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Hybrid MRI linear accelerators (MR-Linac) might enable individualized online adaptation of radiotherapy using quantitative MRI sequences as diffusion-weighted imaging (DWI). The purpose of this study was to investigate the dynamics of lesion apparent diffusion coefficient (ADC) in patients with prostate cancer undergoing MR-guided radiation therapy (MRgRT) on a 1.5T MR-Linac. The ADC values at a diagnostic 3T MRI scanner were used as the reference standard. In this prospective single-center study, patients with biopsy-confirmed prostate cancer who underwent both an MRI exam at a 3T scanner (MRI ) and an exam at a 1.5T MR-Linac (MRL) at baseline and during radiotherapy were included. Lesion ADC values were measured by a radiologist and a radiation oncologist on the slice with the largest lesion. ADC values were compared before . during radiotherapy (during the second week) on both systems via paired t-tests. Furthermore, Pearson correlation coefficient and inter-reader agreement were computed. A total of nine male patients aged 67 ± 6 years [range 60 - 67 years] were included. In seven patients, the cancerous lesion was in the peripheral zone, and in two patients the lesion was in the transition zone. Inter-reader reliability regarding lesion ADC measurement was excellent with an intraclass correlation coefficient of (ICC) > 0.90 both at baseline and during radiotherapy. Thus, the results of the first reader will be reported. In both systems, there was a statistically significant elevation of lesion ADC during radiotherapy (mean MRL-ADC at baseline was 0.97 ± 0.18 × 10 mm /s . mean MRL-ADC during radiotherapy 1.38 ± 0.3 × 10 mm /s, yielding a mean lesion ADC elevation of 0.41 ± 0.20 × 10 mm /s, p < 0.001). Mean MRI -ADC at baseline was 0.78 ± 0.165 × 10 mm /s . mean MRI -ADC during radiotherapy 0.99 ± 0.175 × 10 mm /s, yielding a mean lesion ADC elevation of 0.21 ± 0.96 × 10 mm /s p < 0.001). The absolute ADC values from MRL were consistently significantly higher than those from MRI at baseline and during radiotherapy (p < = 0.001). However, there was a strong positive correlation between MRL-ADC and MRI -ADC at baseline ( = 0.798, p = 0.01) and during radiotherapy ( = 0.863, p = 0.003). Lesion ADC as measured on MRL increased significantly during radiotherapy and ADC measurements of lesions on both systems showed similar dynamics. This indicates that lesion ADC as measured on the MRL may be used as a biomarker for evaluation of treatment response. In contrast, absolute ADC values as calculated by the algorithm of the manufacturer of the MRL showed systematic deviations from values obtained on a diagnostic 3T MRI system. These preliminary findings are promising but need large-scale validation. Once validated, lesion ADC on MRL might be used for real-time assessment of tumor response in patients with prostate cancer undergoing MR-guided radiation therapy.

Cure- and toxicity rates after intensity-modulated radiotherapy (IMRT) of prostate cancer are dose-and volume dependent. We prospectively studied the potential for organ at risk (OAR) sparing and compensation of tumor movement with the coverage probability (CovP) concept. Twenty-eight prostate cancer patients (median age 70) with localized disease (cT1c-2c, N0, M0) and intermediate risk features (prostate-specific antigen [PSA] < 20, Gleason score ≤ 7b) were treated in a prospective study with the CovP concept. Planning-CTs were performed on three subsequent days to capture form changes and movement of prostate and OARs. The clinical target volume (CTV) prostate and the OARs (bladder and rectum) were contoured in each CT. The union of CTV1-3 was encompassed by an isotropic margin of 7 mm to define the internal target volume (ITV). Dose prescription/escalation depended on coverage of all CTVs within the ITV. IMRT was given in 39 fractions to 78 Gy using the Monte-Carlo algorithm. Short-term androgen deprivation was recommended and given in 78.6% of patients. Long-term toxicity was evaluated in 26/28 patients after a median follow-up of 7.1 years. At last follow-up, late bladder toxicity (Radiation Therapy Oncology Group, RTOG) G1 was observed in 14.3% of patients and late rectal toxicities (RTOG) of G1 (7.1%) and of G2 (3.6%) were observed. No higher graded toxicity occurred. After 7.1 years, biochemical control (biochemically no evidence of disease, bNED) was 95.5%, prostate cancer-specific survival and the distant metastasis-free survival after 7.1 years were 100% each. CovP-based IMRT was feasible in a clinical study. Dose escalation with the CovP concept was associated by a low rate of toxicity and a high efficacy regarding local and distant control.

Results of three randomized clinical trials (RCTs) comparing adjuvant radiotherapy (ART) and early salvage radiotherapy (eSRT) of prostate carcinoma and a subsequent meta-analysis of the individual patient data from these RCTs were recently published. The results suggest that early eSRT is as effective and potentially less toxic than ART. Therefore, eSRT should be considered the standard of care. However, due to limitations in the RCTs, ART remains a valid treatment option in patients with the combination of high-risk features such as Gleason Score (GS) 8–10, positive surgical margins (R1) and pathological T-stage 3 or 4 (pT3/4). This article provides a critical appraisal of the RCTs and the rationale for recommendations adopted in the current national guidelines regarding patients with high-risk features after radical prostatectomy (RP): ART should be offered in case of pT3/pT4 and R1 and Gleason Score 8–10; ART can be offered in case of pT3/pT4 and R0 and Gleason Score 8–10 as well as in case of multifocal R1 (including pT2) and Gleason Score 8–10. In any case, the alternative treatment option of eSRT in case of rising PSA should be discussed with the patient.

ZusammenfassungHintergrundDer potenzielle Nutzen des verbesserten Weichteilkontrastes von MR-Sequenzen gegenüber der Computertomographie (CT) für die Radiotherapie des Prostatakarzinoms ist bekannt und führt zu konsistenteren und kleineren Zielvolumina sowie verbesserter Risikoorganschonung. Hybridgeräte aus Magnetresonanztomographie (MRT) und Linearbeschleuniger (MR-Linac) stellen eine neue vielversprechende Erweiterung der radioonkologischen Therapieoptionen dar.Material und MethodenDieser Artikel gibt eine Übersicht über bisherige Erfahrungen, Indikationen, Vorteile und Herausforderungen für die Radiotherapie des primären Prostatakarzinoms mit dem 1,5-T-MR-Linac.ErgebnisseAlle strahlentherapeutischen Therapieindikationen für das primäre Prostatakarzinom können mit dem 1,5-T-MR-Linac abgedeckt werden. Die potenziellen Vorteile umfassen die tägliche MR-basierte Lagekontrolle in Bestrahlungsposition und die Möglichkeit der täglichen Echtzeitanpassung des Bestrahlungsplans an die aktuelle Anatomie der Beckenorgane (adaptive Strahlentherapie). Zusätzlich werden am 1,5-T-MR-Linac funktionelle MRT-Sequenzen für individuelles Response-Assessment für die Therapieanpassung untersucht. Dadurch soll das therapeutische Fenster weiter optimiert werden. Herausforderungen stellen u. a. die technische Komplexität und die Dauer der Behandlungssitzung dar.SchlussfolgerungDer 1,5-T-MR-Linac erweitert das radioonkologische Spektrum in der Therapie des Prostatakarzinoms und bietet Vorteile durch tagesaktuelle MRT-basierte Zielvolumendefinition und Planadaptation. Weitere klinische Untersuchungen sind notwendig, um die Patienten zu identifizieren, die von der Behandlung am MR-Linac gegenüber anderen strahlentherapeutischen Methoden besonders profitieren.

PurposeThe extent of lymphadenectomy and clinical features influence the risk of occult nodes in node-negative prostate cancer. We derived a simple estimation model for the negative predictive value (npv) of histopathologically node-negative prostate cancer patients (pN0) to guide adjuvant treatment.MethodsApproximations of sensitivities in detecting lymph node metastasis from current publications depending on the number of removed lymph nodes were used for a theoretical deduction of a simplified formulation of npv assuming a false node positivity of 0.ResultsA theoretical formula of npv = p(N0IpN0) = (100 − prevalence) / (100 − sensitivity × prevalence) was calculated (sensitivity and preoperative prevalence in %). Depending on the number of removed lymph nodes (nLN), the sensitivity of pN0-staged prostate cancer was derived for three sensitivity levels accordingly: sensitivity = f(nLN) = 9 × nLN /100 for 0 ≤ nLN ≤ 8 and f(nLN) = (nLN + 70) /100 for 9 ≤ nLN ≤ 29 and f(nLN) = 1 for nLN ≥ 30.ConclusionWe developed a theoretical formula for estimation of the npv in pN0-staged prostate cancer patients. It is a sine qua non to use the formula in a clinically experienced context before deciding to electively irradiate pelvic lymph nodes or to intensify adjuvant systemic treatment.

The objective of this study is to conduct a qualitative and a quantitative image quality and lesion evaluation in patients undergoing MR-guided radiation therapy (MRgRT) for prostate cancer on a hybrid magnetic resonance imaging and linear accelerator system (MR-Linac or MRL) at 1.5 Tesla. This prospective study was approved by the institutional review board. A total of 13 consecutive patients with biopsy-confirmed prostate cancer and an indication for MRgRT were included. Prior to radiation therapy, each patient underwent an MR-examination on an MRL and on a standard MRI scanner at 3 Tesla (MRI3T). Three readers (two radiologists and a radiation oncologist) conducted an independent qualitative and quantitative analysis of T2-weighted (T2w) and diffusion-weighted images (DWI). Qualitative outcome measures were as follows: zonal anatomy, capsule demarcation, resolution, visibility of the seminal vesicles, geometric distortion, artifacts, overall image quality, lesion conspicuity, and diagnostic confidence. All ratings were performed on an ordinal 4-point Likert scale. Lesion conspicuity and diagnostic confidence were firstly analyzed only on MRL. Afterwards, these outcome parameters were analyzed in consensus with the MRI3T. Quantitative outcome measures were as follows: anteroposterior and right left diameter of the prostate, lesion size, PI-RADS score (Prostate Imaging—Reporting and Data System) and apparent diffusion coefficient (ADC) of the lesions. Intergroup comparisons were computed using the Wilcoxon-sign rank test and t tests. A post-hoc regression analysis was computed for lesion evaluation. Finally, inter-/intra-reader agreement was analyzed using the Fleiss kappa and intraclass correlation coefficient. For T2w images, the MRL showed good results across all quality criteria (median 3 and 4). Furthermore, there were no significant differences between MRL and MRI3T regarding capsule demarcation or geometric distortion. For the DWI, the MRL performed significantly less than MRI3T across most image quality criteria with a median ranging between 2 and 3. However, there were no significant differences between MRL and MRI3T regarding geometric distortion. In terms of lesion conspicuity and diagnostic confidence, inter-reader agreement was fair for MRL alone (Kappa = 0.42) and good for MRL in consensus with MRI3T (Kappa = 0.708). Thus, lesion conspicuity and diagnostic confidence could be significantly improved when reading MRL images in consensus with MRI3T (Odds ratio: 9- to 11-fold for the T2w images and 5- to 8–fold for the DWI) (p < 0.001). For measures of lesion size, anterior-posterior and right-left prostate diameter, inter-reader and intersequence agreement were excellent (ICC > 0.90) and there were no significant differences between MRL and MRI3T among all three readers. In terms of Prostate Imaging Reporting and Data System (PIRADS) scoring, no significant differences were observed between MRL and MRI3T. Finally, there was a significant positive linear relationship between lesion ADC measurements (r = 0.76, p < 0.01) between the ADC values measured on both systems. In conclusion, image quality for T2w was comparable and diagnostic even without administration of spasmolytic- or contrast agents, while DWI images did not reach diagnostic level and need to be optimized for further exploitation in the setting of MRgRT. Diagnostic confidence and lesion conspicuity were significantly improved by reading MRL in consensus with MRI3T which would be advisable for a safe planning and treatment workflow. Finally, ADC measurements of lesions on both systems were comparable indicating that, lesion ADC as measured on the MRL could be used as a biomarker for evaluation of treatment response, similar to examinations using MRI3T.

Since the beginning of the pandemic in 2020, COVID-19 has changed the medical landscape. International recommendations for localized prostate cancer (PCa) include deferred treatment and adjusted therapeutic routines. To longitudinally evaluate changes in PCa treatment strategies in urological and radiotherapy departments in Germany, a link to a survey was sent to 134 institutions covering two representative baseline weeks prior to the pandemic and 13 weeks from March 2020 to February 2021. The questionnaire captured the numbers of radical prostatectomies, prostate biopsies and case numbers for conventional and hypofractionation radiotherapy. The results were evaluated using descriptive analyses. A total of 35% of the questionnaires were completed. PCa therapy increased by 6% in 2020 compared to 2019. At baseline, a total of 69 radiotherapy series and 164 radical prostatectomies (RPs) were documented. The decrease to 60% during the first wave of COVID-19 particularly affected low-risk PCa. The recovery throughout the summer months was followed by a renewed reduction to 58% at the end of 2020. After a gradual decline to 61% until July 2020, the number of prostate biopsies remained stable (89% to 98%) during the second wave. The use of RP fluctuated after an initial decrease without apparent prioritization of risk groups. Conventional fractionation was used in 66% of patients, followed by moderate hypofractionation (30%) and ultrahypofractionation (4%). One limitation was a potential selection bias of the selected weeks and the low response rate. While the diagnosis and therapy of PCa were affected in both waves of the pandemic, the interim increase between the peaks led to a higher total number of patients in 2020 than in 2019. Recommendations regarding prioritization and fractionation routines were implemented heterogeneously, leaving unexplored potential for future pandemic challenges.

Introduction: Novel MRI-linear accelerator hybrids (MR-Linacs, MRL) promise an optimization of radiotherapy (RT) through daily MRI imaging with enhanced soft tissue contrast and plan adaptation on the anatomy of the day. These features might potentially improve salvage RT of prostate cancer (SRT), where the clinical target volume is confined by the mobile organs at risk (OAR) rectum and bladder. So far, no data exist about the feasibility of the MRL technology for SRT. In this study, we prospectively examined patients treated with SRT on a 1.5 T MRL and report on workflow, feasibility and acute toxicity. Patients and Methods: Sixteen patients were prospectively enrolled within the MRL-01 study (NCT: NCT04172753). All patients were staged and had an indication for SRT after radical prostatectomy according to national guidelines. RT consisted of 66 Gy in 33 fractions or 66.5/70 Gy in 35 fractions in case of a defined high-risk region. On the 1.5 T MRL, daily plan adaption was performed using one of two workflows: adapt to shape (ATS, using contour adaptation and replanning) or adapt to position (ATP, rigid replanning onto the online anatomy with virtual couch shift). Duration of treatment steps, choice of workflow and treatment failure were recorded for each fraction of each patient. Patient-reported questionnaires about patient comfort were evaluated as well as extensive reporting of acute toxicity (patient reported and clinician scored). Results: A total of 524/554 (94.6%) of fractions were successfully treated on the MRL. No patient-sided treatment failures occurred. In total, ATP was chosen in 45.7% and ATS in 54.3% of fractions. In eight cases, ATP was performed on top of the initial ATS workflow. Mean (range) duration of all fractions (on-table time until end of treatment) was 25.1 (17.6–44.8) minutes. Mean duration of the ATP workflow was 20.60 (17.6–25.2) minutes and of the ATS workflow 31.3 (28.2–34.1) minutes. Patient-reported treatment experience questionnaires revealed high rates of tolerability of the treatment procedure. Acute toxicity (RTOG, CTC as well as patient-reported CTC, IPSS and ICIQ) during RT and 3 months after was mild to moderate with a tendency of recovery to baseline levels at 3 months post RT. No G3+ toxicity was scored for any item. Conclusions: In this first report on SRT of prostate cancer patients on a 1.5 T MRL, we could demonstrate the feasibility of both available workflows. Daily MR-guided adaptive SRT of mean 25.1 min per fraction was well tolerated in this pretreated collective, and we report low rates of acute toxicity for this treatment. This study suggests that SRT on a 1.5 T MRL can be performed in clinical routine and it serves as a benchmark for future analyses.

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

Die Strahlentherapie ist einer der Eckpfeiler in der Behandlung von onkologischen Erkrankungen mit der stetigen Herausforderung, die erforderliche Dosis in möglichst kurzer Zeit mit maximaler Präzision auf die gewünschten Strukturen zu applizieren und die Normalgewebe hierbei bestmöglich zu schonen. Aufgrund der Lagevariabilität von Tumoren und häufiger Tumorschrumpfung im Verlauf der Strahlentherapie ist die adaptive Strahlentherapie, bei welcher während einer Bestrahlungsserie der Bestrahlungsplan kontinuierlich angepasst wird, eine vielversprechende Entwicklung. Mittels MR-Linac-Hybridgeräten, die einen Linearbeschleuniger und einen Magnetresonanztomographen in einem Gerät vereinen, ist nun auch eine online adaptive magnetresonanztomographiebasierte Strahlentherapie möglich. Die Magnetresonanztomographie (MRT) bietet aufgrund des höheren Weichteilkontrasts die Möglichkeit einer präziseren Definition der Zielstrukturen und Risikoorgane und erlaubt es häufig, höhere Dosen auch in der Nähe von kritischen Strukturen applizieren zu können. So kann Patienten eine effektive, gutverträgliche und nichtinvasive Therapie angeboten werden. Häufige Indikationen für die Bestrahlung an einem MR-Linac sind die Behandlung von Lymphknotenmetastasen, die Behandlung des Prostatakarzinoms, insbesondere mittels Ultrahypofraktionierung, sowie die hochdosierte Bestrahlung von Lebermetastasen und des hepatozellulären Karzinoms ohne Anlage von röntgendichten Markern („fiducials“). Bei Patienten mit frühen Rektumkarzinomen wird eine MRT-geführte adaptive Dosiseskalation untersucht. Die MRT-Komponente ermöglicht zudem die Visualisierung funktioneller MRT-Parameter, welche z. B. bei neuartigen innovativen Konzepten in der Behandlung von Kopf-Hals-Tumoren eingesetzt werden.