Anti-EGFR-Based Therapy in Recurrent or Metastatic HNSCC - What Difference Does it Make?

Patients with R/M HNSCC treated with palliative first-line therapy at Hannover Medical School between October 2005 and December 2016 have been included to show changes in survival following broad utilization of cetuximab. Treatment periods were defined from 10/2005 to 12/2008 (Period A) and 01/2009 to 12/2016. Overall survival did not improve over time. However, in subgroup analysis cetuximab utilized at any time vs. never showed a significant improve of overall survival (11.3 vs. 6.3 months, HR: 0.55, 95%-CI: 0.4-0.8, p = 0.04). Therefore, this study supports the application of cetuximab in this real-world population.

Radiosurgery for ventricular tachycardia (RAVENTA): interim analysis of a multicenter multiplatform feasibility trial.

BACKGROUND: Single-session cardiac stereotactic radiation therapy (SBRT) has demonstrated promising results for patients with refractory ventricular tachycardia (VT). However, the full safety profile of this novel treatment remains unknown and very limited data from prospective clinical multicenter trials are available. METHODS: The prospective multicenter multiplatform RAVENTA (radiosurgery for ventricular tachycardia) study assesses high-precision image-guided cardiac SBRT with 25 Gy delivered to the VT substrate determined by high-definition endocardial and/or epicardial electrophysiological mapping in patients with refractory VT ineligible for catheter ablation and an implanted cardioverter defibrillator (ICD). Primary endpoint is the feasibility of full-dose application and procedural safety (defined as an incidence of serious [grade ≥ 3] treatment-related complications ≤ 5% within 30 days after therapy). Secondary endpoints comprise VT burden, ICD interventions, treatment-related toxicity, and quality of life. We present the results of a protocol-defined interim analysis. RESULTS: Between 10/2019 and 12/2021, a total of five patients were included at three university medical centers. In all cases, the treatment was carried out without complications. There were no serious potentially treatment-related adverse events and no deterioration of left ventricular ejection fraction upon echocardiography. Three patients had a decrease in VT episodes during follow-up. One patient underwent subsequent catheter ablation for a new VT with different morphology. One patient with local VT recurrence died 6 weeks after treatment in cardiogenic shock. CONCLUSION: The interim analysis of the RAVENTA trial demonstrates early initial feasibility of this new treatment without serious complications within 30 days after treatment in five patients. Recruitment will continue as planned and the study has been expanded to further university medical centers. TRIAL REGISTRATION NUMBER: NCT03867747 (clinicaltrials.gov). Registered March 8, 2019. Study start: October 1, 2019.

Neoadjuvant versus definitive radiochemotherapy of locoregionally advanced oesophageal cancer-who benefits?

PURPOSE: For years, there have been discussions on whether neoadjuvant radiochemotherapy followed by surgery (nRCT-S) is superior to definitive radiochemotherapy (dRCT) as the standard of care for locoregionally advanced oesophageal cancer (OC). This retrospective study aimed to evaluate our patient cohort regarding differences in survival and recurrence between nRCT­S and dRCT. METHODS: Data from 68 patients with dRCT and 33 patients with nRCT­S treated from 2010 to 2018 were analysed. Comorbidities were recorded using the Charlson Comorbidity Index (CCI). Recurrence patterns were recorded as in-field or out-field. Kaplan-Meier analyses were used to compare survival data (overall survival [OS], progression-free survival [PFS], and locoregional control [LRC]). RESULTS: Patients with nRCT­S showed significantly lower CCI values than those with dRCT (p = 0.001). The median follow-up was 47 months. The median OS times were 31 months for nRCT­S and 12 months for dRCT (p = 0.009), the median PFS times were 11 and 9 months, respectively (p = 0.057), and the median LRC times were not reached and 23 months, respectively (p = 0.037). The only further factor with a significant impact on OS was the CCI (p = 0.016). In subgroup analyses for comorbidities regarding differences in OS, the superiority of the nRCT­S remained almost significant for CCI values 2-6 (p = 0.061). CONCLUSION: Our study showed significantly longer OS and LRC for patients with nRCT­S than for those with dRCT. Due to different comorbidities in the groups, it can be deduced from the subgroup analysis that patients with few comorbidities seem to especially profit from nRCT­S.

Primary and secondary gliosarcoma: differences in treatment and outcome.

INTRODUCTION: There are only few studies comparing differences in the outcome of primary versus secondary gliosarcoma. This study aimed to review the outcome and survival of patients with primary or secondary gliosarcoma following surgical resection and adjuvant treatment. The data were also matched with data of patients with primary and secondary glioblastoma (GBM). PATIENTS AND METHODS: Treatment histories of 10 patients with primary gliosarcoma and 10 patients with secondary gliosarcoma were analysed and compared. Additionally, data of 20 patients with primary and 20 patients with secondary GBM were analysed and compared. All patients underwent surgical resection of the tumour in our department. Follow-up data, progression-free survival (PFS), and median overall survival (mOS) were evaluated. RESULTS: The median PFS in patients with primary gliosarcoma was significantly higher than in patients with secondary gliosarcoma (p = 0.037). The 6-month PFS rates were 80.0% in patients with primary and 30.0% in patients with secondary gliosarcoma. Upon recurrence, five patients with primary gliosarcoma and four patients with secondary gliosarcoma underwent repeat surgical resection. The mOS of patients with primary gliosarcoma was significantly higher than that of patients with secondary gliosarcoma (p = 0.031). The percentage of patients surviving at 1-year/2-year follow-up in primary gliosarcoma was 70%/20%, while it was only 10%/10% in secondary gliosarcoma. When PFS and mOS of primary gliosarcoma was compared to primary GBM, there were no statistically differences (p = 0.509; p = 0.435). The PFS and mOS of secondary gliosarcoma and secondary GBM were also comparable (p = 0.290 and p = 0.390). CONCLUSION: Patients with primary gliosarcoma have a higher PFS and mOS compared to those with secondary gliosarcoma. In the case of tumour recurrence, patients with secondary gliosarcoma harbour an unfavourable prognosis with limited further options. The outcome of patients with primary or secondary gliosarcoma is comparable to that of patients with primary or secondary GBM.

Moderately HRT vs. CRT for localized prostate cancer using image-guided VMAT with SIB: evaluation of acute and late toxicities.

PURPOSE: This retrospective study aims at investigating the effects of moderately hypofractionated radiation therapy (HRT) on acute and late toxicities as well as on early biochemical control and therapeutic efficiency compared to conventional radiation therapy (CRT) in prostate cancer. PATIENTS AND METHODS: We analyzed 55 HRT patients irradiated with the total dose of 60 Gy in 20 fractions delivered over 4 weeks. These patients were compared to a control group of 55 patients who received CRT with a total of <78 Gy in 37-39 fractions delivered over circa 8 weeks. External beam radiation therapy (EBRT) was conducted using daily image-guided (cone beam CT) volumetric modulated arc therapy (VMAT) and a simultaneously integrated boost (SIB) for both groups to protect the rectum. Acute toxicities were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v5, whereas chronic toxicities were assessed in accordance with LENT-SOMA. Patient traits were compared by implementing t­tests and Wilcoxon-Whitney tests for continuous variables, whereas discrete characteristics were evaluated by applying two-tailed Fisher's exact tests. In addition, we calculated average treatment effects (ATE). Thereby, propensity score matching (PSM) based on nearest-neighbor matching considering age, comorbidities, and risk stratification as covariates was applied. The statistical analysis was conducted using Stata 14.2 (StataCorp LLC, TX, USA). RESULTS: As confirmed by the descriptive tests, the ATE revealed that the intensity and occurrence of urinary frequency (p = 0.034) and proctitis (p = 0.027) significantly decreased for the HRT group, whereas all other acute toxicities did not differ significantly between the HRT and CRT groups. For late toxicities, neither statistical tests nor ATE estimation showed significant differences. Also, no significant difference was found regarding the decrease in prostate specific antigen (PSA) after a median follow-up of 13 months (range 2-28 months), which indicates biochemical freedom from progression. CONCLUSION: HRT offers several medical and economic advantages and should therefore be considered as a useful alternative to CRT.

Efficiency of moderately hypofractionated radiotherapy in NSCLC cell model.

Background: The current standard of radiotherapy for inoperable locally advanced NSCLCs with single fraction doses of 2.0 Gy, results in poor outcomes. Several fractionation schedules have been explored that developed over the past decades to increasingly more hypofractionated treatments. Moderate hypofractionated radiotherapy, as an alternative treatment, has gained clinical importance due to shorter duration and higher patient convenience. However, clinical trials show controversial results, adding to the need for pre-clinical radiobiological studies of this schedule. Methods: We examined in comparative analysis the efficiency of moderate hypofractionation and normofractionation in four different NSCLC cell lines and fibroblasts using several molecular-biological approaches. Cells were daily irradiated with 24x2.75 Gy (moderate hypofractionation) or with 30x2 Gy (normofractionation), imitating the clinical situation. Proliferation and growth rate via direct counting of cell numbers, MTT assay and measurements of DNA-synthesizing cells (EdU assay), DNA repair efficiency via immunocytochemical staining of residual γH2AX/53BP1 foci and cell surviving via clonogenic assay (CSA) were experimentally evaluated. Results: Overall, the four tumor cell lines and fibroblasts showed different sensitivity to both radiation regimes, indicating cell specificity of the effect. The absolute cell numbers and the CSA revealed significant differences between schedules (P < 0.0001 for all employed cell lines and both assays) with a stronger effect of moderate hypofractionation. Conclusion: Our results provide evidence for the similar effectiveness and toxicity of both regimes, with some favorable evidence towards a moderate hypofractionation. This indicates that increasing the dose per fraction may improve patient survival and therapy outcomes.

Moderately Hypofractionated Radio(chemo)therapy With Simultaneous Integrated Boost for Recurrent, Previously Irradiated, High-grade Glioma.

BACKGROUND/AIM: The therapy of recurrent, previously irradiated, high-grade gliomas is still a major interdisciplinary challenge, and the overall prognosis remains poor. Reirradiation has been established as a major component of the management of relapse, in addition to further debulking surgery and systemic options. Herein, we present a moderately hypofractionated reirradiation concept with simultaneous integrated boost for such recurrent, previously irradiated tumors. PATIENTS AND METHODS: From October 2019 to January 2021, 12 patients with recurrent malignant gliomas were re-irradiated. All patients had previously undergone surgery and irradiation with mostly normal fractions at the time of primary therapy. Radiotherapy of relapse was performed in all patients with 33 Gy, with 2.2 Gy single dose with a simultaneously integrated boost of 40.05 Gy with a single dose of 2.67 Gy in 15 fractions. Nine out of the 12 patients underwent debulking surgery before reirradiation, and seven patients received concurrent chemotherapy with temozolomide. The mean follow-up was 15.5 months. RESULTS: The median overall survival after recurrence was 9.3 months. The survival rate after 1 year was 33%. Toxicity during radiotherapy was low. In two patients, small areas of radionecrosis were observed at follow-up magnetic resonance imaging in the target volume; these patients were clinically asymptomatic. CONCLUSION: Moderate hypofractionation shortens the duration of radiotherapy and thereby improves accessibility for patients with limited mobility and prognosis, and achieves a respectable overall survival rate. Furthermore, the extent of late toxicity is also acceptable in these preirradiated patients.

Linac-Based Ultrahypofractionated Partial Breast Irradiation (APBI) in Low-Risk Breast Cancer: First Results of a Monoinstitutional Observational Analysis.

Purpose: For adjuvant radiotherapy of low-risk breast cancer after breast-conserving surgery, there have been many trials of hypofractionation and partial breast irradiation (PBI) over the years, with proven mild long-term toxicity. The aim of this study was to introduce a short-course dose-adapted concept, proven in whole breast irradiation (WBI) for use in accelerated partial breast irradiation (APBI), while monitoring dosimetric data and toxicity. Methods: From April 2020 to March 2022, 61 patients with low-risk breast cancer or ductal carcinoma in situ (DCIS) were treated at a single institution with percutaneous APBI of 26 Gy in five fractions every other day after breast-conserving surgery. Dosimetric data for target volume and organs at risk were determined retrospectively. Acute toxicity was evaluated. Results: The target volume of radiotherapy comprised an average of 19% of the ipsilateral mamma. The burden on the heart and lungs was very low. The mean cardiac dose during irradiation of the left breast was only 0.6 Gy. Two out of three patients remained without any acute side effects. Conclusions: Linac-based APBI is an attractive treatment option for patients with low-risk breast cancer in whom neither WBI nor complete omission of radiotherapy appears to be an adequate alternative.

Using a Further Planning MRI after Neoadjuvant Androgen Deprivation Therapy Significantly Reduces the Radiation Exposure of Organs at Risk in External Beam Radiotherapy of Prostate Cancer.

Radiotherapy for prostate cancer is often preceded by neoadjuvant androgen deprivation therapy (ADT), which leads to a reduction in the size of the prostate. This study examines whether it is relevant for treatment planning to acquire a second planning magnetic resonance imaging (MRI) after ADT (=MRI 2) or whether it can be planned without disadvantage based on an MRI acquired before starting ADT (=MRI 1). The imaging data for the radiotherapy treatment planning of 17 patients with prostate cancer who received two planning MRIs (before and after neoadjuvant ADT) were analyzed as follows: detailed comparable radiation plans were created separately, each based on the planning CT scan and either MRI 1 or MRI 2. After ADT for an average of 17.2 weeks, the prostate was reduced in size by an average of 24%. By using MRI 2 for treatment planning, the V60Gy of the rectum could be significantly relieved by an average of 15% with the same coverage of the target volume, and the V70Gy by as much as 33% (compared to using MRI 1 alone). Using a second MRI for treatment planning after neoadjuvant ADT in prostate cancer leads to a significant relief for the organs at risk, especially in the high dose range, with the same irradiation of the target volume, and should therefore be carried out regularly. Waiting for the prostate to shrink after a few months of ADT contributes to relief for the organs at risk and to lowering the toxicity. However, the use of reduced target volumes requires an image-guided application, and the oncological outcome needs to be verified in further studies.

Quality assurance process within the RAdiosurgery for VENtricular TAchycardia (RAVENTA) trial for the fusion of electroanatomical mapping and radiotherapy planning imaging data in cardiac radioablation.

A novel quality assurance process for electroanatomical mapping (EAM)-to-radiotherapy planning imaging (RTPI) target transport was assessed within the multi-center multi-platform framework of the RAdiosurgery for VENtricular TAchycardia (RAVENTA) trial. A stand-alone software (CARDIO-RT) was developed to enable platform independent registration of EAM and RTPI of the left ventricle (LV), based on pre-generated radiotherapy contours (RTC). LV-RTC were automatically segmented into the American-Heart-Association 17-segment-model and a manual 3D-3D method based on EAM 3D-geometry data and a semi-automated 2D-3D method based on EAM screenshot projections were developed. The quality of substrate transfer was evaluated in five clinical cases and the structural analyses showed substantial differences between manual target transfer and target transport using CARDIO-RT.

Stereotactic arrhythmia radioablation: A multicenter pre-post intervention safety evaluation of the implantable cardioverter-defibrillator function.

BACKGROUND: Stereotactic arrhythmia radioablation (STAR) appears to be beneficial in selected patients with therapy-refractory ventricular tachycardia (VT). However, high-dose radiotherapy used for STAR-treatment may affect functioning of the patients' implantable cardioverter defibrillator (ICD) by direct effects of radiation on ICD components or cardiac tissue. Currently, the effect of STAR on ICD functioning remains unknown. METHODS: A retrospective pre-post multicenter study evaluating ICD functioning in the 12-month before and after STAR was performed. Patients with (non)ischemic cardiomyopathies with therapy-refractory VT and ICD who underwent STAR were included and the occurrence of ICD-related adverse events was collected. Evaluated ICD parameters included sensing, capture threshold and impedance. A linear mixed-effects model was used to investigate the association between STAR, radiotherapy dose and changes in lead parameters over time. RESULTS: In total, 43 patients (88% male) were included in this study. All patients had an ICD with an additional right atrial lead in 34 (79%) and a ventricular lead in 17 (40%) patients. Median ICD-generator dose was 0.1 Gy and lead tip dose ranged from 0-32 Gy. In one patient (2%), a reset occurred during treatment, but otherwise, STAR and radiotherapy dose were not associated with clinically relevant alterations in ICD leads parameters. CONCLUSIONS: STAR treatment did not result in major ICD malfunction. Only one radiotherapy related adverse event occurred during the study follow-up without patient harm. No clinically relevant alterations in ICD functioning were observed after STAR in any of the leads. With the reported doses STAR appears to be safe.

Moderately Hypofractionated Radiotherapy Without Chemotherapy in Elderly or Frail Patients With Head and Neck Cancer.

BACKGROUND: Comorbidity and frailty are relevant limitations of normofractionated combined radiochemotherapy for squamous cell head and neck cancer (HNSCC), especially in elderly patients. This retrospective study aimed to evaluate the efficacy and toxicity of moderately hypofractionated radiotherapy (HRT) without chemotherapy in patients ineligible for concurrent radiochemotherapy. PATIENTS AND METHODS: Between 2011 and 2018, 51 elderly/frail patients with HNSCC were treated with either definitive (n=23) or adjuvant (n=28) moderate HRT. A dose of 45 Gy was given to the primary tumour region and cervical nodes with a sequential boost up to 50 in the adjuvant and 55 Gy in the definitive cure setting (2.5 Gy/fraction). Patient outcomes of locoregional control, overall survival, and acute and late toxicity were analysed. RESULTS: After a median follow-up of 6 months for the definitive HRT group and 28.5 months for the adjuvant HRT group, we found a median overall survival of 6 vs. 55 months (log-rank test: p<0.001) and a median locoregional control of 9 months vs. not reached (log-rank test: p=0.008), respectively. The 2-year rates of locoregional control were 28.5% for the definitive HRT group vs. 75.2% for the adjuvant HRT group. No acute or late grade 4-5 toxicity occurred; grade 3 toxicity was rarely documented. CONCLUSION: HRT in elderly/frail patients with HNSCC who are unfit for chemotherapy leads to acceptable local control with moderate toxicity in a short overall treatment time. Especially in the postoperative situation, HRT can be considered an appropriate alternative to normofractionated radio(chemo)therapy. Definitive HRT can be a treatment alternative, especially for multimorbid patients.

Stereotactic radioablation for ventricular tachycardia.

Non-invasive stereotactic radioablation of ventricular tachycardia (VT) substrate has been proposed as a novel treatment modality for patients not eligible for catheter-based ablation or in whom this approach has failed. Initial clinical results are promising with good short-term efficacy in VT suppression and tolerable side effects. This article reviews the current clinical evidence for cardiac radioablation and gives an overview of important preclinical and translational results. Practical guidance is provided, and a cardiac radioablation planning and treatment workflow based on expert consensus and the authors' institutional experience is set out.

The Prognostic Value of Liquid Biopsies for Benefit of Salvage Radiotherapy in Relapsed Oligometastatic Prostate Cancer.

To assess the prognostic value of "liquid biopsies" for the benefit of salvage RT in oligometastatic prostate cancer relapse, we enrolled 44 patients in the study between the years 2016 and 2020. All the patients were diagnosed as having an oligometastatic prostate cancer relapse on prostate-specific membrane antigen (PSMA)-targeted PET-CT and underwent irradiation at the Department of Radiotherapy at the Hannover Medical School. Tumor cells and total RNA, enriched from the liquid biopsies of patients, were processed for the subsequent quantification analysis of relative transcript levels in real-time PCR. In total, 54 gene transcripts known or suggested to be associated with prostate cancer or treatment outcome were prioritized for analysis. We found significant correlations between the relative transcript levels of several investigated genes and the Gleason score, PSA (prostate-specific antigen) value, or UICC stage (tumor node metastasis -TNM classification of malignant tumors from Union for International Cancer Control). Furthermore, a significant association of MTCO2, FOXM1, SREBF1, HOXB7, FDXR, and MTRNR transcript profiles was found with a temporary and/or long-term benefit from RT. Further studies on larger patients cohorts are necessary to prove our preliminary findings for establishing liquid biopsy tests as a predictive examination method prior to salvage RT.

Effectiveness of hypofractionated and normofractionated radiotherapy in a triple-negative breast cancer model.

Breast cancer (BC) is one of the most diagnosed malignant carcinomas in women with a triple-negative breast cancer (TNBC) phenotype being correlated with poorer prognosis. Fractionated radiotherapy (RT) is a central component of breast cancer management, especially after breast conserving surgery and is increasingly important for TNBC subtype prognosis. In recent years, moderately hypofractionated radiation schedules are established as a standard of care, but many professionals remain skeptical and are concerned about their efficiency and side effects. In the present study, two different triple-negative breast cancer cell lines, a non-malignant breast epithelial cell line and fibroblasts, were irradiated daily under normofractionated and hypofractionated schedules to evaluate the impact of different irradiation regimens on radiation-induced cell-biological effects. During the series of radiotherapy, proliferation, growth rate, double-strand DNA break-repair (DDR), cellular senescence, and cell survival were measured. Investigated normal and cancer cells differed in their responses and receptivity to different irradiation regimens, indicating cell line/cell type specificity of the effect. At the end of both therapy concepts, normal and malignant cells reach almost the same endpoint of cell count and proliferation inhibition, confirming the clinical observations in the follow-up at the cellular level. These result in cell lines closely replicating the irradiation schedules in clinical practice and, to some extent, contributing to the understanding of growth rate or remission of tumors and the development of fibrosis.

Moderately Hypofractionated Intensity-modulated Radiotherapy With a Simultaneous Integrated Boost for Locally Advanced Head and Neck Cancer - Do Modern Techniques Fulfil Their Promise?

BACKGROUND: Intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) and moderate hypofractionation offers an opportunity for defining individual doses and a reduction in overall treatment time in locally advanced head and neck cancer (HNSCC). We present retrospective data on toxicity and locoregional control of a patient cohort treated with an IMRT-SIB concept in comparison to normo-fractionated 3D-conformal radiotherapy (3D-RT). PATIENTS AND METHODS: Between 2012 and 2014, 67 patients with HNSCC (stages III-IVB) were treated with IMRT-SIB either definitively or in the postoperative setting. These patients were matched with those of patients treated with normo-fractionated 3D-RT before mid-2012 and their clinical courses were compared. Chemotherapy or cetuximab was given concomitantly in both groups in the definitive situation (postoperatively, dependent on risk factors). RESULTS: Significantly less toxicity was found in favor of IMRT-SIB concerning dysphagia, dermatitis, xerostomia, fibrosis, and lymphedema. After a median follow-up of 31 months (range=2-104 months), 3-year locoregional control was 73% for those treated with IMRT-SIB versus 78% for those treated with 3D-RT. CONCLUSION: This moderately hypofractionated IMRT-SIB concept was shown to be feasible, incurring less toxicity than conventional 3D-RT.