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BackgroundSalvage radiation therapy (sRT) is often the sole curative option in patients with biochemical recurrence after radical prostatectomy. After sRT, we developed and validated a nomogram to predict freedom from biochemical failure. ObjectiveThis study aims to evaluate prostate-specific membrane antigen–positron emission tomography (PSMA-PET)–based sRT efficacy for postprostatectomy prostate-specific antigen (PSA) persistence or recurrence. Objectives include developing a random survival forest (RSF) model for predicting biochemical failure, comparing it with a Cox model, and assessing predictive accuracy over time. Multinational cohort data will validate the model’s performance, aiming to improve clinical management of recurrent prostate cancer. MethodsThis multicenter retrospective study collected data from 13 medical facilities across 5 countries: Germany, Cyprus, Australia, Italy, and Switzerland. A total of 1029 patients who underwent sRT following PSMA-PET–based assessment for PSA persistence or recurrence were included. Patients were treated between July 2013 and June 2020, with clinical decisions guided by PSMA-PET results and contemporary standards. The primary end point was freedom from biochemical failure, defined as 2 consecutive PSA rises >0.2 ng/mL after treatment. Data were divided into training (708 patients), testing (271 patients), and external validation (50 patients) sets for machine learning algorithm development and validation. RSF models were used, with 1000 trees per model, optimizing predictive performance using the Harrell concordance index and Brier score. Statistical analysis used R Statistical Software (R Foundation for Statistical Computing), and ethical approval was obtained from participating institutions. ResultsBaseline characteristics of 1029 patients undergoing sRT PSMA-PET–based assessment were analyzed. The median age at sRT was 70 (IQR 64-74) years. PSMA-PET scans revealed local recurrences in 43.9% (430/979) and nodal recurrences in 27.2% (266/979) of patients. Treatment included dose-escalated sRT to pelvic lymphatics in 35.6% (349/979) of cases. The external outlier validation set showed distinct features, including higher rates of positive lymph nodes (47/50, 94% vs 266/979, 27.2% in the learning cohort) and lower delivered sRT doses (

Background: The European Society for Radiotherapy & Oncology (ESTRO) Advisory Committee for Radiation Oncology Practice (ACROP) panel on prostate bed delineation reflected on macroscopic local recurrences in patients referred for postoperative radiotherapy (PORT), a challenging situation without standardized approach, and decided to propose a consensus recommendation on target volume selection and definition. Methods: An ESTRO ACROP contouring consensus panel consisting of 12 radiation oncologists and one radiologist, all with subspecialty expertise in prostate cancer, was established. Participants were asked to delineate the prostate bed clinical target volumes (CTVs) in two separate clinically relevant scenarios: a local recurrence at the seminal vesicle bed and one apically at the level of the anastomosis. Both recurrences were prostate-specific membrane antigen (PSMA)-avid and had an anatomical correlate on magnetic resonance imaging (MRI). Participants also answered case-specific questionnaires addressing detailed recommendations on target delineation. Discussions via electronic mails and videoconferences for final editing and consensus were performed. Results: Contouring of the two cases confirmed considerable variation among the panelists. Finally, however, a consensus recommendation could be agreed upon. Firstly, it was proposed to always delineate the entire prostate bed as clinical target volume and not the local recurrence alone. The panel judged the risk of further microscopic disease outside of the visible recurrence too high to safely exclude the rest of the prostate bed from the CTV. A focused, “stereotactic” approach should be reserved for re-irradiation after previous PORT. Secondly, the option of a focal boost on the recurrence was discussed. Conclusion: Radiation oncologists are increasingly confronted with macroscopic local recurrences visible on imaging in patients referred for postoperative radiotherapy. It was recommended to always delineate and irradiate the entire prostate bed, and not the local recurrence alone, whatever the exact location of that recurrence. Secondly, specific dose-escalation on the macroscopic recurrence should only be considered if an anatomic correlate is visible. Such a focal boost is probably feasible, provided that OAR constraints are prioritized. Possible dose is also dependent on the location of the recurrence. Its potential benefit should urgently be investigated in prospective clinical trials.

Background: Previous studies with the majority of breast cancer (BC) patients treated up to 2000 provided evidence that radiation dose to the heart from radiotherapy (RT) was linearly associated with increasing risk for long-term cardiac disease. RT techniques changed substantially over time. This study aimed to investigate the dose-dependent cardiac risk in German BC patients treated with more contemporary RT. Methods: In a cohort of 11,982 BC patients diagnosed in 1998–2008, we identified 494 women treated with 3D-conformal RT who subsequently developed a cardiac event. Within a nested case-control approach, these cases were matched to 988 controls. Controls were patients without a cardiac event after RT until the index date of the corresponding case. Separate multivariable conditional logistic regression models were used to assess the association of radiation to the complete heart and to the left anterior heart wall (LAHW) with cardiac events. Results: Mean dose to the heart for cases with left-sided BC was 4.27 Gy and 1.64 Gy for cases with right-sided BC. For controls, corresponding values were 4.31 Gy and 1.66 Gy, respectively. The odds ratio (OR) per 1 Gy increase in dose to the complete heart was 0.99 (95% confidence interval (CI): 0.94–1.05, P = .72). The OR per 1 Gy increase in LAHW dose was 1.00 (95% CI: 0.98–1.01, P = .68). Conclusions: Contrary to previous studies, our study provided no evidence that radiation dose to the heart from 3D-conformal RT for BC patients treated between 1998 and 2008 was associated with risk of cardiac events.

Purpose/Objective: Radiotherapy to the prostate bed is a potentially curative salvage option after radical prostatectomy. Although prostate bed contouring guidelines are available in the literature, important variabilities exist. The objective of this work is to provide a contemporary consensus guideline for prostate bed delineation for postoperative radiotherapy. Methods: An ESTRO-ACROP contouring consensus panel consisting of 11 radiation oncologists and one radiologist, all with known subspecialty expertise in prostate cancer, was established. Participants were asked to delineate the prostate bed clinical target volumes (CTVs) in 3 separate clinically relevant scenarios: adjuvant radiation, salvage radiation with PSA progression, and salvage radiation with persistently elevated PSA. These cases focused on the presence of positive surgical margin, extracapsular extension, and seminal vesicles involvement. None of the cases had radiographic evidence of local recurrence on imaging. A single computed tomography (CT) dataset was shared via FALCON platform and contours were performed using EduCaseTM software. Contours were analyzed qualitatively using heatmaps which provided a visual assessment of controversial regions and quantitatively analyzed using Sorensen-Dice similarity coefficients. Participants also answered case-specific questionnaires addressing detailed recommendations on target delineation. Discussions via electronic mails and videoconferences for final editing and consensus were performed. Results: The mean CTV for the adjuvant case was 76 cc (SD = 26.6), salvage radiation with PSA progression was 51.80 cc (SD = 22.7), and salvage radiation with persistently elevated PSA 57.63 cc (SD = 25.2). Compared to the median, the mean Sorensen-Dice similarity coefficient for the adjuvant case was 0.60 (SD 0.10), salvage radiation with PSA progression was 0.58 (SD = 0.12), and salvage radiation with persistently elevated PSA 0.60 (SD = 0.11). A heatmap for each clinical scenario was generated. The group agreed to proceed with a uniform recommendation for all cases, independent of the radiotherapy timing. Several controversial areas of the prostate bed CTV were identified based on both heatmaps and questionnaires. This formed the basis for discussions via videoconferences where the panel achieved consensus on the prostate bed CTV to be used as a novel guideline for postoperative prostate cancer radiotherapy. Conclusion: Variability was observed in a group formed by experienced genitourinary radiation oncologists and a radiologist. A single contemporary ESTRO-ACROP consensus guideline was developed to address areas of dissonance and improve consistency in prostate bed delineation, independent of the indication.There is important variability in existing contouring guidelines for postoperative prostate bed (PB) radiotherapy (RT) after radical prostatectomy. This work aimed at providing a contemporary consensus guideline for PB delineation. An ESTRO ACROP consensus panel including radiation oncologists and a radiologist, all with known subspecialty expertise in prostate cancer, delineated the PB CTV in 3 scenarios: adjuvant RT, salvage RT with PSA progression, and salvage RT with persistently elevated PSA. None of the cases had evidence of local recurrence. Contours were analysed qualitatively using heatmaps for visual assessment of controversial regions and quantitatively using Sorensen-Dice coefficient. Case-specific questionnaires were also discussed via e-mails and videoconferences for consensus. Several controversial areas of the PB CTV were identified based on both heatmaps and questionnaires. This formed the basis for discussions via videoconferences. Finally, a contemporary ESTRO-ACROP consensus guideline was developed to address areas of dissonance and improve consistency in PB delineation, independent of the indication.

Introduction68Ga-PSMA PET/CT is associated with unprecedented sensitivity for localization of biochemically recurrent prostate cancer at low PSA levels prior to radiotherapy. Aim of the present analysis is to examine whether patients undergoing postoperative, salvage radiotherapy (sRT) of the prostatic fossa with no known nodal or distant metastases on conventional imaging (CT and/or MRI) and on positron emission tomography/computed tomography (68Ga-PSMA PET/CT) will have an improved biochemical recurrence-free survival (BRFS) compared to patients with no known nodal or distant metastases on conventional imaging only.Material and MethodsThis retrospective analysis is based on 459 patients (95 with and 364 without 68Ga-PSMA PET/CT). BRFS (PSA < post-sRT Nadir + 0.2 ng/ml) was the primary study endpoint. This was first analysed by Kaplan-Meier and uni- and multivariate Cox regression analysis for the entire cohort and then again after matched-pair analysis using tumor stage, Gleason score, PSA at time of sRT and radiation dose as matching parameters.ResultsMedian follow-up was 77.5 months for patients without and 33 months for patients with 68Ga-PSMA PET/CT. For the entire cohort, tumor stage (pT2 vs. pT3-4; p=

For a patient suffering from non-metastatic prostate cancer, the individualized recommendation of radiotherapy has to be the fruit of a multidisciplinary approach in the context of a Tumor Board, to be explained carefully to the patient to obtain his informed consent. External beam radiotherapy is now delivered by intensity modulated radiotherapy, considered as the gold standard. From a radiotherapy perspective, low-risk localized prostate cancer is treated by image guided intensity modulated radiotherapy, or brachytherapy if patients meet the required eligibility criteria. Intermediate-risk patients may benefit from intensity modulated radiotherapy combined with 4–6 months of androgen deprivation therapy; intensity modulated radiotherapy alone or combined with brachytherapy can be offered to patients unsuitable for androgen deprivation therapy due to co-morbidities or unwilling to accept it to preserve their sexual health. High-risk prostate cancer, i.e. high-risk localized and locally advanced prostate cancer, requires intensity modulated radiotherapy with long-term (≥2 years) androgen deprivation therapy with luteinizing hormone releasing hormone agonists. Post-operative irradiation, either immediate or early deferred, is proposed to patients classified as pT3pN0, based on surgical margins, prostate-specific antigen values and quality of life. Whatever the techniques and their degree of sophistication, quality assurance plays a major role in the management of radiotherapy, requiring the involvement of physicians, physicists, dosimetrists, radiation technologists and computer scientists. The patients must be informed about the potential morbidity of radiotherapy and androgen deprivation therapy and followed regularly during and after treatment for tertiary prevention and evaluation. A close cooperation is needed with general practitioners and specialists to prevent and mitigate side effects and maintain quality of life. Keywords: Localized prostate cancer, Locally advanced prostate cancer, Brachytherapy, Intensity modulated radiotherapy, Short-term and long-term androgen deprivation therapy

Background and PurposeSalvage radiotherapy (SRT) is the main potentially curative treatment option for prostate cancer patients with post-prostatectomy PSA progression. Improved diagnostics by positron emission tomography/computed tomography (PET/CT) can lead to adjustments in treatment procedures (e.g. target volume of radiotherapy, androgen deprivation therapy). We analyzed the impact of 68Ga-PSMA-11-PET/CT on the target volume in early biochemical recurrence (PSA up to 0.5 ng/ml).Patients and MethodsWe retrospectively analyzed 76 patients with biochemical recurrence after radical prostatectomy in whom SRT was planned after 68Ga-PSMA-11-PET/CT. All patients had a PSA ≤0.5 ng/ml. An experienced radiation oncologist determined the radiotherapy concept, first with consideration of the PET/CT, second hypothetically based on the clinical and pathological features excluding PET/CT results.ResultsWithout considering the PET/CT, all 76 patients would have been assigned to RT, 60 (79%) to the bed of the prostate and seminal vesicles alone, and 16 (21%) also to the pelvic lymph nodes because of histopathologic risk factors. Uptake indicative for tumor recurrence in 68Ga-PSMA-11-PET/CT was found in 54% of the patients. The median pre-PET/CT PSA level was 0.245 ng/ml (range 0.07–0.5 ng/ml). The results of the PET/CT led to a change in the radiotherapeutic target volume in 21 patients (28%). There were major changes in the target volume including the additional irradiation of lymph nodes or the additional or exclusive irradiation of bone metastases in 13 patients (17%). Minor changes including the additional irradiation of original seminal vesicle (base) position resulted in eight patients (11%).ConclusionUsing 68Ga-PSMA-11-PET/CT for radiation planning, a change in the treatment concept was indicated in 28% of patients. With PET/CT, the actual extent of the tumor can be precisely determined even with PSA values of ≤0.5 ng/ml. Thus, the treatment concept can be improved and individualized. This may have a positive impact on progression free survival. Our results warrant further prospective studies.

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.

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer of the elderly, with high metastatic potential and poor prognosis. In particular, the primary resistance to immune checkpoint inhibitors (ICI) in metastatic (m)MCC patients represents a challenge not yet met by any efficient treatment modality. Herein, we describe a novel therapeutic concept with short-interval, low-dose 177Lutetium (Lu)-high affinity (HA)-DOTATATE [177Lu]Lu-HA-DOTATATE peptide receptor radionuclide therapy (SILD-PRRT) in combination with PD-1 ICI to induce remission in patients with ICI-resistant mMCC. We report on the initial refractory response of two immunocompromised mMCC patients to the PD-L1 inhibitor avelumab. After confirming the expression of somatostatin receptors (SSTR) on tumor cells by [68Ga]Ga-HA-DOTATATE-PET/CT (PET/CT), we employed low-dose PRRT (up to six treatments, mean activity 3.5 GBq per cycle) at 3–6 weeks intervals in combination with the PD-1 inhibitor pembrolizumab to restore responsiveness to ICI. This combination enabled the synergistic application of PD-1 checkpoint immunotherapy with low-dose PRRT at more frequent intervals, and was very well tolerated by both patients. PET/CTs demonstrated remarkable responses at all metastatic sites (lymph nodes, distant skin, and bones), which were maintained for 3.6 and 4.8 months, respectively. Both patients eventually succumbed with progressive disease after 7.7 and 8 months, respectively, from the start of treatment with SILD-PRRT and pembrolizumab. We demonstrate that SILD-PRRT in combination with pembrolizumab is safe and well-tolerated, even in elderly, immunocompromised mMCC patients. The restoration of clinical responses in ICI-refractory patients as proposed here could potentially be used not only for patients with mMCC, but many other cancer types currently treated with PD-1/PD-L1 inhibitors.

Abstract. The MabThera and Involved field Radiotherapy study investigated efficacy and safety of involved field (IF) radiotherapy in combination with the anti-CD20 antibody Rituximab for early-stage follicular lymphoma (FL) in a prospective, single-arm multicenter phase 2 design. Eighty-five stage I–II FL patients received 8 cycles of Rituximab (375 mg/m2) and IF irradiation (30/40 Gy). The primary endpoint was progression-free survival (PFS) 2 years from treatment start. Secondary endpoints were overall survival (OS), complete response rates, toxicity, quality of life, and minimal residual disease (MRD) response with protocol defined visits up to month 30. For the primary endpoint, PFS at 2 years was 85% for the intention-to-treat set. Long-term data were captured in selected sites and evaluated as post hoc analysis in the per protocol (PP) set: PFS and OS were 78% and 96% at 5 years with a median follow-up of 66 or 78 months, respectively. There were 17/76 recurrences in the PP set, of which 14 were outside the radiation volume only. MRD analyses revealed a clonal marker in 36% of patients at diagnosis. All but 1 marker positive patients experienced a molecular treatment response. There were 13 serious adverse events (4 related to the therapy) during the first 30 months. IF radiotherapy combined with Rituximab is well tolerated and highly efficient with low rates of recurrence in the first years in early-stage FL. The efficacy is comparable with more aggressive therapy approaches without compromising the quality of life and maintains for an extended follow-up of more than 5 years.

Two major mechanisms have been proposed to drive the solar eruptions: the ideal magnetohydrodynamic instability and the resistive magnetic reconnection. Due to the close coupling and synchronicity of the two mechanisms, it is difficult to identify their respective contribution to solar eruptions, especially to the critical rapid acceleration phase. Here, to shed light on this problem, we conduct a data-driven numerical simulation for the flux rope eruption on 2011 August 4, and quantify the contributions of the upward exhaust of the magnetic reconnection along the flaring current sheet and the work done by the large-scale Lorentz force acting on the flux rope. Major simulation results of the eruption, such as the macroscopic morphology, early kinematics of the flux rope and flare ribbons, match well with the observations. We estimate the energy converted from the magnetic slingshot above the current sheet and the large-scale Lorentz force exerting on the flux rope during the rapid acceleration phase, and find that (1) the work done by the large-scale Lorentz force is about 4.6 times higher than the former, and (2) decreased strapping force generated by the overlying field facilitates the eruption. These results indicate that the large-scale Lorentz force plays a dominant role in the rapid acceleration phase for this eruption.

Background:  The role of surgical lymph node dissection and adjuvant radiation therapy (RT) in early stage endometrial cancer is no longer clearly defined. The increased appreciation of lymphadenectomy and the absence of survival advantage from adjuvant RT rise controversies how patients should adequately be treated in stage IB endometrial cancer. The aim of this review is to rule out the validity of either treatment option and determine which preference provides the best therapeutic benefit. Methods:  Reports of relevant studies obtained from a search of PubMed and studies referenced in those reports were reviewed. Results:  Based on the available data in the literature, for stage IB grade 1 or 2, the risk of pelvic relapse is considered too low to justify pelvic RT. However, intravaginal RT (IVRT) should be recommended for those ≥ 60 years old or with lymphovascular invasion (LVI). For patients with stage IB grade 3 (and IC all grades), the treatment recommendation is mainly based on whether surgical lymph node staging was performed. These patients have – without surgical lymph node staging – a high risk of pelvic recurrence and should therefore primarily undergo relaparotomy for lymphadenectomy or pelvic RT as second choice. If these patients had a surgical lymph node staging, then IVRT alone is a reasonable alternative to pelvic RT. Conclusion:  Overall survival may not be the only ideal endpoint for stage IB endometrial cancer since causes of death are mostly other than endometrial cancer. Conventional pelvic RT may be overtreatment in some patients, in particular in those patients with a large number of negative lymph nodes after lymphadenectomy. However, negative surgical staging should not be understood as adjuvant RT can be omitted in all patients. [ABSTRACT FROM AUTHOR]

Background and Purpose: In June 1998, proton-beam therapy of ocular tumors started at the Hahn-Meitner Institute Berlin, Germany. The purpose of the present study is to evaluate treatment outcome for uveal melanomas. Patients and Methods: 245 consecutive patients with primary melanoma of the uvea were treated from June 1998 to April 2003 with a 68-MeV proton beam. In 96.2% of all patients, a uniform fractionation scheme was applied: single dose 15 CGE (cobalt gray equivalent), total dose 60 CGE on 4 consecutive days. Follow-up is available in 229 patients. Results: At the time of median follow-up (18.4 months), local control is 96.4% and 95.5% at 3 years. Eye retention rate is 92.6% at 20 months (median follow-up) and 87.5% at 3 years. Conclusion: Proton-beam irradiation of uveal melanomas at the Hahn-Meitner Institute after the first 5 years of its initiation reveals local tumor control and eye retention rates in the range of other centers with larger experience. Delivering high treatment quality in hadron therapy from the beginning has been achieved. [ABSTRACT FROM AUTHOR]

Background and Purpose: Recommendations for radiation ports in adjuvant radiation therapy for rectal cancer are mainly based on analysis of recurrence patterns. To evaluate whether changes in surgical technique have influenced this pattern of recurrence, a multicenter retrospective analysis was carried out on a patient population treated recently. Patients and Methods: 123 patients were evaluated with the help of a CT-based self-developed 3-D data file system and an extensive questionnaire. Major inclusion criteria (one sufficient) for eligibility were: histological confirmation, clear bone destruction, and a positive PET scan, or at least three minor criteria: progressive soft tissue mass, invasion of adjacent organs on follow-up CT or MRI, rising tumor markers, and typical appearance in cross-sectional imaging. Clinical or serologic signs of inflammation were exclusion criteria. Results: Initially, 54% of the evaluated patients were N0; in the remainder, N1 and N2 were distributed evenly. Initial T-category was T1 in 2%, T2 in 24%, T3 in 60%, and T4 in 13%, the male-to-female ratio was 2 : 1. Recurrent tumors were mainly situated in the posterior part of the bony pelvis as displayed in the figures. When abdominoperineal resection was compared to low anterior resection as primary operation, there was a significant difference in extension of recurrent tumors in the inferior parts of the pelvis (p < 0.025 in all statistical tests applied), whereas no significant difference was found in the superior parts of the pelvis. Conclusion: Based on these results, a modest field size reduction in adjuvant radiotherapy for rectal cancer seems feasible, offering the perspective of a reduction in acute and late side effects. [ABSTRACT FROM AUTHOR]

The structure and dynamics of the solar corona is dominated by the magnetic field. In most areas in the corona magnetic forces are so dominant that all non-magnetic forces like plasma pressure gradient and gravity can be neglected in the lowest order. This model assumption is called the force-free field assumption, as the Lorentz force vanishes. This can be obtained by either vanishing electric currents (leading to potential fields) or the currents are co-aligned with the magnetic field lines. First we discuss a mathematically simpler approach that the magnetic field and currents are proportional with one global constant, the so-called linear force-free field approximation. In the generic case, however, the relation between magnetic fields and electric currents is nonlinear and analytic solutions have been only found for special cases, like 1D or 2D configurations. For constructing realistic nonlinear force-free coronal magnetic field models in 3D, sophisticated numerical computations are required and boundary conditions must be obtained from measurements of the magnetic field vector in the solar photosphere. This approach is currently of large interests, as accurate measurements of the photospheric field become available from ground-based (for example SOLIS) and space-born (for example Hinode and SDO) instruments. If we can obtain accurate force-free coronal magnetic field models we can calculate the free magnetic energy in the corona, a quantity which is important for the prediction of flares and coronal mass ejections. Knowledge of the 3D structure of magnetic field lines also help us to interpret other coronal observations, e.g., EUV images of the radiating coronal plasma.