Publications by authors named "Denise Bernhardt"

57 Publications

Surgical Outcome of Trigeminal Schwannomas.

Cancers (Basel) 2021 Mar 15;13(6). Epub 2021 Mar 15.

Department of Neurosurgery, Klinikum rechts der Isar, School of Medicine, Technical University Munich, 81675 Munich, Germany.

(1) Background: As resection of trigeminal schwannomas is challenging, due to anatomical involvement of the anterior, middle and posterior fossa, the appropriate approach is important. We report our experience with surgical resection of trigeminal schwannomas by simple and classic skull-base approaches. (2) Methods: We performed a retrospective single-center study including patients who underwent surgery for trigeminal schwannoma tumors between June 2007 and May 2020, concentrating on surgical technique, extent of resection, postoperative outcome and complications. (3) Results: We included 13 patients (median age 57.5 with range of 36-83 years, 53.8% (7/13) female. The most common preoperative clinical presentations were facial pain in six (46.2%), hypoacusis in four (30.8%), trigeminal nerve hypesthesia in 11 (V1 46.2% (6/13), V2 (61.5% (8/13), V3 46.2% (6/13)) and headache in three (23.1%) patients. In three cases, the tumor was resected in a two-stage technique. The intradural subtemporal approach was performed in six cases, the extradural technique in two cases, the retrosigmoid approach in five cases, a Kawase approach in two cases and the transnasal endoscopic approach in one case. The gross total resection rate was 76.9% (10/13) and the median follow-up time 24.0 (0-136) months. Three (23.1%) patients developed postoperative anesthesia in at least one branch of the trigeminal nerve. Trigeminal motor function was preserved in 11 (84.6%) patients. Ten of the 11 patients (76.9%) who reported decreased gustation, cerebellar ataxia, visual impairment, or headache improved postoperatively. Two (15.4%) patients exhibited minimal facial palsy (House and Brackmann II-III), which resolved during the follow-up. The total adverse event rate requiring surgical intervention during follow-up was 7.7%. Surgery-related mortality was 0%. (4) Conclusions: Trigeminal schwannomas are rare benign lesions with intra- and extracranial extension. Considering the low operative morbidity and satisfying functional outcome, gross total resection of trigeminal schwannomas is achievable by classic, but also individually tailored approaches. More invasive or combined techniques were not needed with meticulous surgical planning.
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http://dx.doi.org/10.3390/cancers13061310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002014PMC
March 2021

Retrospective analysis of outcome and toxicity after postoperative radiotherapy in patients with squamous cell carcinoma of the lip.

Tumori 2021 Mar 1:300891621996805. Epub 2021 Mar 1.

Department of Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany.

Background: Carcinomas of the lips are a relatively common malignancy of the head and neck region, accounting for roughly one quarter of all oral cavity cancers. Compared to other oral cancer sites, this location has a favorable prognosis, with 5-year survival rates between 85% and 95%. This study summarizes our institutional experience in utilizing postoperative radiation for patients with squamous cell carcinoma of the upper and/or lower lip following incomplete surgical resection or positive lymph node involvement with extracapsular extension.

Methods: We retrospectively reviewed the medical records of all patients at the University Hospital of Heidelberg between 2005 and 2018 treated with postoperative radiotherapy of the upper and lower lip. Nineteen patients were identified with a median age at diagnosis of 67 years (range, 41-95 years), with 58% male and 42% female patients. Fourteen patients (73.7%) underwent neck dissection, with 5 (35.7%) found to have extracapsular extension (ECE) and positive resection margin (R1/2), 2 (14.3%) only ECE, and 7 (50.0%) with only R1/2. All patients received a median cumulative dose of 66.0 Gy (range, 60.0-70.0 Gy) in a median of 2.0 Gy per fraction (range, 1.8-2.2 Gy).

Results: Median follow-up was 5.2 years. The median progression-free survival (PFS) was 3.9 years (range, 0.2-12.4 years), local disease-free survival (LDFS) was 4 years (range, 1-12 years) and overall survival (OS) was 5.2 years (range, 0.2-12.4 years). The 5-year Kaplan-Meier estimates for OS, PFS, and LDFS were 61.4%, 85.7%, and 100.0%, respectively. At last follow-up, 13 patients (68.4%) were still alive. Although no patient developed locoregional relapse, two patients developed distant relapse at a median of 15 months after radiotherapy. There was a statistically significant improvement in OS in patients treated with higher radiotherapy doses (>60.0 Gy, = 0.044) compared to lower radiotherapy doses. PFS was significantly improved among patients who had N0 disease, with a negative resection margin, without ECE, and who were treated with intensity-modulated radiotherapy to doses >60.0 Gy. No grade 3/4 toxicity was detected; the most common grade 1/2 toxicities included dermatitis (n = 11, 57.9%), oral mucositis (n = 8, 42.1%), and dysphagia (n = 8, 42.1%).

Conclusion: Our results demonstrate excellent local control and OS with acceptable toxicity when utilizing postoperative radiotherapy in patients with squamous cell carcinoma of the upper and lower lip, despite unfavorable characteristics (advanced T or N stage and/or ECE).
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http://dx.doi.org/10.1177/0300891621996805DOI Listing
March 2021

Radiation oncology as part of medical education-current status and possible digital future prospects.

Strahlenther Onkol 2021 Jun 23;197(6):528-536. Epub 2020 Nov 23.

Department of Radiation Oncology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.

Purpose: Education as part of medical education is currently changing rapidly. Not least because of the corona crisis, more and more digital teaching formats and innovative teaching concepts such as the flipped classroom model are finding their way into teaching. We analyzed the acceptance and effectiveness of traditional teaching methods as well as the interest in innovative e‑learning methods among medical students in the field of radiation oncology at the medical school of the Technical University of Munich.

Methods: We carried out an online-based survey as well as a knowledge test on all students from two terms who had completed the seminar series of radiation oncology. The survey comprised seven questions on the frequency of participation, acceptance, and judgment of the effectiveness in terms of learning and on a potential use of e‑learning methods using a six-point Likert scale. The test consisted of 10 multiple-choice questions.

Results: Traditional teaching methods are largely accepted by students and most students consider the current learning format to be effective in terms of the teaching effect in the field of radiation oncology. However, only about 50% of all knowledge questions were answered correctly. The possible use of e‑learning methods was judged critically or desired in roughly equal parts among the students.

Conclusion: Traditional seminars enjoy a high level of acceptance among students. Effectiveness with regard to the internalization of content taught, however, should be increased. After all, the future seems to lie in the integration of e‑learning in the form of educational videos and practical seminars.
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http://dx.doi.org/10.1007/s00066-020-01712-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682521PMC
June 2021

Reply to: "Call of duty: neuro-oncology outpatient management during the COVID-19 pandemic in Milan, Italy".

Neuro Oncol 2020 12;22(12):1893

Department of Radiation Oncology, Technical University of Munich, Rechts der Isar Hospital, Munich, Germany.

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http://dx.doi.org/10.1093/neuonc/noaa203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499714PMC
December 2020

Fibroblast Activation Protein (FAP) specific PET for advanced target volume delineation in glioblastoma.

Radiother Oncol 2020 09 27;150:159-163. Epub 2020 Jun 27.

Department of Radiation Oncology, Heidelberg University Hospital, Germany; Heidelberg Institute of Radiation Oncology (HIRO), Germany; National Center for Tumor Diseases (NCT), Germany; Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberg Ion-Beam Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, Germany; German Cancer Consortium (DKTK), partner site, Heidelberg, Germany. Electronic address:

Fibroblast Activation Protein (FAP)-specific Positron Emission Tomography (PET) has shown promising results in various cancers. This pilot study compares FAP-specific PET to MRI for treatment planning in 13 Glioblastoma patients. The resulting incongruent volumes could provide additional information for radiotherapy or biopsy planning.
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http://dx.doi.org/10.1016/j.radonc.2020.06.040DOI Listing
September 2020

[Target volume reduction by F-FDG-PET/CT-based involved-field irradiation of advanced non-small cell lung cancer possible new standard: results of the PET-plan study].

Strahlenther Onkol 2020 Aug;196(8):743-746

Institut für Strahlenmedizin (IRM), Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Oberschleißheim, Deutschland.

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http://dx.doi.org/10.1007/s00066-020-01643-7DOI Listing
August 2020

Evaluation of First-line Radiosurgery vs Whole-Brain Radiotherapy for Small Cell Lung Cancer Brain Metastases: The FIRE-SCLC Cohort Study.

JAMA Oncol 2020 07;6(7):1028-1037

Department of Neurosurgery, New York University Langone Medical Center, New York.

Importance: Although stereotactic radiosurgery (SRS) is preferred for limited brain metastases from most histologies, whole-brain radiotherapy (WBRT) has remained the standard of care for patients with small cell lung cancer. Data on SRS are limited.

Objective: To characterize and compare first-line SRS outcomes (without prior WBRT or prophylactic cranial irradiation) with those of first-line WBRT.

Design, Setting, And Participants: FIRE-SCLC (First-line Radiosurgery for Small-Cell Lung Cancer) was a multicenter cohort study that analyzed SRS outcomes from 28 centers and a single-arm trial and compared these data with outcomes from a first-line WBRT cohort. Data were collected from October 26, 2017, to August 15, 2019, and analyzed from August 16, 2019, to November 6, 2019.

Interventions: SRS and WBRT for small cell lung cancer brain metastases.

Main Outcomes And Measures: Overall survival, time to central nervous system progression (TTCP), and central nervous system (CNS) progression-free survival (PFS) after SRS were evaluated and compared with WBRT outcomes, with adjustment for performance status, number of brain metastases, synchronicity, age, sex, and treatment year in multivariable and propensity score-matched analyses.

Results: In total, 710 patients (median [interquartile range] age, 68.5 [62-74] years; 531 men [74.8%]) who received SRS between 1994 and 2018 were analyzed. The median overall survival was 8.5 months, the median TTCP was 8.1 months, and the median CNS PFS was 5.0 months. When stratified by the number of brain metastases treated, the median overall survival was 11.0 months (95% CI, 8.9-13.4) for 1 lesion, 8.7 months (95% CI, 7.7-10.4) for 2 to 4 lesions, 8.0 months (95% CI, 6.4-9.6) for 5 to 10 lesions, and 5.5 months (95% CI, 4.3-7.6) for 11 or more lesions. Competing risk estimates were 7.0% (95% CI, 4.9%-9.2%) for local failures at 12 months and 41.6% (95% CI, 37.6%-45.7%) for distant CNS failures at 12 months. Leptomeningeal progression (46 of 425 patients [10.8%] with available data) and neurological mortality (80 of 647 patients [12.4%] with available data) were uncommon. On propensity score-matched analyses comparing SRS with WBRT, WBRT was associated with improved TTCP (hazard ratio, 0.38; 95% CI, 0.26-0.55; P < .001), without an improvement in overall survival (median, 6.5 months [95% CI, 5.5-8.0] for SRS vs 5.2 months [95% CI, 4.4-6.7] for WBRT; P = .003) or CNS PFS (median, 4.0 months for SRS vs 3.8 months for WBRT; P = .79). Multivariable analyses comparing SRS and WBRT, including subset analyses controlling for extracranial metastases and extracranial disease control status, demonstrated similar results.

Conclusions And Relevance: Results of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP without a decrease in overall survival, are similar to those observed in settings in which SRS is already established.
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http://dx.doi.org/10.1001/jamaoncol.2020.1271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273318PMC
July 2020

Fatigue following radiotherapy of low-risk early breast cancer - a randomized controlled trial of intraoperative electron radiotherapy versus standard hypofractionated whole-breast radiotherapy: the COSMOPOLITAN trial (NCT03838419).

Radiat Oncol 2020 Jun 1;15(1):134. Epub 2020 Jun 1.

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg University, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Background: Fatigue is one of the most common and distressing side-effects of breast cancer radiotherapy. According to current guidelines, accelerated partial breast irradiation (APBI) may be considered as an alternative treatment option for women with early-stage low-risk breast cancer. One method for APBI is single-dose intraoperative radiotherapy (IORT) applied directly to the tumor bed during breast conserving surgery (BCS). The COSMOPOLITAN trial therefore aims to analyze the intensity of fatigue following single-shot IORT with electrons (IOERT) compared to conventional hypofractionated whole breast irradiation (WBI) in low risk early breast cancer patients.

Methods: This trial is conducted as a multicenter, prospective, randomized, two-arm phase II study comparing the intensity of fatigue in early-stage breast cancer (cT1cN0cM0, tumor size < 2,5 cm, ER pos. Her2neu neg., age > 50 years) treated either with WBI or APBI after BCS. Secondary outcomes investigated are tumor control, overall survival (OS), disease-free survival (DFS), acute and chronic toxicity, quality of life (QoL) and cosmesis. A total of 202 patients will be randomized into two arms: Patients in arm A will receive WBI (40.05 Gy, 15 fractions) after surgical resection, while patients in arm B will receive IOERT (21 Gy to the 90%-isodose) during BCS. Fatigue will be assessed 12 weeks post surgery with the help of the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale.

Discussion: The present trial aims to evaluate treatment response to compare single-shot intraoperative electron APBI to conventional WBI following BCS in early-stage low risk breast cancer patients. Fatigue is selected as the primary, patient-reported endpoint due its major clinical relevance.

Trial Registration: The study is prospectively registered on February 12th, 2019: Clinicaltrials.gov, NCT03838419. "Intraoperative Electron Radiotherapy for Low-risk Early Breast Cancer (COSMOPOLITAN)".

Study Status: Ongoing study. Start of recruitment was December 2019.
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http://dx.doi.org/10.1186/s13014-020-01581-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268450PMC
June 2020

Stereotactic Cavity Irradiation or Whole-Brain Radiotherapy Following Brain Metastases Resection-Outcome, Prognostic Factors, and Recurrence Patterns.

Front Oncol 2020 8;10:693. Epub 2020 May 8.

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.

Following the resection of brain metastases (BM), whole-brain radiotherapy (WBRT) is a long-established standard of care. Its position was recently challenged by the less toxic single-session radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) of the resection cavity, reducing dose exposure of the healthy brain. We analyzed 101 patients treated with either SRS/FSRT ( = 50) or WBRT ( = 51) following BM resection over a 5-year period. Propensity score adjustment was done for age, total number of BM, timepoint of BM diagnosis, controlled primary and extracranial metastases. A Cox Proportional Hazards model with univariate and multivariate analysis was fitted for overall survival (OS), local control (LC) and distant brain control (DBC). Median patient age was 61 (interquartile range, IQR: 56-67) years and the most common histology was non-small cell lung cancer, followed by breast cancer. 38% of the patients had additional unresected BM. Twenty-four patients received SRS, 26 patients received FSRT and 51 patients received WBRT. Median OS in the SRS/FSRT subgroup was not reached (IQR NA-16.7 months) vs. 12.6 months (IQR 21.3-4.4) in the WBRT subgroup (hazard ratio, HR 3.3, 95%-CI: [1.5; 7.2] < 0.002). Twelve-months LC-probability was 94.9% (95%-CI: [88.3; 100.0]) in the SRS subgroup vs. 81.7% (95%-CI: [66.6; 100.0]) in the WBRT subgroup (HR 0.2, 95%-CI: [0.01; 0.9] = 0.037). Twelve-months DBC-probabilities were 65.0% (95%-CI: [50.8; 83.0]) and 58.8% (95%-CI: [42.9; 80.7]), respectively (HR 1.4, 95%-CI: [0.7; 2.7] = 0.401). In propensity score-adjusted multivariate analysis, incomplete resection negatively impacted OS (HR 3.9, 95%-CI: [2.0;7.4], < 0.001) and LC (HR 5.4, 95%-CI: [1.3; 21.9], = 0.018). Excellent clinical performance (HR 0.4, 95%-CI: [0.2; 0.9], = 0.030) and better graded prognostic assessment (GPA) score (HR 0.4, 95%-CI: [0.2; 1.0], = 0.040) were prognostic of superior OS. A higher number of BM was associated with a greater risk of developing new distant BM (HR 5.6, 95%-CI: [1.0; 30.4], = 0.048). In subgroup analysis, larger cavity volume (HR 1.1, 95%-CI: [1.0; 1.3], = 0.033) and incomplete resection (HR 12.0, 95%-CI: [1.2; 118.3], = 0.033) were associated with inferior LC following SRS/FSRT. This is the first propensity score-adjusted direct comparison of SRS/FSRT and WBRT following the resection of BM. Patients receiving SRS/FSRT showed longer OS and LC compared to WBRT. Future analyses will address the optimal choice of safety margin, dose and fractionation for postoperative stereotactic RT of the resection cavity.
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http://dx.doi.org/10.3389/fonc.2020.00693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232539PMC
May 2020

Single-Isocenter Volumetric Modulated Arc Therapy vs. CyberKnife M6 for the Stereotactic Radiosurgery of Multiple Brain Metastases.

Front Oncol 2020 8;10:568. Epub 2020 May 8.

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.

Stereotactic radiosurgery (SRS) is becoming more frequently used for patients with multiple brain metastases (BMs). Single-isocenter volumetric modulated arc therapy (SI-VMAT) is an emerging alternative to dedicated systems such as CyberKnife (CK). We present a dosimetric comparison between CyberKnife M6 and SI-VMAT, planned at RayStation V8B, for the simultaneous SRS of five or more BM. Twenty treatment plans of CK-based single-session SRS to ≥5 brain metastases were replanned using SI-VMAT for delivery at an Elekta VersaHD linear accelerator. Prescription dose was 20 or 18 Gy, conformally enclosing at least 98% of the total planning target volume (PTV), with PTV margin-width adapted to the respective SRS technique. Comparatively analyzed quality metrics included dose distribution to the healthy brain (HB), including different isodose volumes, conformity, and gradient indices. Estimated treatment time was also compared. Median HB isodose volumes for 3, 5, 8, 10, and 12 Gy were consistently smaller for CK-SRS compared to SI-VMAT ( < 0.001). Dose falloff outside the target volume, as expressed by the gradient indices GI_high and GI_low, was consistently steeper for CK-SRS compared to SI-VMAT ( < 0.001). CK-SRS achieved a median GI_high of 3.1 [interquartile range (IQR), 2.9-1.3] vs. 5.0 (IQR 4.3-5.5) for SI-VMAT ( < 0.001). For GI_low, the results were 3.0 (IQR, 2.9-3.1) for CK-SRS vs. 5.6 (IQR, 4.3-5.5) for SI-VMAT ( < 0.001). The median conformity index (CI) was 1.2 (IQR, 1.1-1.2) for CK-SRS vs. 1.5 (IQR, 1.4-1.7) for SI-VMAT ( < 0.001). Estimated treatment time was shorter for SI-VMAT, yielding a median of 13.7 min (IQR, 13.5-14.0) compared to 130 min (IQR, 114.5-154.5) for CK-SRS ( < 0.001). SI-VMAT offers enhanced treatment efficiency in cases with multiple BM, as compared to CyberKnife, but requires compromise regarding conformity and integral dose to the healthy brain. Additionally, delivery at a conventional linear accelerator (linac) may require a larger PTV margin to account for delivery and setup errors. Further evaluations are warranted to determine whether the detected dosimetric differences are clinically relevant. SI-VMAT could be a reasonable alternative to a dedicated radiosurgery system for selected patients with multiple BM.
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http://dx.doi.org/10.3389/fonc.2020.00568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225280PMC
May 2020

Neuro-oncology Management During the COVID-19 Pandemic With a Focus on WHO Grade III and IV Gliomas.

Neuro Oncol 2020 May 5. Epub 2020 May 5.

Technical University of Munich (TUM), School of Medicine and Klinikum rechts der Isar, Department of Radiation Oncology, Munich.

Background: Because of the increased risk in cancer patients of developing complications caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), physicians have to balance the competing risks of the negative impact of the pandemic and the primary tumor. In this consensus statement, an international group of experts present mitigation strategies and treatment guidance for patients suffering from high grade gliomas (HGG) during the coronavirus disease 2019 (COVID-19) pandemic.

Method / Results: 16 international experts in the treatment of HGG contributed to this consensus-based practice recommendation including neuro-oncologists, neurosurgeons, radiation -oncologists and a medical physicist. Generally, treatment of neuro-oncological patients cannot be significantly delayed and initiating therapy should not be outweighed by COVID-19. We present detailed interdisciplinary treatment strategies for molecular subgroups in two pandemic scenarios, a scale-up phase and a crisis phase.

Conclusion: This practice recommendation presents a pragmatic framework and consensus-based mitigation strategies for the treatment of HGG patients during the SARS-CoV-2 pandemic.
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http://dx.doi.org/10.1093/neuonc/noaa113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239150PMC
May 2020

Paclitaxel for treatment of advanced small cell lung cancer (SCLC): a retrospective study of 185 patients.

J Thorac Dis 2020 Mar;12(3):782-793

Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.

Background: Etoposide-/platinum-based chemotherapy is the standard first-line treatment for extensive-disease small cell lung cancer (SCLC), but responses are short-lived and subsequent options limited. Here, we present our experience with paclitaxel in advanced treatment lines.

Methods: We retrospectively studied the clinical course of all paclitaxel-treated SCLC patients between 2005 and 2015 in our institution. Prognostic and predictive factors were analyzed by Kaplan-Meier and Cox regression analyses.

Results: A total of 185 patients [119 men, median age 65 years, median ECOG performance status (PS) 1] were identified. One hundred and sixty-eight patients had extensive disease (ED) at the time of paclitaxel therapy. Paclitaxel was mainly given as third- or fourth-line therapy (93%). The response rate (RR) was 17% and disease control rate (DCR) 28%. Patients reached a median progression-free survival (PFS) of 1.6 (95% CI: 1.4-1.8) months and median overall survival (OS) of 3.3 (95% CI: 2.8-3.9) months. Main toxicities were fatigue (25%) and polyneuropathy (17%). Dose reduction of ≥25% was associated with shorter PFS [1.9 (95% CI: 1.5-2.3) . 1.4 (95% CI: 1.3-1.5) months; P=0.004]. Further independent predictive factors for PFS were gender, age, and hepatic/brain metastases (P<0.05). Tumor response to paclitaxel, PS, number and location of metastases, dose reduction, and smoking history were significant factors for OS in univariable analyses (P<0.05), while PS, dose reduction, status of cerebral/hepatic metastases, tumor response, and smoking history were retained as independent prognostic factors in multivariable testing. Notably, ECOG PS 2 patients had toxicity rates similar to ECOG PS 0-1 patients (63% . 62%), as well as a comparable DCR (29% . 28%), which was associated with prolonged survival (4.5 3.2 months for refractory cases, P=0.034).

Conclusions: Paclitaxel has clinically relevant activity in heavily pretreated SCLC. While patients with good PS and no cerebral/hepatic metastases derive the greatest benefit, ECOG PS 2 per se should not be used as a criterion to exclude patients.
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http://dx.doi.org/10.21037/jtd.2019.12.74DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139030PMC
March 2020

First statement on preparation for the COVID-19 pandemic in large German Speaking University-based radiation oncology departments.

Radiat Oncol 2020 Apr 7;15(1):74. Epub 2020 Apr 7.

Department of Radiation Oncology, Technical University of Munich (TUM), Klinikum rechts der Isar, Ismaninger Straße 22, D-81675 München, Munich, Germany.

The COVID-19 pandemic is challenging modern radiation oncology. At University Hospitals, we have a mandate to offer high-end treatments to all cancer patients. However, in times of crisis we must learn to prioritize resources, especially personnel. Compromising oncological outcome will blur all statistics, therefore all measures must be taken with great caution. Communication with our neighboring countries, within societies and between departments can help meet the challenge. Here, we report on our learning system and preparation measures to effectively tackle the COVID-19 challenge in University-Based Radiation Oncology Departments.
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http://dx.doi.org/10.1186/s13014-020-01527-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136995PMC
April 2020

A matched-pair analysis comparing stereotactic radiosurgery with whole-brain radiotherapy for patients with multiple brain metastases.

J Neurooncol 2020 May 1;147(3):607-618. Epub 2020 Apr 1.

Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Introduction: Stereotactic radiosurgery (SRS) is an emerging treatment for patients with multiple brain metastases (BM). The present work compares the SRS of multiple brain metastases with whole-brain radiotherapy (WBRT).

Methods: We performed a matched-pair analysis for 128 patients with multiple BM treated with either SRS or WBRT over a 5-year period. Patients were matched pairwise for seven potential prognostic factors. A mixed Cox Proportional Hazards model with univariate and multivariate analysis was fitted for overall survival (OS). Distant intracranial progression-free survival (icPFS) and local control were assessed using a Fine and Gray subdistribution hazard model and considering death as competing event.

Results: Patients undergoing SRS had a median of 4 BM (range 3-16). 1-year local control of individual BM following SRS was 91.7%. Median OS in the SRS subgroup was 15.7 months (IQR 9.7-36.4) versus 8.0 months (interquartile range, IQR 3.8-18.0) in the WBRT subgroup (HR 2.25, 95% CI [1.5; 3.5], p < 0.001). Median icPFS was 8.6 (IQR 3.4-18.0) versus 22.4 (IQR 5.6-28.6) months, respectively (HR for WBRT 0.41, 95% CI [0.24; 0.71], p = 0.001). Following SRS, synchronous BM diagnosis (HR 2.51, 95% CI [1.30; 4.70], p = 0.004), higher initial number of BM (HR 1.21, 95% CI [1.10; 1.40], p = 0.002) and lung cancer histology (HR 2.05, 95% CI [1.10; 3.80], p = 0.024) negatively impacted survival. Excellent clinical performance (KPI 90%) was a positive prognosticator (HR 0.38, 95% CI [0.20; 0.72], p = 0.003), as was extracerebral tumor control (HR 0.48, 95% CI [0.24; 0.97], p = 0.040). Higher initial (HR 1.19, 95% CI [1.00; 1.40], p < 0.013) and total number of BM (HR 1.23, 95% CI [1.10; 1.40], p < 0.001) were prognostic for shorter icPFS.

Conclusion: This is the first matched-pair analysis to compare SRS alone versus WBRT alone for multiple BM. OS was prolonged in the SRS subgroup and generally favorable in the entire cohort. Our results suggest SRS as a feasible and effective treatment for patients with multiple BM.
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http://dx.doi.org/10.1007/s11060-020-03447-2DOI Listing
May 2020

Analysis of a Surgical Series of 21 Cerebral Radiation Necroses.

World Neurosurg 2020 05 10;137:e462-e469. Epub 2020 Feb 10.

Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany.

Background: There is no standard approach to differentiate cerebral radiation necrosis from tumor recurrence and no standard treatment pathway for symptomatic lesions. In addition, reports on histology-proven radiation necrosis and the underlying pathophysiology are scarce and highly relevant.

Methods: Our monocentric, retrospective analysis included 21 histology-proven cerebral radiation necroses. Our study focused on 1) potential risk factors for the development of radiation necrosis, 2) radiologic and histopathologic features of individual necroses, and 3) the suitability of previously reported magnetic resonance imaging (MRI)-based methods to identify radiation necroses based on specific structural image features.

Results: Average time between radiation treatment and development of necrosis was 4.68 years (95% confidence interval, 0.19-9.55 years). Matching available MRI data sets with those of patients with tumor lesions, we compared specificity and sensitivity of 3 previously reported methods to identify radionecrosis based on imaging criteria. In our hands, none of these methods reached a sensitivity ≥70%. Radionecrosis presented with large edema and showed increased levels of cell proliferation, as inferred by Ki-67 staining. Surgical removal of radiation necrosis proved to be a safe approach with low permanent morbidity (<5%) and no mortality.

Conclusions: Although the overall incidence of cerebral radiation necrosis is low, our data suggest an increasing incidence over the last 2 decades, which is likely associated with the use of stereotactic radiotherapy. There are no imaging standards to identify radiation necrosis on standard MRI with structural sequences. Surgical removal of radiation necrosis is associated with low morbidity and mortality.
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http://dx.doi.org/10.1016/j.wneu.2020.02.005DOI Listing
May 2020

Percutaneous Endoscopic Gastrostomy Tube Placement in Patients with Head and Neck Cancer Treated with Radiotherapy.

Cancer Manag Res 2020 8;12:127-136. Epub 2020 Jan 8.

Department of Radiation Oncology, University Hospital of Heidelberg, Heidelberg 69120, Germany.

Background And Aim: The primary aim of our study was to evaluate percutaneous endoscopic gastrostomy (PEG) tube placement depending on body weight and body mass index in patients undergoing radiotherapy (RT) for head and neck cancer (HNC). A secondary aim was to evaluate the course of weight change following PEG placement.

Methods: We retrospectively reviewed the medical records of 186 patients with HNC undergoing radiotherapy (RT) or chemoradiotherapy (CRT) at our institution between January 2010 and August 2017. Initial weight and nutritional intake were analyzed prior to RT initiation and then followed throughout treatment until completion. Based on these data, the indication of PEG placement was determined. Medical records were also reviewed to analyze PEG-related acute toxicities.

Results: A total of 186 patients met inclusion criteria. Patients were most commonly male (n=123, 66.1%) with squamous cell carcinoma (n=164, 88.2%). Patients who had dysphagia prior to treatment initiation as well as patients with a BMI <18.5 kg/m needed PEG placement earlier during the treatment course. Low-grade toxicities related to PEG insertion were observed in 10.7% patients, with peristomal pain and redness adjacent to the PEG tube insertion site being most common. High-grade toxicities, such as peritonitis and organ injury, were found in 4.9% of patients.

Conclusion: Underweight patients and those with preexisting dysphagia should be closely screened during RT for weight loss and decreased oral intake. For weight loss greater than 4.5% during the treatment of HNC, early PEG-tube placement should be considered. Further prospective studies are needed to confirm these findings, and delineate a scoring system for timing of PEG use (prophylactic vs reactive) as well as assess the quality of life in patients with HNC who receive PEG placement.
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http://dx.doi.org/10.2147/CMAR.S218432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955619PMC
January 2020

Stereotactic body radiotherapy (SBRT) for adrenal metastases of oligometastatic or oligoprogressive tumor patients.

Radiat Oncol 2020 Feb 4;15(1):30. Epub 2020 Feb 4.

Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Introduction: Local ablative treatment strategies are frequently offered to patients diagnosed with oligometastatic disease. Stereotactic body radiotherapy (SBRT), as ablative treatment option, is well established for lung and liver metastases, whereas for isolated adrenal gland metastases the level of evidence is scarce.

Material And Methods: This single-institution analysis of oligometastatic or oligoprogressive disease was limited to patients who received SBRT to adrenal metastasis between 2012 and 2019. Patient, tumor, treatment characteristics, and dosimetric parameters were analyzed for evaluation of their effect on survival outcomes.

Results: During the period of review 28 patients received ablative SBRT to their adrenal gland metastases. Most common primary tumors were non-small cell lung cancers (46%) with most patients diagnosed with a single adrenal gland metastasis (61%), which occurred after a median time of 14 months. SBRT was delivered to a median biological effective dose at α/β of 10 (BED) of 75 Gy (range: 58-151 Gy). Median gross tumor volume (GTV) and median planning target volume (PTV) were 42 and 111 mL, respectively. The homogeneity and conformity indices were 1.17 (range: 1.04-1.64) and 0.5 (range: 0.4.0.99), respectively, with the conformity index being affected by dose restrictions to organs at risk (OARs) in 50% of the patients. Overall response rate based on RECIST criteria was 86% (CR = 29%, PR = 57%) with 2-year local control (LC) of 84.8%, 2-year progression-free survival (PFS) of 26.3%, and 1-and 2-year overall survival (OS) of 46.6 and 32.0%, respectively. During follow up, only two local recurrences occurred. A trend for superior LC was seen if BED was ≥75Gy (p = 0.101) or if the PTV was < 100 ml (p = 0.072). SBRT was tolerated well with only mild toxicity.

Conclusion: SBRT for adrenal metastases resulted in promising LC with low toxicity. Treatment response appeared to be superior, if SBRT was applied with higher BED. As the close proximity of OARs often limits the application of sufficiently high doses, further dose escalations strategies and techniques should be investigated in future.
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http://dx.doi.org/10.1186/s13014-020-1480-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001286PMC
February 2020

Intensity Modulated Radiotherapy (IMRT) With Carbon Ion Boost in the Multimodal Treatment of Salivary Duct Carcinoma.

Front Oncol 2019 20;9:1420. Epub 2019 Dec 20.

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.

To assess outcomes and treatment related toxicity following intensity-modulated radiotherapy (IMRT) and a Carbon Ion Radiotherapy (CIRT) boost for salivary duct carcinoma (SDC). Twenty-eight consecutive patients with SDC who underwent a postoperative (82%) or definitive (18%) radiation therapy between 2010 and 2017 were assessed in this retrospective single-center analysis. CIRT boost was delivered with median 18 Gy(RBE) in 6 daily fractions, followed by an TomoTherapy-based IMRT (median 54 Gy in 27 daily fractions). Treatment-related acute toxicity was assessed according to CTCAE Version 4. Tumors were most commonly located in the major salivary glands ( = 25; 89%); 23 patients (82%) received previous surgery (R0: 30%; R1: 57%; R2: 4%; RX: 19%). Median follow-up was 30 months. Four patients (14%) experienced a local relapse and 3 (11%) developed locoregional recurrence. The two-year local control (LC) and locoregional control (LRC) was 96 and 93%, respectively. Median disease-free survival (DFS) was 27 months, metastasis-free survival (MFS) was 69 months, and overall survival (OS) was 93 months. Acute grade 3 toxicity occurred in 11 patients (mucositis, dermatitis, xerostomia; = 2 each (7%) were the most common) and 2 osteonecroses of the mandibular (grade 3) occurred. No patients experienced grade ≥4 toxicities. Multimodal therapy approaches with surgery followed by IMRT and CIRT boost for SDC leads to good local and locoregional disease control. However, the frequent occurrence of distant metastases limits the prognosis and requires optimization of adjuvant systemic therapies.
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http://dx.doi.org/10.3389/fonc.2019.01420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932999PMC
December 2019

Dose-Limiting Organs at Risk in Carbon Ion Re-Irradiation of Head and Neck Malignancies: An Individual Risk-Benefit Tradeoff.

Cancers (Basel) 2019 Dec 13;11(12). Epub 2019 Dec 13.

Heidelberg University Hospital, Department of Radiation Oncology, 69120 Heidelberg, Germany.

: Carbon ion re-irradiation (CIR) was evaluated to investigate treatment planning and the consequences of individual risk-benefit evaluations concerning dose-limiting organs at risk (OAR). : A total of 115 consecutive patients with recurrent head and neck cancer (HNC) were analyzed after initial radiotherapy and CIR at the same anatomical site. Toxicities were evaluated in line with the Common Terminology Criteria for Adverse Events 4.03. : The median maximum cumulative equivalent doses applied in fractions of 2 Gy (EQD2) to the brainstem, optic chiasm, ipsilateral optic nerve, and spinal cord were 56.8 Gy (range 0.94-103.9), 51.4 Gy (range 0-120.3 Gy), 63.6 Gy (range 0-146.1 Gy), and 28.8 Gy (range 0.2-87.7 Gy). The median follow up after CIR was 24.0 months (range 2.5-72.0 months). The cumulative rates of acute and late severe (≥grade III) side effects after CIR were 1.8% and 14.3%. : In recurrent HNC, an individual risk-benefit tradeoff is frequently inevitable due to unfavorable location of tumors in close proximity to vital OAR. There are uncertainties about the dose tolerance of OAR after CIR, which warrant increased awareness about the potential treatment toxicity and further studies on heavy ion re-irradiation.
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http://dx.doi.org/10.3390/cancers11122016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966577PMC
December 2019

Rare entities in head-and-neck cancer: salvage re-irradiation with carbon ions.

Radiat Oncol 2019 Nov 12;14(1):202. Epub 2019 Nov 12.

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.

Background: The objective of this investigation is to evaluate the outcomes and toxicity of carbon-ion re-irradiation (CIR) in patients with rare head and neck cancers (HNC). There is a paucity of data regarding treatment approaches in this patient cohort, which we aim to address in this work.

Methods: Thirty-two (n = 32) consecutive patients with uncommon HNC treated between 2010 and 2017 were retrospectively analyzed in terms of clinical outcomes, patterns of failure, and toxicity.

Results: Mucoepidermoid carcinoma (MEC) was the most common histology (22%). Patients received a median cumulative dose equivalent in 2 Gy fractions (EQD) after CIR of 128.6 Gy (range, 105.8-146.5 Gy). The local and distant control rates 1 year after CIR were 66 and 72%. No serious acute or late toxicity (≥ grade 3) after CIR was observed.

Conclusions: CIR may represent an effective and safe treatment alternative to palliative systemic therapies in these rare indications.
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http://dx.doi.org/10.1186/s13014-019-1406-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852923PMC
November 2019

The Phase 1/2 ACCEPT Trial: Concurrent Cetuximab and Intensity Modulated Radiation Therapy with Carbon Ion Boost for Adenoid Cystic Carcinoma of the Head and Neck.

Int J Radiat Oncol Biol Phys 2020 01 3;106(1):167-173. Epub 2019 Oct 3.

Department of Radiation Oncology, University Hospital Gießen and Marburg (UKGM), Marburg, Germany.

Purpose: The adenoid cystic carcinoma (ACC), Erbitux, and Particle Therapy (ACCEPT) phase 1/2 trial (NCT01192087) evaluated a combined-modality approach (concurrent cetuximab and intensity modulated radiation therapy with carbon ion boost) for newly diagnosed nonmetastatic head and neck ACC.

Methods And Materials: Twenty-three patients with ACC were enrolled between June 2012 and June 2017 after initial diagnosis or postoperatively. All received a 400 mg/m cetuximab loading dose a week before radiation therapy, followed by weekly 250 mg/m doses starting on the first day of radiation therapy. The carbon ion radiation therapy boost was 24 Gy (relative biological effectiveness) in 8 daily fractions, followed by intensity modulated radiation therapy (54 Gy). The primary endpoint was safety and feasibility (defined based on Common Terminology Criteria for Adverse Events grade ≥3 events). Secondary endpoints included local and distant relapse, disease-free survival, and overall survival.

Results: Disease was most commonly in the paranasal sinuses (30%), palate (17%), and nasopharynx (17%). Nine (39%) patients underwent surgery (R1: 22%, R2: 78%). Median follow-up was 38.5 months. No patients experienced grade 4 to 5 events. Rates of grade 3 rash and radiation dermatitis were 17% and 22%, respectively. Grade 2 and 3 mucositis and dysgeusia occurred in 43% and 48% and in 9% and 0%, respectively. Grade 2 to 3 dysphagia and xerostomia were present in 43% and 4% and in 26% and 0%, respectively. At last follow-up, 5 (22%) patients experienced in-field relapse and 6 (26%) developed distant metastases. The 3-year disease-free survival was 67%, and median overall survival was 54 months.

Conclusions: Outcomes of this trial were satisfactory. Although the trial did not meet the predefined criteria of feasibility owing to the comparatively high rates of grade 3 dermatitis, numbers are comparable to existing data on cetuximab + radiation therapy.
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http://dx.doi.org/10.1016/j.ijrobp.2019.09.036DOI Listing
January 2020

Second breast conserving therapy after ipsilateral breast tumor recurrence - a 10-year experience of re-irradiation.

J Contemp Brachytherapy 2019 Aug 29;11(4):312-319. Epub 2019 Aug 29.

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.

Purpose: The aim of this study is to evaluate the efficacy and toxicity of post-operative partial breast re-irradiation with multi-catheter brachytherapy after second breast conserving therapy (BCT) in patients with small, low-risk ipsilateral breast tumor recurrence (IBTR).

Material And Methods: Between 2008 and 2018, 19 consecutive patients with low-risk IBTR (max. rpT1 cN0 cM0, Her2 negative, preferably positive hormone receptor status) who refused mastectomy were treated with salvage lumpectomy, followed by post-operative partial breast re-irradiation with multi-catheter brachytherapy. Eight patients were irradiated using PDR brachytherapy (49.8-50.4 Gy in pulses of 0.5-0.7 Gy) and 11 patients using HDR brachytherapy (34.2 Gy in fractions of 3.8 Gy or 32 Gy in fractions of 4 Gy). All patients had undergone prior BCT for their primary tumor, followed by adjuvant whole breast radiotherapy. Local control (LC), locoregional control (LRC), overall survival (OS), disease-free survival (DFS) as well as toxicity were evaluated in the present study.

Results: After a median follow-up of 65 months following IBTR (18-120 months), only one second IBTR in 19 patients was diagnosed 77 months after re-irradiation, resulting in a LC rate of 100% at 5 years. DFS and OS rates were both 100% at 5 years following re-irradiation. Except for the above mentioned second IBTR, no regional or distant relapse was recorded. Regarding toxicity, 63% of patients developed adverse events (CTCAE grade ≤ 2), with fibrosis detected in 37% (7/19) of patients, necrosis in 11% (2/19), hyperpigmentation in 47% (9/19), and telangiectasia in 11% (2/19), respectively. No patient showed a high-grade (CTCAE grade ≥ 3) adverse event.

Conclusions: In case of small, low-risk IBTR, adjuvant re-irradiation using multi-catheter brachytherapy is a feasible, safe, and effective treatment method after repeated lumpectomy, and an alternative to mastectomy.
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http://dx.doi.org/10.5114/jcb.2019.87001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737570PMC
August 2019

Carbon Ion Reirradiation for Recurrent Head and Neck Cancer: A Single-Institutional Experience.

Int J Radiat Oncol Biol Phys 2019 11 23;105(4):803-811. Epub 2019 Jul 23.

Heidelberg University Hospital, Department of Radiation Oncology, Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany; Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany; German Cancer Consortium (DKTK), partner site Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Purpose: This study aimed to assess the feasibility of carbon ion reirradiation (CIR) for recurrent head and neck cancer (HNC).

Methods And Materials: This retrospective study included 229 patients with recurrent HNC who were treated with CIR between 2010 and 2017. We assessed progression-free survival, overall survival, pattern of failure, and toxicity. Of the primary tumors, 54.1% were adenoid cystic carcinomas, 26.2% were squamous cell carcinomas, 8.3% were adenocarcinomas, and 11.4% were other tumor entities.

Results: The median radiation therapy interval was 3.9 years (range, 0.3-46.5 years), and patients received a median dose of 51 Gy (relative biological effectiveness [RBE]; range, 30-66 Gy [RBE]) in 3 Gy (RBE) fractions. The median cumulative lifetime dose after CIR was 132.8 Gy (range, 88.8-155.0 Gy). The median local progression-free survival after CIR was 24.2 months (95% confidence interval, 19.4-29.0 months), and the median overall survival was 26.1 months (95% confidence interval, 21.9-30.3 months). Serious acute toxicity (grade ≥3) after CIR included laryngeal edema, grade 4 (n = 2; 0.9%); dysphagia, grade 3 (n = 3; 1.3%); fistula, grade 3 (n = 1; 0.4%); and impaired hearing, grade 3 (n = 1; 0.4%). Late toxicities of grades 3 or higher (n = 18; 14.5%) included central nervous system necrosis, grades 4/3 (n = 1; 0.8%/n = 5; 4.0%); optic nerve disorder, grades 4/3 (n = 2; 1.6%/n = 2; 1.6%); impaired hearing, grade 3 (n = 5; 4.0%), osteonecrosis, grade 3 (n = 1; 0.8%); and carotid blowout, grade 4 (n = 1; 0.8%).

Conclusions: In patients with locally recurrent HNC, CIR was a feasible, effective treatment with acceptable toxicity and good local control. Thus, CIR represented a valuable alternative to surgical salvage and palliative chemotherapy in selected patients.
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http://dx.doi.org/10.1016/j.ijrobp.2019.07.021DOI Listing
November 2019

Long-term Follow-up and Patterns of Recurrence of Patients With Oligometastatic NSCLC Treated With Pulmonary SBRT.

Clin Lung Cancer 2019 11 27;20(6):e667-e677. Epub 2019 Jun 27.

Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Introduction: This multicenter study aims to analyze outcome as well as early versus late patterns of recurrence following pulmonary stereotactic body radiotherapy (SBRT) for patients with oligometastatic non-small-cell lung cancer (NSCLC).

Materials And Methods: This analysis included 301 patients with oligometastatic NSCLC treated with SBRT for 336 lung metastases. Although treatment of the primary tumor consisted of surgical resection, radiochemotherapy, and/or systemic therapy, pulmonary oligometastases were treated with SBRT.

Results: The median follow-up time was 16.1 months, resulting in 2-year overall survival (OS), local control (LC), and distant control (DC) of 62.2%, 82.0%, and 45.2%, respectively. Multivariate analysis identified age (P = .019) and histologic subtype (P = .028), as well as number of metastatic organs (P < .001) as independent prognostic factors for OS. LC was superior for patients with favorable histologic subtype (P = .046) and SBRT with a higher biological effective dose at isocenter (P = .037), whereas DC was inferior for patients with metastases in multiple organs (P < .001) and female gender (P = .027). Early (within 24 months) local or distant progression was observed in 15.3% and 36.5% of the patients. After 24 months, the risk of late local failure was low, with 3- and 4-year local failure rates of only 4.0%, and 7.6%. In contrast, patients remained at a high risk of distant progression with 3- and 4-year failure rates of 13.3% and 24.1%, respectively, with no plateau observed.

Conclusion: SBRT for pulmonary oligometastatic NSCLC resulted in favorable LC and promising OS. The dominant failure pattern is distant with a continuously high risk of disease progression for many years.
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http://dx.doi.org/10.1016/j.cllc.2019.06.024DOI Listing
November 2019

Definitive radiotherapy vs. postoperative radiotherapy for lower gingival carcinomas of the mandible : A single-center report about outcome and toxicity.

Strahlenther Onkol 2019 Sep 2;195(9):819-829. Epub 2019 Jul 2.

Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Purpose: To assess radiotherapy (RT) outcomes in patients with gingival carcinoma and growth up to or involvement of the lower jaw bone.

Methods: This was a retrospective analysis of 51 patients with squamous cell carcinomas of the gingiva. Patients received definitive (group 1, 31.4%) or postoperative (group 2, 66.7%) RT between 2005 and 2017 at the Department of Radiation Oncology, University Hospital Heidelberg. The primary endpoint was overall survival (OS) in both treatment groups. Other endpoints were local-disease-free survival (LDFS), progression-free survival (PFS) and treatment-related toxicity (Common Terminology Criteria for Adverse Events, CTCAE, Version 4.03).

Results: Median age at first diagnosis was 63 years. All patients had a local advanced disease (American Joint Commission on Cancer [AJCC] stage III-IV). After a median follow-up of 22 months (range 3-145 months), 20 patients (39.2%) were still alive. At 5 years, OS rate was 36.6%. No significant differences in OS (p = 0.773), PFS (p = 0.350) and LDFS (p = 0.399) were observed between the two groups. Most common higher-grade acute RT-related complications (≥ grade 3) were dermatitis (78.2%), oral mucositis (61.7%), xerostomia (51.5%), and loss of taste (74.6%). Three cases (5.8%) of osteoradionecrosis (ORN) of the lower jaw were detected after 15-31 months.

Conclusions: Definitive and postoperative RT have similar treatment outcomes for patients with lower gingiva carcinomas of the lower jaw. The most common acute complications (grade ≥3) were dermatitis, oral mucositis, xerostomia and loss of taste.
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http://dx.doi.org/10.1007/s00066-019-01484-zDOI Listing
September 2019

Whole-brain helical tomotherapy with integrated boost for brain metastases in patients with malignant melanoma - final results of the BRAIN-RT trial.

Cancer Manag Res 2019 24;11:4669-4676. Epub 2019 May 24.

Department of Radiation Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany.

Patients with multiple brain metastases (BMs) from malignant melanoma have a poor prognosis. Recent developments in radiation techniques allow simultaneous integrated boost (SIB) concepts while sparing organs at risk. Data on conventional versus dose-escalated radiation approaches in multiple BMs from malignant melanoma are warranted. In this prospective, single-center, randomized two-armed study (trial ID: DRKS00005127), patients with multiple BMs from malignant melanoma were treated with either conventional whole-brain radiotherapy (WBRT) applying 30 Gy in 10 fractions (standard arm) or helical tomotherapy applying 30 Gy to the whole brain with an integrated boost to metastases of 50 Gy in 10 fractions and sparing of the hippocampus (HA-WBRT, experimental arm). The primary endpoint was treatment-related toxicity, while secondary endpoints were imaging response, intracerebral progression-free survival (PFS), overall survival (OS) and quality of life. The study was stopped early due to slow patient recruitment. A total number of 7 patients were enrolled (standard arm n=3, experimental arm n=4), and were followed-up for a median time of 5 months between August 2013 and July 2017. All patients were treated according to protocol. The median OS, intracerebral PFS and follow-up time were 5 months, 2 months and 5 months, respectively. The local control in every individual BM was significantly longer in the experimental versus the standard arm. No patient developed radiation-related high-grade toxicities. HA-WBRT with SIB results in improved local control in the individual melanoma BMs without radiation-associated high-grade toxicities. Survival times were comparable to published data.
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http://dx.doi.org/10.2147/CMAR.S204729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538835PMC
May 2019

Clinical Management of Blood⁻Brain Barrier Disruptions after Active Raster-Scanned Carbon Ion Re-Radiotherapy in Patients with Recurrent Head-and-Neck Cancer.

Cancers (Basel) 2019 Mar 19;11(3). Epub 2019 Mar 19.

Department of Radiation Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany.

The aim of the current evaluation was to assess central nervous system necrosis (CNSN) after re-irradiation with carbon ions (CR) in two-hundred seventeen ( = 217) patients with recurrent head-and-neck cancer (HNC). Thirty-six ( = 36) patients with CNSN were assessed retrospectively regarding clinical symptoms and radiographic response. CNSN were classified according to clinical management in line with the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. At a median follow-up of 25.3 months (range 3.3⁻79.9 months), the median time interval until occurrence of grade I, II, and III CNSN was 9.2 months (range 2.8⁻75.0 months), 10.2 months (range 2.3⁻60.5 months), and 16.6 months (range 8.7⁻32.5 months), respectively. In one patient with an adenocarcinoma infiltrating the frontal lobe, an extensive CNSN grade IV was suspected but the patient declined surgical intervention. Radiographic response after treatment of CNSN grade I, II, and III, defined as ≥25% reduction of the T2 alteration on Magnetic Resonance Imaging (MRI), was observed in 4 (16.0%), 5 (29.4%), and 4 (80%) patients, respectively. CNSN occurred late and frequent after re-irradiation with carbon ions in patients with HNC infiltrating the base of skull. The clinical outcome with adequate treatment was encouraging but correct diagnosis of CNSN remains challenging.
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http://dx.doi.org/10.3390/cancers11030383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469035PMC
March 2019

Pre-Operative Versus Post-Operative Radiosurgery of Brain Metastases-Volumetric and Dosimetric Impact of Treatment Sequence and Margin Concept.

Cancers (Basel) 2019 Mar 1;11(3). Epub 2019 Mar 1.

Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.

Background: Pre-operative radiosurgery (SRS) preceding the resection of brain metastases promises to circumvent limitations of post-operative cavity SRS. It minimizes uncertainties regarding delineation and safety margins and could reduce dose exposure of the healthy brain (HB).

Methods: We performed a systematic treatment plan comparison on 24 patients who received post-operative radiosurgery of the resection cavity at our institution. Comparative treatment plans were calculated for hypofractionated stereotactic radiotherapy (7 × 5 Gray (Gy)) in a hypothetical pre-operative (pre-op) and two post-operative scenarios, either with (extended field, post-op-E) or without the surgical tract (involved field, post-op-I). Detailed volumetric comparison of the resulting target volumes was performed, as well as dosimetric comparison focusing on targets and the HB.

Results: The resection cavity was significantly smaller and different in morphology from the pre-operative lesion, yielding a low Dice Similarity Coefficient (DSC) of 53% ( = 0.019). Post-op-I and post-op-E targets showed high similarity (DSC = 93%), and including the surgical tract moderately enlarged resulting median target size (18.58 ccm vs. 22.89 ccm, < 0.001). Dosimetric analysis favored the pre-operative treatment setting since it significantly decreased relevant dose exposure of the HB (Median volume receiving 28 Gy: 6.79 vs. 10.79 for pre-op vs. post-op-E, < 0.001). Dosimetrically, pre-operative SRS is a promising alternative to post-operative cavity irradiation that could furthermore offer practical benefits regarding delineation and treatment planning. Comparative trials are required to evaluate potential clinical advantages of this approach.
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http://dx.doi.org/10.3390/cancers11030294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468393PMC
March 2019

Outcome and prognostic factors following palliative craniospinal irradiation for leptomeningeal carcinomatosis.

Cancer Manag Res 2019 17;11:789-801. Epub 2019 Jan 17.

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany,

Background: Leptomeningeal carcinomatosis (LC) is a severe complication of metastatic tumor spread to the central nervous system. Prognosis is dismal with a median overall survival (OS) of ~10-15 weeks. Treatment options include radiotherapy (RT) to involved sites, systemic chemo- or targeted therapy, intrathecal chemotherapy and best supportive care with dexamethasone. Craniospinal irradiation (CSI) is a more aggressive radiotherapeutic approach, for which very limited data exists. Here, we report on our 10-year experience with palliative CSI of selected patients with LC.

Patients And Methods: Twenty-five patients received CSI for the treatment of LC at our institution between 2008 and 2018. Patients were selected individually for CSI based on clinical performance, presenting symptoms and estimated benefit. Median patient age was 53 years (IQR: 45-59), and breast cancer was the most common primary. Additional brain metastases were found in 18 patients (72.0%). RT was delivered at a TomoTherapy machine, using helical intensity-modulated radiotherapy (IMRT). The most commonly prescribed dose was 36 Gy in 20 fractions, corresponding to a median biologically equivalent dose of 40.8 Gy (IQR: 39.0-2.5). Clinical performance and neurologic function were assessed before and in response to therapy, and deficits were retrospectively quantified on the 5-point neurologic function scale (NFS). A Cox proportional hazards model with univariate and multivariate analyses was fitted for survival.

Results: Twenty-one patients died and four were alive at the time of analysis. Median OS from LC diagnosis was 19.3 weeks (IQR: 9.3-34.0, 95% CI: 11.0-32.0). In univariate analysis, a Karnofsky performance scale index (KPI) ≥70% (=0.001), age ≤55 years at LC diagnosis (=0.022), cerebrospinal fluid (CSF) protein <100 mg/dL (=0.018) and no more than mild or moderate neurologic deficits (NFS ≤2; =0.007) were predictive of longer OS. So were the neurologic response to treatment (=0.018) and the application of systemic therapy after RT completion (=0.029). The presence of CSF flow obstruction was predictive of shorter OS (=0.026). In multivariate analysis, age at LC diagnosis (=0.018), KPI (<0.001) and neurologic response (=0.037) remained as independent prognostic factors for longer OS. Treatment-associated toxicity was manageable and mostly grades I and II according to the Common Terminology Criteria for Adverse Events v4.0. Eight patients (32%) developed grade III myelosuppression. Neurologic symptom stabilization could be achieved in 40.0% and a sizeable improvement in 28.0% of all patients.

Conclusion: CSI for the treatment of LC is feasible and may have therapeutic value in carefully selected patients, alleviating symptoms or delaying neurologic deterioration. OS after CSI was comparable to the rates described in current literature for patients with LC. The use of modern irradiation techniques such as helical IMRT is warranted to limit toxicity. Patient selection should take into account prognostic factors such as age, clinical performance, neurologic function and the availability of systemic treatment options.
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http://dx.doi.org/10.2147/CMAR.S182154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340499PMC
January 2019

Palliative Radiotherapy for Leptomeningeal Carcinomatosis-Analysis of Outcome, Prognostic Factors, and Symptom Response.

Front Oncol 2018 8;8:641. Epub 2019 Jan 8.

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.

The purpose of this article is to report our institution's 10-year experience on palliative radiotherapy for the treatment of leptomeningeal carcinomatosis (LC), assessing survival, neurologic outcome, and prognostic factors. We retrospectively analyzed 110 patients who received palliative radiotherapy for LC between 2008 and 2018. The most common histologies were breast cancer ( = 43, 39.1%) and non-small cell lung cancer (NSCLC) ( = 31, 28.2%). Radiotherapy was administered as whole-brain radiotherapy (WBRT) ( = 51, 46.4%), focal spinal RT ( = 11, 10.0%) or both ( = 47, 42.7%). Twenty-five patients (22.7%) were selected for craniospinal irradiation. Clinical performance and neurologic function were quantified on the neurologic function scale (NFS) before and in response to therapy. A Cox Proportional Hazards model with univariate and multivariate analysis was fitted for survival. Ninety-eight patients (89.1%) died and 12 (10.9%) were alive at the time of analysis. Median OS from LC diagnosis and from the beginning of RT was 13.9 weeks (IQR: 7.1-34.0) and 9.9 weeks (IQR: 5.3-26.3), respectively. In univariate analysis, prognostic of longer OS were a Karnofsky performance scale index (KPI) of ≥70% (HR 0.20, 95%-CI: [0.13; 0.32], < 0.001), initially moderate neurological deficits (NFS ≤2) (HR 0.32, 95% CI: [0.19; 0.52], < 0.001), symptom response to RT (HR 0.41, 95%-CI: [0.26; 0.67], < 0.001) and the administration of systemic therapy (HR 0.51, 95%-CI: [0.33; 0.78], = 0.002). Prognostic of inferior OS were high-grade myelosuppression (HR 1.78, 95% CI: [1.06; 3.00], = 0.03) and serum LDH levels >500 U/l (HR 3.62, 95% CI: [1.76; 7.44], < 0.001). Clinical performance, symptom response and serum LDH stayed independently prognostic for survival in multivariate analysis. RT was well-tolerated and except for grade III myelosuppression in 19 cases (17.3%), no high-grade acute toxicities were observed. Neurologic symptom stabilization was achieved in 83 cases (75.5%) and a sizeable improvement in 39 cases (35.5%). Radiotherapy is a well-tolerated and efficacious means of providing symptom palliation for patients with LC, delaying neurologic deterioration while probably not directly influencing survival. Prognostic factors such as clinical performance, neurologic response and serum LDH can be used for patient stratification to facilitate treatment decisions.
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http://dx.doi.org/10.3389/fonc.2018.00641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331444PMC
January 2019