patients were either not suitable for intracervical brachytherapy for a variety of reasons or refused the brachytherapy. To achieve an adequate dose within the tumor, a CK boost was applied after fiducial implantation. In 29 patients, a dose of either five times 6 Gy or five times 5 Gy was prescribed to the target volume. Two patients received three times 5 Gy. The target dose was prescribed to the 70% isodose. Treatment toxicity was documented once weekly regarding vaginal mucositis, bladder, and bowel irritation according to CTCAE v. 4.03. If possible 3 months after completion of treatment intracervical curettage was performed to exclude residual tumor and the patients were followed up clinically. Sparing of organs at risk (OAR) and outcome in terms of local control (LC), overall survival (OS), and progression-free survival (PFS) were assessed.

Results: Of the 31 patients, 30 have completed CK boost therapy. The median follow-up time was 40 months (range 5-84 months). General treatment tolerability was good. Except for 1 patient, who had diarrhea grade 3, no treatment related side effects above grade 2 were reported. Sparing of OAR was excellent. The 1‑, 3‑, and 5‑year OS rates were 89, 60, and 57% respectively across all stages. Seven patients showed progression (28%), only two of them with local relapse (8%), resulting in an LC rate of 92% after 3 and 5 years. Mean PFS was 41 months (range 2-84 months). Patients with local recurrence had PFS of 5 and 8 months. Five patients developed distant metastases. Fifteen patients (48%) underwent intracervical curettage 3 months after completion of treatment of which 14 (93%) had complete pathologic response.

Conclusion: Brachytherapy remains the standard of care for patients diagnosed with cervical cancer and indication for primary chemoradiation. In terms of local control, CyberKnife®-based boost concepts provide excellent local control. It can be an alternative for patients who cannot receive adequate brachytherapy. Distant relapse still remains a challenge in this context.
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http://dx.doi.org/10.1007/s00066-020-01685-xDOI Listing
September 2020

Quantitative volumetric assessment of baseline enhancing tumor volume as an imaging biomarker predicts overall survival in patients with glioblastoma.

Acta Radiol 2020 Sep 16:284185120953796. Epub 2020 Sep 16.

Department of Radiation Oncology, Charité Universitätsmedizin Berlin, Berlin, Germany.

Background: Glioblastoma multiforme (GBM) is the commonest malignant primary brain tumor and still has one of the worst prognoses among cancers in general. There is a need for non-invasive methods to predict individual prognosis in patients with GBM.

Purpose: To evaluate quantitative volumetric tissue assessment of enhancing tumor volume on cranial magnetic resonance imaging (MRI) as an imaging biomarker for predicting overall survival (OS) in patients with GBM.

Material And Methods: MRI scans of 49 patients with histopathologically confirmed GBM were analyzed retrospectively. Baseline contrast-enhanced (CE) MRI sequences were transferred to a segmentation-based three-dimensional quantification tool, and the enhancing tumor component was analyzed. Based on a cut-off percentage of the enhancing tumor volume (PoETV) of >84.78%, samples were dichotomized, and the OS and intracranial progression-free survival (PFS) were evaluated. Univariable and multivariable analyses, including variables such as sex, Karnofsky Performance Status score, -methylguanine-DNA-methyltransferase status, age, and resection status, were performed using the Cox regression model.

Results: The median OS and PFS were 16.9 and 7 months in the entire cohort, respectively. Patients with a CE tumor volume of >84.78% showed a significantly shortened OS (12.9 months) compared to those with a CE tumor volume of ≤84.78% (17.7 months) (hazard ratio [HR] 2.72; 95% confidence interval [CI] 1.22-6.03;  = 0.01). Multivariable analysis confirmed that PoETV had a significant prognostic role (HR 2.47; 95% CI 1.08-5.65;  = 0.03).

Conclusion: We observed a correlation between PoETV and OS. This imaging biomarker may help predict the OS of patients with GBM.
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http://dx.doi.org/10.1177/0284185120953796DOI Listing
September 2020

Lead-time bias does not falsify the efficacy of early salvage radiotherapy for recurrent prostate cancer.

Radiother Oncol 2021 01 11;154:255-259. Epub 2020 Sep 11.

Dept. Radiation Oncology, University Hospital Ulm, Germany. Electronic address:

Background: In prostate cancer (PCa) recurring after radical prostatectomy (RP), salvage radiotherapy (SRT) is recommended to be given at PSA <0.5 ng/ml. It has been speculated, that the advantage from early SRT is mainly caused by lead-time bias: Calculating from time of SRT, earlier treatment would per-se result in longer time to event/censoring compared with later treatment, but not extend the interval from RP to post-SRT failure.

Methods: In 603 consecutive PCa patients receiving SRT between 1997 and 2017, we compared outcomes, calculating from time of irradiation vs. time of surgery.

Results: In multivariable analysis, tumor stage pT3-4, pathological Gleason score GS ≤6 vs. GS 7 vs. GS ≥8, post-RP PSA persistence (nadir ≥0.1 ng/ml), and the pre-SRT PSA (continuous or with cutoff 0.4 ng/ml) were significant risk-factors for biochemical progression (BCR) and progression-free survival (PFS) post-SRT and post-RP. A pre-SRT PSA <0.4 ng/ml was a significant discriminator for Kaplan-Meier rates of BCR and PFS. The Cox model for overall survival (OS) included age at RP (continuous), pT2 vs. pT3-4, and pre-SRT PSA (continuous) as significant predictors. However, no significant cutoff for the pre-SRT PSA could be identified to differentiate Kaplan-Meier estimates of OS, possibly because there were too few events, as 88% of the patients were still alive at last follow-up.

Conclusions: The pre-SRT PSA has a significant impact on BCR, PFS and potentially on OS, calculating either from RP or from SRT to event/censoring, respectively. This contradicts the hypothesis of lead-time bias falsifying the advantage from early SRT.
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http://dx.doi.org/10.1016/j.radonc.2020.09.009DOI Listing
January 2021

Prognostic value of baseline [18F]-fluorodeoxyglucose positron emission tomography parameters MTV, TLG and asphericity in an international multicenter cohort of nasopharyngeal carcinoma patients.

PLoS One 2020 30;15(7):e0236841. Epub 2020 Jul 30.

Department of Positron Emission Tomography, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.

Purpose: [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) parameters have shown prognostic value in nasopharyngeal carcinomas (NPC), mostly in monocenter studies. The aim of this study was to assess the prognostic impact of standard and novel PET parameters in a multicenter cohort of patients.

Methods: The established PET parameters metabolic tumor volume (MTV), total lesion glycolysis (TLG) and maximal standardized uptake value (SUVmax) as well as the novel parameter tumor asphericity (ASP) were evaluated in a retrospective multicenter cohort of 114 NPC patients with FDG-PET staging, treated with (chemo)radiation at 8 international institutions. Uni- and multivariable Cox regression and Kaplan-Meier analysis with respect to overall survival (OS), event-free survival (EFS), distant metastases-free survival (FFDM), and locoregional control (LRC) was performed for clinical and PET parameters.

Results: When analyzing metric PET parameters, ASP showed a significant association with EFS (p = 0.035) and a trend for OS (p = 0.058). MTV was significantly associated with EFS (p = 0.026), OS (p = 0.008) and LRC (p = 0.012) and TLG with LRC (p = 0.019). TLG and MTV showed a very high correlation (Spearman's rho = 0.95), therefore TLG was subesequently not further analysed. Optimal cutoff values for defining high and low risk groups were determined by maximization of the p-value in univariate Cox regression considering all possible cutoff values. Generation of stable cutoff values was feasible for MTV (p<0.001), ASP (p = 0.023) and combination of both (MTV+ASP = occurrence of one or both risk factors, p<0.001) for OS and for MTV regarding the endpoints OS (p<0.001) and LRC (p<0.001). In multivariable Cox (age >55 years + one binarized PET parameter), MTV >11.1ml (hazard ratio (HR): 3.57, p<0.001) and ASP > 14.4% (HR: 3.2, p = 0.031) remained prognostic for OS. MTV additionally remained prognostic for LRC (HR: 4.86 p<0.001) and EFS (HR: 2.51 p = 0.004). Bootstrapping analyses showed that a combination of high MTV and ASP improved prognostic value for OS compared to each single variable significantly (p = 0.005 and p = 0.04, respectively). When using the cohort from China (n = 57 patients) for establishment of prognostic parameters and all other patients for validation (n = 57 patients), MTV could be successfully validated as prognostic parameter regarding OS, EFS and LRC (all p-values <0.05 for both cohorts).

Conclusions: In this analysis, PET parameters were associated with outcome of NPC patients. MTV showed a robust association with OS, EFS and LRC. Our data suggest that combination of MTV and ASP may potentially further improve the risk stratification of NPC patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236841PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392321PMC
September 2020