Fractionated stereotactic radiotherapy of intracranial postoperative cavities after resection of brain metastases - Clinical outcome and prognostic factors.

Background and Purpose: After surgical resection of brain metastases (BM), radiotherapy (RT) is indicated. Postoperative stereotactic radiosurgery (SRS) reduces the risk of local progression and neurocognitive decline compared to whole brain radiotherapy (WBRT). Aside from the optimal dose and fractionation, little is known about the combination of systemic therapy and postoperative fractionated stereotactic radiotherapy (fSRT), especially regarding tumour control and toxicity. Methods: In this study, 105 patients receiving postoperative fSRT with 35 Gy in 7 fractions performed with Cyberknife were retrospectively reviewed. Overall survival (OS), local control (LC) and total intracranial brain control (TIBC) were analysed via Kaplan-Meier method. Cox proportional hazards models were used to identify prognostic factors. Results: Median follow-up was 20.8 months. One-year TIBC was 61.6% and one-year LC was 98.6%. Median OS was 28.7 (95%-CI: 16.9-40.5) months. In total, local progression (median time not reached) occurred in 2.0% and in 20.4% radiation-induced contrast enhancements (RICE) of the cavity (after median of 14.3 months) were diagnosed. Absence of extracranial metastases was identified as an independent prognostic factor for superior OS (p = <0.001) in multivariate analyses, while a higher Karnofsky performance score (KPS) was predictive for longer OS in univariate analysis (p = 0.041). Leptomeningeal disease (LMD) developed in 13% of patients. Conclusion: FSRT after surgical resection of BM is an effective and safe treatment approach with excellent local control and acceptable toxicity. Further prospective randomized trials are needed to establish standardized therapeutic guidelines.

Stereotactic ultrahypofractionated MR-guided radiotherapy for localized prostate cancer - Acute toxicity and patient-reported outcomes in the prospective, multicenter SMILE phase II trial.

Background: Due to superior image quality and daily adaptive planning, MR-guided stereotactic body radiation therapy (MRgSBRT) has the potential to further widen the therapeutic window in radiotherapy of localized prostate cancer. This study reports on acute toxicity rates and patient-reported outcomes after MR-guided adaptive ultrahypofractionated radiotherapy for localized prostate cancer within the prospective, multicenter phase II SMILE trial. Materials and methods: A total of 69 patients with localized prostate cancer underwent MRgSBRT with daily online plan adaptation. Inclusion criteria comprised a tumor stage ≤ T3a, serum PSA value ≤ 20 ng/ml, ISUP Grade group ≤ 4. A dose of 37.5 Gy was prescribed to the PTV in five fractions on alternating days with an optional simultaneous boost of 40 Gy to the dominant intraprostatic lesion defined by multiparametric MRI. Acute genitourinary (GU-) and gastrointestinal (GI-) toxicity, as defined by CTCAE v. 5.0 and RTOG as well as patient-reported outcomes according to EORTC QLQ-C30 and -PR25 scores were analyzed at completion of radiotherapy, 6 and 12 weeks after radiotherapy and compared to baseline symptoms. Results: There were no toxicity-related treatment discontinuations. At the 12-week follow-up visit, no grade 3 + toxicities were reported according to CTCAE. Up until the 12-week visit, in total 16 patients (23 %) experienced a grade 2 GU or GI toxicity. Toxicity rates peaked at the end of radiation therapy and subsided within the 12-week follow-up period. At the 12-week follow-up visit, no residual grade 2 GU toxicities were reported and 1 patient (1 %) had residual grade 2 enteritic symptoms. With exception to a significant improvement in the emotional functioning score following MRgSBRT, no clinically meaningful changes in the global health status nor in relevant subscores were reported. Conclusion: Daily online-adaptive MRgSBRT for localized prostate cancer resulted in an excellent overall toxicity profile without any major negative impact on quality of life.

Whole-pelvic irradiation with boost to involved nodes and prostate in node-positive prostate cancer-long-term data from the prospective PLATIN-2 trial.

PURPOSE: Node-positive prostate cancer is a potentially curable disease. Definitive radiotherapy to the prostate and lymphatic drainage is an effective treatment option but prospective long-term outcome data are scarce. Thus, the current study aimed to evaluate the toxicity and efficacy of definitive radiation therapy for men with prostate cancer and nodal metastases using modern irradiation techniques. METHODS: A total of 40 treatment-naïve men with node-positive prostate cancer were allocated to the trial. All patients received definitive radiation therapy at two German university hospitals between 2009 and 2018. Radiation was delivered as intensity-modulated radiation therapy (IMRT) with 51 Gy to the lymphatic drainage with simultaneous integrated boost (SIB) up to 61.2 Gy to involved nodes and 76.5 Gy to the prostate in 34 fractions. Feasibility and safety, overall and progression-free survival, toxicity, and quality of life measurements were analyzed. RESULTS: During a median follow-up of 79 months, median overall survival was 107 months and progression-free survival was 78 months. Based on imaging follow-up, no infield relapse was reported during the first 24 months of follow-up. There were 3 (8%) potentially treatment-related grade 3 toxicities. Common iliac node involvement was associated with a higher risk of progression (HR 15.8; 95% CI 2.1-119.8; p = 0.007). CONCLUSION: Definitive radiation to the lymphatic drainage with SIB to the involved nodes and prostate is a safe and effective treatment approach for patients with treatment-naïve, node-positive prostate cancer with excellent infield tumor control rates and tolerable toxicity. Location rather than number of involved nodes is a major risk factor for progression.

Isocitrate-dehydrogenase-mutant lower grade glioma in elderly patients: treatment and outcome in a molecularly characterized contemporary cohort.

PURPOSE: Lower-grade glioma (LGG) is rare among patients above the age of 60 ("elderly"). Previous studies reported poor outcome, likely due to the inclusion of isocitrate dehydrogenase (IDH) wildtype astrocytomas and advocated defensive surgical and adjuvant treatment. This study set out to question this paradigm analyzing a contemporary cohort of patients with IDH mutant astrocytoma and oligodendroglioma WHO grade 2 and 3. METHODS: Elderly patients treated in our department for a supratentorial, hemispheric LGG between 2009 and 2019 were retrospectively analyzed for patient-, tumor- and treatment-related factors and progression-free survival (PFS) and compared to patients aged under 60. Inclusion required the availability of subtype-defining molecular data and pre- and post-operative tumor volumes. RESULTS: 207 patients were included, among those 21 elderlies (10%). PFS was comparable between elderly and younger patients (46 vs. 54 months; p = 0.634). Oligodendroglioma was more common in the elderly (76% vs. 46%; p = 0.011). Most patients underwent tumor resection (elderly: 81% vs. younger: 91%; p = 0.246) yielding comparable residual tumor volumes (elderly: 7.8 cm3; younger: 4.1 cm3; p = 0.137). Adjuvant treatment was administered in 76% of elderly and 61% of younger patients (p = 0.163). Uni- and multi-variate survival analyses identified a tumor crossing the midline, surgical strategy, and pre- and post-operative tumor volumes as prognostic factors. CONCLUSION: Elderly patients constitute a small fraction of molecularly characterized LGGs. In contrast to previous reports, favorable surgical and survival outcomes were achieved in our series comparable to those of younger patients. Thus, intensified treatment including maximal safe resection should be advocated in elderly patients whenever feasible.

Distinguishing Benign and Malignant Findings on [68 Ga]-FAPI PET/CT Based on Quantitative SUV Measurements.

AIM/PURPOSE: Fibroblast activation protein (FAP) is overexpressed by cancer-associated fibroblasts. However, activated fibroblasts have been shown to play a significant role also in certain benign conditions such as wound healing or chronic inflammation. Therefore, the current study aimed to identify whether FAPI uptake might differ between malignant lesions and benign conditions. MATERIAL AND METHODS: We retrospectively analyzed 155 patients with various cancer types who received [68 Ga]-FAPI-04/02-PET/CT between July 2017 and March 2020. SUVmax, SUVmean, and lesion-to-background ratios (LBR) of FAPI uptake were measured in benign processes compared to malignant lesions (primary and/or 2 exemplary metastases). In addition, receiver operating characteristic (ROC) curve analysis was conducted to compare the predictive capabilities of semiquantitative PET/CT parameters. Furthermore, the sensitivity, specificity, optimal cutoff value, and 95% confidence interval (CI) were determined for each parameter. RESULTS: Benign lesions exhibited significantly lower FAPI uptake compared to malignant lesions (mean SUVmax benign vs. malignant: 4.2 vs. 10.6; p < 0.001). In ROC analysis, cutoff values of these lesions (benign vs. malignant) were established based on SUVmax, SUVmean, and LBR. The SUVmax cutoff value for all lesions was 5.5 and the corresponding sensitivity, specificity, accuracy, and AUC were 78.8%, 85.1%, 82.0%, and 0.89%, respectively. CONCLUSION: Our aim was to systematically analyze the pattern of FAPI uptake in benign and malignant processes. This investigation demonstrates that FAPI uptake might be useful to differentiate malignant and benign findings due to different patho-physiological origins.

Detecting and Locating the Site of Local Relapse Using 18F-PSMA-1007 Imaging After Primary Treatment of 135 Prostate Cancer Patients-Potential Impact on PSMA-Guided Radiation Therapy.

PURPOSE: Due to limited imaging options, the visualization of a local relapse of prostate cancer used to pose a considerable challenge. However, since the integration of 18F-PSMA-1007-PET/CT into the clinic, a relapsed tumor can now easily be detected by hybrid imaging. The present study aimed to evaluate and map the allocate relapse in a large cohort of prostate cancer patients focusing on individual patient management conclusions for radiation therapy. PROCEDURES: The current study included 135 men with prostate cancer after primary treatment who underwent 18F-PSMA-1007-PET/CT due to biochemical relapse detecting a local relapse. Imaging data were reassessed and analyzed with regard to relapse locations. For the correlation of tumor foci with clinical data, we used binary logistic regression models as well as the Kruskal-Wallis test and Mann-Whitney test. RESULTS: In total, 69.6% of all patients (mean age: 65 years) underwent prostatectomy while 30.4% underwent radiation therapy. PET imaging detected most frequently a unifocal relapse (72.6%). There was a statistically significantly higher rate of ipsilateral cases among the relapsed tumors. Comparing both treatment approaches, tumors relapsed most commonly within the posterior region after surgery and transition/peripheral zone after radiation therapy, respectively. CONCLUSIONS: The present study confirms that 18F-PSMA-1007-PET/CT is highly suitable for the localization and allocation of a local relapse in patients with prostate cancer. The data enable further optimizing dose prescriptions and target volume delineations of radiation therapy in the future.

Life-threatening hemophagocytic syndrome triggered by disseminated toxoplasmosis in a young patient with previously unknown AIDS.

Hemophagocytic syndrome is a rare life-threatening disorder that can be triggered by various conditions such as HIV infection and opportunistic agents. We report a case of disseminated toxoplasmosis complicated with severe hemophagocytic syndrome and revealing an unknown acquired immunodeficiency syndrome. The patient presented with multiple organ failure in intensive care unit. Once diagnosed, he benefitted from etoposide infusion, administration of specific anti-toxoplasmosis treatments and secondary antiretroviral therapy. He was alive at intensive care unit discharge and returned home with little sequalae. This case illustrates both the importance of rapid investigations of hemophagocytic syndrome etiologies in HIV positive patients and the necessity to prompt etoposide and specific treatments in order to improve potentially dramatic outcomes.

Neoadjuvant irradiation of extremity soft tissue sarcoma with ions (Extrem-ion): study protocol for a randomized phase II pilot trial.

BACKGROUND: The standard of care treatment for soft tissue sarcoma of the extremities is a wide resection in combination with pre- or postoperative radiotherapy with high local control rates, sparing patients the necessity of amputation without compromising on overall survival rates. The currently preferred timing of radiotherapy is under debate. Albeit having higher rates of acute wound complications, late side effects like fibrosis, joint stiffness or edema are less frequent in preoperative compared to postoperative radiotherapy. This can be explained in smaller treatment volumes and a lower dose in the preoperative setting. Particles allow better sparing of surrounding tissues at risk, and carbon ions additionally offer biologic advantages and are preferred in less radiosensitive tumors. Hypofractionation allows for a significantly shorter treatment duration. METHODS: Extrem-ion is a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the extremities will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5-6 fractions per week] in each arm). The primary objective is the proportion of therapies without wound healing disorder the first 120 days after surgery or discontinuation of treatment for any reason related to the treatment. The secondary endpoints of the study consist of local control, local progression-free survival, disease-free survival, overall survival, and quality of life. DISCUSSION: The aim of this study is to confirm that hypofractionated, preoperative radiotherapy is safe and feasible. The potential for reduced toxicity by the utilization of particle therapy is the rational of this trial. A subsequent randomized phase III trial will compare the hypofractionated proton and carbon ion irradiation in regards to local control. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04946357 ; Retrospectively registered June 30, 2021.

Stereotactic MRI-guided radiation therapy for localized prostate cancer (SMILE): a prospective, multicentric phase-II-trial.

BACKGROUND: Normofractionated radiation regimes for definitive prostate cancer treatment usually extend over 7-8 weeks. Recently, moderate hypofractionation with doses per fraction between 2.2 and 4 Gy has been shown to be safe and feasible with oncologic non-inferiority compared to normofractionation. Radiobiologic considerations lead to the assumption that prostate cancer might benefit in particular from hypofractionation in terms of tumor control and toxicity. First data related to ultrahypofractionation demonstrate that the overall treatment time can be reduced to 5-7 fractions with single doses > 6 Gy safely, even with simultaneous focal boosting of macroscopic tumor(s). With MR-guided linear accelerators (MR-linacs) entering clinical routine, invasive fiducial implantations become unnecessary. The aim of the multicentric SMILE study is to evaluate the use of MRI-guided stereotactic radiotherapy for localized prostate cancer in 5 fractions regarding safety and feasibility. METHODS: The study is designed as a prospective, one-armed, two-stage, multi-center phase-II-trial with 68 patients planned. Low- and intermediate-risk localized prostate cancer patients will be eligible for the study as well as early high-risk patients (cT3a and/or Gleason Score ≤ 8 and/or PSA ≤ 20 ng/ml) according to d'Amico. All patients will receive definitive MRI-guided stereotactic radiation therapy with a total dose of 37.5 Gy in 5 fractions (single dose 7.5 Gy) on alternating days. A focal simultaneous integrated boost to MRI-defined tumor(s) up to 40 Gy can optionally be applied. The primary composite endpoint includes the assessment of urogenital or gastrointestinal toxicity ≥ grade 2 or treatment-related discontinuation of therapy. The use of MRI-guided radiotherapy enables online plan adaptation and intrafractional gating to ensure optimal target volume coverage and protection of organs at risk. DISCUSSION: With moderate hypofractionation being the standard in definitive radiation therapy for localized prostate cancer at many institutions, ultrahypofractionation could be the next step towards reducing treatment time without compromising oncologic outcomes and toxicities. MRI-guided radiotherapy could qualify as an advantageous tool as no invasive procedures have to precede in therapeutic workflows. Furthermore, MRI guidance combined with gating and plan adaptation might be essential in order to increase treatment effectivity and reduce toxicity at the same time.

Head-to-head Intra-individual Comparison of [68Ga]-FAPI and [18F]-FDG PET/CT in Patients with Bladder Cancer.

AIM/PURPOSE: Fibroblast activation protein-(FAP)-ligands, a novel class of tracers for PET/CT imaging, demonstrated promising results in previous studies in various malignancies compared to standard [18F]FDG PET/CT. 68Ga-labeled fibroblast activation protein inhibitor-([68Ga]Ga-DOTA-FAPI)-PET/CT impresses with sharp contrasts in terms of high tumor uptake and low background noise leading to clear delineation. [18F]FDG PET/CT has limited accuracy in bladder cancer due to high background signal. Therefore, we sought to evaluate the diagnostic potential of [68Ga]FAPI in patients with bladder cancer. MATERIAL AND METHODS: This retrospective analysis consisted of 8 patients (median age 66), 7 of whom underwent both [68Ga]FAPI and [18F]FDG PET/CT scans with a median time interval of 5 days (range 1-20 days). Quantification of tracer uptake was determined with SUVmax and SUVmean. Furthermore, the tumor-to-background ratio (TBR) was derived by dividing the SUVmax of tumor lesions by the SUVmax of adipose tissue, skeletal muscle, and blood pool. RESULTS: Overall, 31 metastases were detected in five patients including lymph node metastases (n = 23), bone metastases (n = 4), lung metastases (n = 3), and a peritoneal metastasis (n = 1). In one patient, [68Ga]FAPI demonstrated significant uptake in the primary tumor located in the bladder wall. [68Ga]FAPI-PET/CT demonstrated significantly higher uptake compared to [18F]FDG PET/CT with higher mean SUVmax (8.2 vs. 4.6; p = 0.01). Furthermore, [68Ga]FAPI detected additional 30% (n = 9) lesions, missed by [18F]FDG. TBR demonstrated favorable uptake for [68Ga]FAPI in comparison to [18F]FDG. Significant differences were determined with regard to metastasis/blood pool ([68Ga]FAPI 5.3 vs [18F]FDG 1.9; p = 0.001). CONCLUSION: [68Ga]FAPI-PET/CT is a promising diagnostic radioligand for patients with bladder cancer. This first described analysis of FAP-ligand in bladder cancer revealed superiority over [18F]FDG in a small patient cohort. Thus, this so far assumed potential has to be confirmed and extended by larger and prospective studies.

MR-guided adaptive versus ITV-based stereotactic body radiotherapy for hepatic metastases (MAESTRO): a randomized controlled phase II trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is an established local treatment method for patients with hepatic oligometastasis or oligoprogression. Liver metastases often occur in close proximity to radiosensitive organs at risk (OARs). This limits the possibility to apply sufficiently high doses needed for optimal local control. Online MR-guided radiotherapy (oMRgRT) is expected to hold potential to improve hepatic SBRT by offering superior soft-tissue contrast for enhanced target identification as well as the benefit of gating and daily real-time adaptive treatment. The MAESTRO trial therefore aims to assess the potential advantages of adaptive, gated MR-guided SBRT compared to conventional SBRT at a standard linac using an ITV (internal target volume) approach. METHODS: This trial is conducted as a prospective, randomized, three-armed phase II study in 82 patients with hepatic metastases (solid malignant tumor, 1-3 hepatic metastases confirmed by magnetic resonance imaging (MRI), maximum diameter of each metastasis ≤ 5 cm (in case of 3 metastases: sum of diameters ≤ 12 cm), age ≥ 18 years, Karnofsky Performance Score ≥ 60%). If a biologically effective dose (BED) ≥ 100 Gy (α/ß = 10 Gy) is feasible based on ITV-based planning, patients will be randomized to either MRgRT or ITV-based SBRT. If a lesion cannot be treated with a BED ≥ 100 Gy, the patient will be treated with MRgRT at the highest possible dose. Primary endpoint is the non-inferiority of MRgRT at the MRIdian Linac® system compared to ITV-based SBRT regarding hepatobiliary and gastrointestinal toxicity CTCAE III or higher. Secondary outcomes investigated are local, locoregional (intrahepatic) and distant tumor control, progression-free survival, overall survival, possible increase of BED using MRgRT if the BED is limited with ITV-based SBRT, treatment-related toxicity, quality of life, dosimetric parameters of radiotherapy plans as well as morphological and functional changes in MRI. Potential prognostic biomarkers will also be evaluated. DISCUSSION: MRgRT is known to be both highly cost- and labor-intensive. The MAESTRO trial aims to provide randomized, higher-level evidence for the dosimetric and possible consecutive clinical benefit of MR-guided, on-table adaptive and gated SBRT for dose escalation in critically located hepatic metastases adjacent to radiosensitive OARs. TRIAL REGISTRATION: The study has been prospectively registered on August 30th, 2021: Clinicaltrials.gov, "Magnetic Resonance-guided Adaptive Stereotactic Body Radiotherapy for Hepatic Metastases (MAESTRO)", NCT05027711.

MR-guided adaptive stereotactic body radiotherapy (SBRT) of primary tumor for pain control in metastatic pancreatic ductal adenocarcinoma (mPDAC): an open randomized, multicentric, parallel group clinical trial (MASPAC).

BACKGROUND: Pain symptoms in the upper abdomen and back are prevalent in 80% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC), where the current standard treatment is a systemic therapy consisting of at least doublet-chemotherapy for fit patients. Palliative low-dose radiotherapy is a well-established local treatment option but there is some evidence for a better and longer pain response after a dose-intensified radiotherapy of the primary pancreatic cancer (pPCa). Stereotactic body radiation therapy (SBRT) can deliver high radiation doses in few fractions, therefore reducing chemotherapy-free intervals. However, prospective data on pain control after SBRT of pPCa is very limited. Therefore, we aim to investigate the impact of SBRT on pain control in patients with mPDAC in a prospective trial. METHODS: This is a prospective, double-arm, randomized controlled, international multicenter study testing the added benefit of MR-guided adaptive SBRT of the pPca embedded between standard of care-chemotherapy (SoC-CT) cycles for pain control and prevention of pain in patients with mPDAC. 92 patients with histologically proven mPDAC and at least stable disease after initial 8 weeks of SoC-CT will be eligible for the trial and 1:1 randomized in 3 centers in Germany and Switzerland to either experimental arm A, receiving MR-guided SBRT of the pPCa with 5 × 6.6 Gy at 80% isodose with continuation of SoC-CT thereafter, or control arm B, continuing SoC-CT without SBRT. Daily MR-guided plan adaptation intents to achieve good target coverage, while simultaneously minimizing dose to organs at risk. Patients will be followed up for minimum 6 and maximum of 18 months. The primary endpoint of the study is the "mean cumulative pain index" rated every 4 weeks until death or end of study using numeric rating scale. DISCUSSION: An adequate long-term control of pain symptoms in patients with mPDAC is an unmet clinical need. Despite improvements in systemic treatment, local complications due to pPCa remain a clinical challenge. We hypothesize that patients with mPDAC will benefit from a local treatment of the pPCa by MR-guided SBRT in terms of a durable pain control with a simultaneously favorable safe toxicity profile translating into an improvement of quality-of-life. TRIAL REGISTRATION: German Registry for Clinical Trials (DRKS): DRKS00025801. Meanwhile the study is also registered at ClinicalTrials.gov with the Identifier: NCT05114213.

Integration of radiation oncology teaching in medical studies by German medical faculties due to the new licensing regulations : An overview and recommendations of the consortium academic radiation oncology of the German Society for Radiation Oncology (DEGRO).

The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included.

FAP imaging in rare cancer entities-first clinical experience in a broad spectrum of malignancies.

PURPOSE: 68 Ga-FAPI (fibroblast activation protein inhibitor) is a rapidly evolving and highly promising radiotracer for PET/CT imaging, presenting excellent results in a variety of tumor entities, particularly in epithelial carcinomas. This retrospective analysis sought to evaluate the potential and impact of FAPI-PET/CT in rare cancer diseases with respect to improvement in staging and therapy, based on tracer uptake in normal organs and tumors. MATERIAL AND METHODS: Fifty-five patients with rare tumor entities, defined by a prevalence of 1 person out of 2000 or less, received a 68 Ga-FAPI-PET/CT scan. Fourteen women and 41 men (median age 60) were included within the following subgroups: cancer of unknown primary (n = 10), head and neck cancer (n = 13), gastrointestinal and biliary-pancreatic cancer (n = 17), urinary tract cancer (n = 4), neuroendocrine cancer (n = 4), and others (n = 7). Tracer uptake was quantified by standardized uptake values SUVmax and SUVmean and the tumor-to-background ratio (TBR) was determined (SUVmax tumor/SUVmean organ). RESULTS: In 20 out of 55 patients, the primary tumor was identified and 31 patients presented metastases (n = 88), characterized by a high mean SUVmax in primary (10.1) and metastatic lesions (7.6). The highest uptake was observed in liver metastases (n = 6) with a mean SUVmax of 9.8 and a high TBR of 8.7, closely followed by peritoneal carcinomatosis (n = 16) presenting a mean SUVmax of 9.8 and an excellent TBR of 29.6. In terms of the included subgroups, the highest uptake regarding mean SUVmax was determined in gastrointestinal and biliary-pancreatic cancer with 9.8 followed closely by urinary tract cancer with 9.5 and head and neck cancer (9.1). CONCLUSION: Due to excellent tumor visualization and, thereby, sharp contrasts in terms of high TBRs in primary and metastatic lesions in different rare malignancies, 68 Ga-FAPI-PET/CT crystallizes as a powerful and valuable imaging tool, particularly with respect to epithelial carcinomas, and therefore an enhancement to standard diagnostics imaging methodologies. The realization of further and prospective studies is of large importance to confirm the potential of FAP imaging in oncology.

Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer.

BACKGROUND: The improved efficacy of tyrosine kinase inhibitors (TKI) mandates reappraisal of local therapy (LT) for brain metastases (BM) of oncogene-driven non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This study included all epidermal growth factor receptor-mutated (EGFR+, n = 108) and anaplastic lymphoma kinase-rearranged (ALK+, n = 33) TKI-naive NSCLC patients diagnosed with BM in the Thoraxklinik Heidelberg between 2009 and 2019. Eighty-seven patients (62%) received early LT, while 54 (38%) received delayed (n = 34; 24%) or no LT (n = 20; 14%). LT comprised stereotactic (SRT; n = 40; 34%) or whole-brain radiotherapy (WBRT; n = 77; 66%), while neurosurgical resection was carried out in 19 cases. RESULTS: Median overall survival (OS) was 49.1 months for ALK+ and 19.5 months for EGFR+ patients (P = 0.001), with similar median intracranial progression-free survival (icPFS) (15.7 versus 14.0 months, respectively; P = 0.80). Despite the larger and more symptomatic BM (P < 0.001) of patients undergoing early LT, these experienced longer icPFS [hazard ratio (HR) 0.52; P = 0.024], but not OS (HR 1.63; P = 0.12), regardless of the radiotherapy technique (SRT versus WBRT) and number of lesions. High-risk oncogene variants, i.e. non-del19 EGFR mutations and 'short' EML4-ALK fusions (mainly variant 3, E6:A20), were associated with earlier intracranial progression (HR 2.97; P = 0.001). The longer icPFS with early LT was also evident in separate analyses of the EGFR+ and ALK+ subsets. CONCLUSIONS: Despite preferential use for cases with poor prognostic factors, early LT prolongs the icPFS, but not OS, in TKI-treated EGFR+/ALK+ NSCLC. Considering the lack of survival benefit, and the neurocognitive effects of WBRT, patients presenting with polytopic BM may benefit from delaying radiotherapy, or from radiosurgery of multiple or selected lesions. For SRT candidates, the improved tumor control with earlier radiotherapy should be weighed against the potential toxicity and the enhanced intracranial activity of newer TKI. High-risk EGFR/ALK variants are associated with earlier intracranial failure and identify patients who could benefit from more aggressive management.

Novel FAP ligands enable improved imaging contrast in sarcoma patients due to FAPI-PET/CT.

PURPOSE: A high expression of fibroblast activation protein (FAP) was observed in multiple sarcomas, indicating an enormous potential for PET/CT using 68Ga-radiolabeled inhibitors of FAP (FAPI). Therefore, this retrospective study aimed to evaluate the role of the novel hybrid imaging probe for sarcomas as a first clinical evaluation. METHODS: A cohort of 15 patients underwent 68Ga-FAPI-PET/CT for staging or restaging. The acquisition of PET scans was performed 60 min after administration of 127 to 308 MBq of the tracer. The uptake of 68Ga-FAPI in malignant tissue as well as in healthy organs was quantified by standardized uptake values SUVmean and SUVmax. RESULTS: Excellent tumor-to-background ratios (> 7) could be achieved due to low background activity and high SUVmax in primary tumors (median 7.16), local relapses (median 11.47), and metastases (median 6.29). The highest uptake was found for liposarcomas and high-grade disease (range 18.86-33.61). A high SUVmax (> 10) was observed for clinically more aggressive disease. CONCLUSION: These preliminary findings suggest a high potential for the clinical use of 68Ga-FAPI-PET/CT for patients diagnosed with sarcoma.

Individual 3D-printed fixation masks for radiotherapy: first clinical experiences.

PURPOSE: To show the feasibility of 3D-printed fixation masks for whole brain radiation therapy in a clinical setting and perform a first comparison to an established thermoplastic mask system. METHODS: Six patients were irradiated with whole brain radiotherapy using individually 3D-printed masks. Daily image guidance and position correction were performed prior to each irradiation fraction. The vectors of the daily position correction were compared to two collectives of patients, who were irradiated using the standard thermoplastic mask system (one cohort with head masks; one cohort with head and neck masks). RESULTS: The mean systematic errors in the experimental cohort ranged between 0.59 and 2.10 mm which is in a comparable range to the control groups (0.18 mm-0.68 mm and 0.34 mm-2.96 mm, respectively). The 3D-printed masks seem to be an alternative to the established thermoplastic mask systems. Nevertheless, further investigation will need to be performed. CONCLUSION: The prevailing study showed a reliable and reproducible interfractional positioning accuracy using individually 3D-printed masks for whole brain irradiation in a clinical routine. Further investigations, especially concerning smaller target volumes or other areas of the body, need to be performed before using the system on a larger basis.

Neoadjuvant irradiation of retroperitoneal soft tissue sarcoma with ions (Retro-Ion): study protocol for a randomized phase II pilot trial.

BACKGROUND: Following surgery for soft tissue sarcoma of the retroperitoneum, the predominant pattern of failure is local recurrence, which remains the main cause of death. Radiotherapy is utilized to reduce recurrence rates but the efficacy of this strategy has not been definitely established. As treatment tolerability is more favorable with preoperative radiotherapy, normofractionated neoadjuvant treatment is the current approach. The final results of the prospective, randomized STRASS (EORTC 62092) trial, which compared the efficacy of this combined treatment to that of surgery alone, are still awaited; preliminary results presented at the 2019 ASCO Annual Meeting indicated that combined treatment is associated with better local control in patients with liposarcoma (74.5% of the cohort, 11% benefit in abdominal progression free survival after 3 years, p = 0.049). Particles allow better sparing of surrounding tissues at risk, e.g., bowel epithelium, and carbon ions additionally offer biologic advantages and are preferred in slow growing tumors. Furthermore, hypofractionation allows for a significantly shorter treatment interval with a lower risk of progression during radiotherapy. METHODS AND DESIGN: We present a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the retroperitoneum will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5-6 fractions per week] in each arm). The primary objective is the safety and feasibility based on the proportion of grade 3-5 toxicity (CTCAE, version 5.0) in the first 12 months after surgery or discontinuation of treatment for any reason related to the treatment. Local control, local progression-free survival, disease-free survival, overall survival, and quality of life are the secondary endpoints of the study. DISCUSSION: The aim of this study is to confirm that hypofractionated, accelerated preoperative radiotherapy is safe and feasible. The rationale for the use of particle therapy is the potential for reduced toxicity. The data will lay the groundwork for a randomized phase III trial comparing hypofractionated proton and carbon ion irradiation with regard to local control. TRIAL REGISTRATION: ClinicalTrials.gov NCT04219202 . Retrospectively registered on January 6, 2020.

Simultaneous integrated boost concepts in definitive radiation therapy for esophageal cancer: outcomes and toxicity.

BACKGROUND: Radiation therapy and chemoradiation therapy play a major role in the definitive management of esophageal cancer. Survival in esophageal cancer patients is still relatively poor, mostly due to high rates of local recurrence and distant metastases. It is hypothesized that dose escalation in radiotherapy could improve outcomes. Therefore, this retrospective analysis aimed to investigate the outcomes and toxicity in patients treated with local dose escalation by means of using simultaneous integrated boost concepts. METHODS: Between 2012 and 2018, 101 patients with esophageal carcinoma were analyzed in this monocentric, retrospective study. All patients received definitive chemoradiation or radiation therapy alone as intensity modulated radiotherapy. The prescribed dose was 50.4 Gy in 28 fractions to the primary tumor and the elective lymph nodes as well as a simultaneous integrated boost (SIB) with 58.8 Gy to macroscopic tumor and lymph node metastases. Endpoints were overall survival (OS), progression free survival (PFS), local control rate (LCR) and toxicity. RESULTS: 60 patients (59.4%) received chemoradiation, 41 patients (40.6%) radiotherapy alone. The median follow up was 17 months (range 0-75 months). OS, PFS and LCR were at 63.9%, 53.9% and 59.9% after 1 year and 37.6%, 34.5% and 36.1%, respectively after 3 years. 16 patients (15.8%) in total developed a locoregional recurrence within the field of radiation. In 48 patients (47.5%) at least one grade III° (CTCAE) toxicity was documented during radiotherapy, mostly dysphagia (36 pat., 75%). One patient suffered from a grade IV° pneumonia. CONCLUSION: This retrospective analysis demonstrates that a SIB concept in definitive (chemo)radiation therapy is safe and feasible, showing acceptable outcomes in this patient cohort. Considering that this cohort mainly consists of elderly patients not eligible for chemotherapy in many cases, we emphasize the aspect of SIB radiation therapy as potential partial compensation for omitted simultaneous chemotherapy. Prospective studies are needed for validation.

[Magnetic-resonance-guided radiotherapy : The beginning of a new era in radiation oncology?] / Magnetresonanzgeführte Strahlentherapie : Beginn einer neuen Ära in der Radioonkologie?

CLINICAL ISSUE: Image-guided radiotherapy (IGRT) using X­rays and cone-beam computed tomography (CT) has fostered precision radiotherapy. However, inter- and intrafractional variations of target volume position and organs at risk still limit target volume dose and sparing of radiosensitive organs at risk. METHODOLOGICAL INNOVATIONS: Hybrid machines directly combining linear accelerators and magnetic resonance (MR) imaging allow for live imaging during radiotherapy. PERFORMANCE: Besides highly improved soft tissue contrast, MR-linacs enable online, on-table adaptive radiotherapy. Thus, adaptation of the treatment plan to the anatomy of the day, dose escalation and superior sparing of organs at risk become possible. ACHIEVEMENTS: This article summarizes the underlying intention for the development of MR-guided radiotherapy, technical innovations and challenges as well as the current state-of-the-art. Potential clinical benefits and future developments are discussed. PRACTICAL RECOMMENDATIONS: Increasing availability of MR imaging at linear accelerators calls for the ability to review and interpret MR images. Therefore, close collaborations of diagnostic radiologists and radiation oncologists are mandatory to foster this fascinating technique.