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Introduction The effect of diffusion-weighted magnetic resonance imaging (DWI)-guided dose-painting intensity-modulated radiation therapy (DP-IMRT) on locally advanced recurrent nasopharyngeal carcinoma (NPC) remains unclear. This study aimed to compare the outcomes and toxicities of DWI-guided DP-IMRT in patients with locally recurrent NPC. Methods In this prospective trial, 150 patients with locally advanced recurrent NPC were randomly assigned (1:1) to receive reirradiation with DWI-guided DP-IMRT (DWI group, n  = 75) or conventional MRI-based IMRT (MRI group, n  = 75). In the DWI group, DWI-guided gross tumor volume received escalation to 65.4 Gy/30 fx in 2.18 Gy per fraction, while in the MRI group, the planning target volume was irradiated at 60 Gy/30fx in 2.0 Gy per fraction. The trial was registered at Chictr.org.cn (ChiCTR2100052340) on October 24, 2021. Survival rates were compared, and multivariate analyses were conducted. Results The median follow-up duration was 16 months. Compared with the MRI group, patients in the DWI group had better 18-month progression-free survival (PFS) 75.1% vs. 53.6%; P  = 0.006), local recurrence-free survival (LRFS) (83.4% vs. 61.8%; P  = 0.010), and locoregional recurrence-free survival (73.1% vs. 64.9%; P  = 0.025). Grade 3–4 toxicities between the two groups showed no significant difference. Multivariate analysis revealed that DWI-guided DP-IMRT was an independent prognostic factor for PFS and LRFS. Conclusion Compared with conventional MRI-based IMRT, DWI-guided DP-IMRT improved PFS in patients with recurrent NPC without increasing acute and late toxic effects.

Purpose Glioblastoma is an aggressive malignant cancer of the central nervous system, with disease progression associated with deterioration of neurocognitive function and quality of life (QoL). As such, maintenance of QoL is an important treatment goal. This analysis presents time to deterioration (TtD) of QoL in patients with recurrent glioblastoma receiving Asunercept plus reirradiation (rRT) or rRT alone. Methods Data from patients with a baseline and ≥ 1 post-baseline QoL assessment were included in this analysis. TtD was defined as the time from randomisation to the first deterioration in the EORTC QLQ-C15, PAL EORTC QLQ-BN20 and Medical Research Council (MRC)-Neurological status. Deterioration was defined as a decrease of ≥ 10 points from baseline in the QLQ-C15 PAL overall QoL and functioning scales, an increase of ≥ 10 points from baseline in the QLQ-C15 PAL fatigue scale and the QLQ-BN20 total sum of score, and a rating of “Worse” in the MRC-Neurological status. Patients without a deterioration were censored at the last QoL assessment. Kaplan–Meier estimates were used to describe TtD and treatment groups (Asunercept + rRT or rRT alone) were compared using the log-rank test. Results Treatment with Asunercept + rRT was associated with significant improvement of TtD compared with rRT alone for QLQ-CL15 PAL overall QoL and physical functioning, and MRC Neurological Status (p ≤ 0.05). In the Asunercept + rRT group, QoL was maintained beyond progresison of disease (PoD). Conclusion Treatment with Asunercept plus rRT significantly prolongs TtD and maintains QoL versus rRT alone in recurrent glioblastoma patients.

Purpose Intraprostatic recurrence (IRR) of prostate cancer after radiation therapy is increasingly identified. Our objective was to review the literature to determine the optimal workup for identifying IRR, the management options, and practical considerations for the delivery of re-irradiation as salvage local therapy. Methods We performed a systematic review of available publications and ongoing studies on the topics of IRR, with a focus on salvage re-irradiation. Results Work up of biochemically recurrent prostate cancer includes PSMA PET/CT and multiparametric MRI, followed by biopsy to confirm IRR. Management options include continued surveillance, palliative hormonal therapy, and salvage local therapy. Salvage local therapy can be delivered using re-irradiation with low dose rate brachytherapy, high dose rate (HDR) brachytherapy, and stereotactic body radiotherapy (SBRT), as well as non-radiation modalities, such as cryotherapy, high-intensity focused ultrasound, irreversible electroporation and radical prostatectomy. Data demonstrate that HDR brachytherapy and SBRT have similar efficacy compared to the other salvage local therapy modalities, while having more favorable side effect profiles. Recommendations for radiation therapy planning and delivery using HDR and SBRT based on the available literature are discussed. Conclusion Salvage re-irradiation is safe and effective and should be considered in patients with IRR.

Background Recurrent cervical cancer remains a therapeutic challenge despite advances in primary treatment. The emerging paradigm of oligorecurrence and oligometastasis has opened avenues for curative-intent local therapies, including re-irradiation. Modern radiotherapy techniques have enabled high-dose delivery with acceptable toxicity. This study aims to assess clinical outcomes and treatment-related toxicities in patients with oligorecurrent or oligometastatic cervical cancer treated with modern re-irradiation techniques. Methods This retrospective study included 20 cervical cancer patients with oligorecurrence or synchronous/metachronous oligometastases (≤ 5 lesions) who underwent at least one course of re-irradiation. Survival outcomes including locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis. Genitourinary (GU), gastrointestinal (GI), and hematologic toxicities were assessed and graded based on CTCAE version 5.0. Results The median age was 53 years (range: 33–70), with 75% initially diagnosed at FIGO 2018 stage III. The predominant histologies were squamous cell carcinoma (50%) and adenocarcinoma (45%). Recurrences most commonly involved pelvic (30%) and para-aortic (30%) lymph nodes, with 50% occurring in-field. Stereotactic body radiotherapy (SBRT), volumetric modulated arc therapy (VMAT), and MR-guided adaptive brachytherapy (MR-GABT) were the most commonly used re-irradiation modalities, employed in 95% of patients. Median times to first and second recurrence were 11.1 months (IQR: 6.0–17.3) and 13.7 months (IQR: 5.6–21.7), respectively. At a median follow-up of 33.6 months, PFS, LRRFS, DMFS, and OS rates after the first recurrence were were 31.8%, 33.6%, 60.5%, and 84.2% respectively. Grade ≥ 2 genitourinary (GU), gastrointestinal (GI), and hematologic toxicities were observed in 40%, 25%, and 55% of patients, respectively. Grade 3 hematologic toxiciy was 25% and mostly occurred during chemotherapy administration. No grade ≥ 3 GU or GI toxicities were reported. The mean accumulated D0.03 cc after re-irradiation to bladder, rectum, sigmoid and bowel for in-fied/out-of-field were 83.8 ± 6.7/78.5 ± 7.5), 71.2 ± 3.9/69.5 ± 5.2, 68.0 ± 5.5/61.0 ± 5.3, and 62.9 ± 4.6/62.4 ± 7.1 GyEQD2 (3) , respectively. Conclusion Re-irradiation with contemporary radiotherapy techniques appears to be a feasible and effective salvage option for selected patients with limited recurrent or metastatic cervical cancer, yielding favorable survival and acceptable toxicity profiles.

Reirradiation is a widely accepted option for second-line treatment in patients with recurrent glioma. However, no standard radiation regimen has been defined. Hypofractionation is aimed at reducing patients' burden while maintaining the survival benefit, but may increase the risk of radionecrosis. The primary objective of this study is to determine if reirradiation in just 4 fractions is non-inferior to 10 fractions, regarding survival after reirradiation. RISING trial A was an open label, randomized, non-inferiority, phase III trial with 1:1 allocation for 130 patients among all participating centers but failed to recruit according to planning. RISING trial B will be a phase II, multi-center, clinical trial with a historic control group. The experimental group receives 4 stereotactic fractions. The historic control group has received 10 fractions (standard-of-care) with a biologically equivalent dose on surrounding brain tissue. The primary endpoint is overall survival after reirradiation. The key secondary endpoint is progression-free survival. Other secondary endpoints are recurrence patterns, toxicity (specifically clinically relevant radionecrosis) and anti-edema treatment. We will collect and report on Health-Related Quality of Life (HRQoL) data in the experimental arm. We expect to demonstrate the non-inferiority and safety of a 4-fraction hypofractionation schedule for reirradiation of gliomas. This schedule may then become a standard-of-care option with minimal burden for patients with recurrent glioma, and limited use of scarce healthcare resources. Registered at Netherlands Trial Register (NTR), Trial ID: NL72766.041.20, registered at 07-04-2020, https://www.onderzoekmetmensen.nl/en/trial/52643.

Purpose This study evaluates cumulative dose estimations using deformable image registration (DIR) in robotic stereotactic ablative radiotherapy (SABR)‐based multiple re‐irradiations for liver metastases. It highlights DIR's role and accuracy in adaptive radiotherapy to enhance treatment precision and reduce toxicity. Materials & Methods A retrospective analysis was conducted on 22 patients (age: 42–80, median: 61 years) with liver metastases re‐irradiated using CyberKnife SABR (54 treatments) between June 2016 and February 2024. A comparative analysis of organs‐at‐risk (OAR) volumes was performed using contours derived from DIR and physical summation method to evaluate consistency between the two approaches. Dosimetric analysis involved accumulating doses to organs at risk using physical dose summation and DIR‐based dose summation. To standardize dose assessments, all radiation doses were converted into equivalent doses in 2 Gy fractions (EQD2) and biologically effective doses (BED). The DIR algorithm was quantitatively assessed using similarity indices, including Dice similarity coefficient (DSC) and Jaccard (JD) index. Results The findings demonstrated that organs susceptible to motion, such as the liver and large bowel, exhibited greater variability in volume measurements when evaluated using physical summation. A significant reduction in maximum dose for the liver (p = 0.00) and chest wall (p = 0.05) was observed under DIR‐based dose accumulation (liver‐83.2 ± 28.0 Gy; chest wall‐66.9 ± 18.6 Gy) compared to physical summation (liver‐123.8 ± 55.6 Gy; chest wall‐82.9 ± 22.4 Gy), suggesting overestimation using physical summation. Among the analyzed structures, DIR showed high spatial accuracy for the heart, liver, and external body with Dice scores >  0.90 and Jaccard indices >  0.84, while lower agreement was noted for deformable organs such as the bowel with Dice scores <  0.43 and Jaccard indices <  0.29. Conclusions DIR improved anatomical alignment and provides more anatomically consistent cumulative dose estimation in SABR re‐irradiation, particularly for OARs that are prone to deform. Integrating DIR into adaptive radiotherapy workflows can improve the estimation of dose to OARs while minimizing toxicity risks.

Abstract BACKGROUND Upon progression after upfront radiotherapy to spinal metastases, low-dose re-irradiation conventional external beam radiation (cEBRT) provides limited clinical benefit. Spine stereotactic body radiotherapy (SBRT) allows for dose escalation in the salvage setting with the potential for improved local control. OBJECTIVE To report mature clinical and imaging-based outcomes for salvage SBRT. METHODS A retrospective review was undertaken of consecutive patients with spinal metastases treated with re-irradiation spine SBRT having failed either cEBRT (n = 60 with 1 prior course and n = 17 with 2 or more prior cEBRT courses), or prior SBRT (n = 6) to the same spinal segment. The primary outcome was local failure (LF), and secondary outcomes included overall survival (OS) and the rate of vertebral compression fracture (VCF). RESULTS A total of 43 patients with 83 spinal segments treated with salvage SBRT were reviewed. The crude risk of LF was 18%, and actuarial LF rates at 6, 12, and 24 mo were 7%, 14%, and 19%, respectively. The presence of extensive paraspinal disease (hazard ratio [HR] = 7.1, 95% CI 1.5-34) significantly predicted for LF. The median OS was 13.2 (95% CI 6.1-16.3) mo, and the presence of neurological deficits (HR = 4.7, 95% CI 1.8-12.1) and brain metastases (HR = 2.6, 95% CI 1.1-6.3) were significant prognostic factors. The crude risk of VCF was 4%, and radiation myelopathy was not observed. CONCLUSION These data support the safety and efficacy of spinal re-irradiation with SBRT including patients with prior SBRT and multiple courses of prior cEBRT.

Whole-brain radiotherapy (WBRT) remains a standard treatment for extensive brain metastases, providing symptom relief and improved progression-free survival (PFS). Re-irradiation is often necessary for recurrent disease, particularly in the cerebellum, which accounts for 10–20% of cases. Cerebellar metastases are associated with distinct symptoms and poorer prognoses compared to supratentorial lesions. This study evaluates the outcomes of cerebellar-only re-irradiation for brain metastases, with or without stereotactic radiosurgery (SRS) for supratentorial lesions. A retrospective analysis of 56 patients treated between 2017 and 2023 was conducted. Patients received cerebellar-only re-irradiation after WBRT. Symptom improvement was assessed three months post-treatment. Statistical analyses included t-tests, Mann-Whitney U tests, and multivariable logistic regression. The cohort’s median age was 53 years, with breast cancer being the most prevalent histology (71%). Symptom improvement occurred in 75% of patients, with relief rates of 84.6% for nausea, 80% for headache, and 58.3% for dizziness. Dexamethasone use decreased in 76.3% of cases. Median PFS was 39.2%, with a six-month overall survival of 50%. Only 1.7% of patients developed symptomatic radiation necrosis. Factors associated with symptom improvement included younger age, extended intervals between WBRT and re-irradiation, and higher equivalent dose in 2 Gy fractions (EQD2). Cerebellar-only re-irradiation is an effective, low-toxicity option for recurrent cerebellar metastases. This approach warrants further validation in prospective studies, particularly in comparison to SRS.

Background Treatment for local and locoregional recurrence or second head-and-neck (H&N) cancers after previous radiotherapy is challenging, and re-irradiation carries a significantly increased risk for radiotherapy-related normal tissue toxicities and treatment failure due to a radioresistant tumor phenotype. Here, we analyzed re-irradiation management and outcomes in patients with recurrent or second primary H&N carcinoma using state-of-the-art diagnostic procedures and radiotherapy techniques. Methods Between 2010 and 2019, 48 patients with recurrent or second primary H&N carcinoma received re-radiotherapy at the University of Freiburg Medical Center and were included in this study. Overall survival (OS) and progression-free survival (PFS) were calculated with the Kaplan-Meier method, and univariate Cox-regression analyses were performed to assess the effects of clinico-pathological factors on treatment outcomes. Acute and chronic treatment-related toxicities were quantified using the Common Terminology Criteria for Adverse Events (CTCAE v4.03). Results Thirty-one patients (64.6%) received definitive and 17 (35.4%) adjuvant radiotherapy. Simultaneous chemotherapy was administered in 28 patients (58.3%) with cetuximab as the most commonly used systemic agent ( n  = 17, 60.7%). After a median time of 17 months (range 4 months to 176 months) between first and second radiotherapy, patients were re-irradiated with a median of 58.4 Gy and a treatment completion rate of 87.5% ( n  = 42). Median OS was 25 months with a 1-year OS amounting to 62.4%, and median PFS was 9 months with a 1-year PFS of 37.6%. Univariate analyses demonstrated that both a lower rT-status and a radiotherapy boost were associated with improved OS ( p  < 0.05). There was a trend towards superior OS for patients who received > 50 Gy ( p  = 0.091) and who completed the prescribed radiotherapy ( p  = 0.055). Five patients (10.4%) suffered from at least one grade 3 toxicities, while 9 patients (27.3%) experienced chronic higher-grade toxicities (≥ grade 3) with one (3.0%) grade 4 carotid blowout and one (3.0%) grade 4 osteoradionecrosis. Conclusion Re-irradiation of recurrent or second primary H&N cancer with modern radiation techniques such as intensity-modulated radiotherapy resulted in promising survival rates with acceptable toxicities compared to historical cohorts. Increased re-irradiation doses, utilization of a radiotherapy boost and completion of the re-irradiation treatment were found to result in improved survival.

Recurrent high-grade intracranial malignancies have a grim prognosis and uniform management guidelines are lacking. Re-irradiation is underused due to concerns about irreversible side effects. Pulsed-reduced dose rate radiotherapy (PRDR) aims to reduce toxicity while improving tumor control by exploiting dose-rate effects. We share our initial experience with temporally modulated pulsed proton re-irradiation (TMPPR), focusing on workflow, safety, feasibility, and outcomes for the first patient cohort. TMPPR was administered to patients with recurrent or progressive central nervous system malignancies using intensity modulated proton therapy with three fields. Patient and treatment data were collected, responses categorized using RANO assessment, and toxicities graded using CTCAE v5.0. Five patients received TMPPR between October 2022 and May 2023, with a median age of 54 years (Range: 32–72), and a median time from initial radiotherapy to re-RT of 23 months (Range 14–40). Treatment was completed without delay, with a median dose of 60 GyRBE in 30 fractions. Initial treatment response assessment showed complete (n = 1) or partial (n = 3) responses. Limited toxicity was observed, primarily grade 2 alopecia and one case of radiation necrosis graded at 2. This early experience demonstrates the feasibility of TMPPR delivery, highlighting the importance of prospective evaluations in the re-irradiation setting.