PURPOSE:To investigate spatial associations between cardiac radiation dose and survival following radiotherapy for oesophageal cancer, and to assess whether a previously defined Cardiac Avoidance Area (CAA) from lung radiotherapy is relevant in this patient population. MATERIALS AND METHODS:Patients treated with curative-intent radiotherapy for middle or lower oesophageal cancer between 2009 and 2024 were identified from a large institutional database. Planning CT images and dose distributions were deformably registered to a common reference anatomy for voxel-based analysis. Dose-survival associations were assessed voxel-wise by comparing dose between patients alive and deceased at 12 months, with permutation testing for multiple comparisons. Dose to the CAA was quantified, and survival was evaluated using Kaplan-Meier analysis and multivariable Cox regression including clinical covariates. RESULTS:A total of 452 patients were included. Voxel-based analysis identified a spatially localised heart region where higher radiation dose was significantly associated with poorer 12-month survival, exceeding the 99th percentile of permutation-derived significance. This region partially overlapped with the lung-derived CAA and the left atrium. A maximum CAA dose threshold of 43.5 Gy produced significant survival stratification, with improved median survival in patients receiving lower doses. Maximum CAA dose remained an independent predictor of survival on multivariable analysis. CONCLUSION:Image-based data mining identified a radiosensitive cardiac region associated with survival after oesophageal radiotherapy, overlapping the established CAA from lung cancer. These findings support the relevance of spatially defined cardiac dose metrics and suggest a potential role for targeted cardiac avoidance in oesophageal radiotherapy planning.
BACKGROUND AND PURPOSE:Delineating the clinical target volume (CTV) is an essential part of a radiation oncologist's practice. However, this process is subject to variability due to factors such as clinical experience, institutional standards, and contouring guidelines being followed. We propose a parameterized CTV delineation model for glioma tumors that can tailor to CTV delineation practices. The model is validated based on its ability to replicate different physician-delineated CTVs within our institution. MATERIAL AND METHODS:Five delineation parameters define the model-based CTV for glioma: CTV margin expansion, reduction of CTV margins in the brainstem and optic structures for reduced likelihood of tumor infiltration or preferential sparing, and increase of CTV margins at the ventricles and falx cerebri to account for positional uncertainties. Parameters are fitted by matching the model CTV to the manually-delineated CTVs for patients, maximizing the Dice score. The model is developed using 93 retrospectively collected glioma cases treated by three physicians in our institution. The parameter values for different physicians provide CTV delineation starting points, which was tested by training a classification model using fitted CTV parameters. RESULTS:Physician quality assessments showed no statistically significant difference in quality ratings between model-generated and physician-delineated CTVs (p > 0.05), with both groups achieving an average quality rating of 2.3 (0: unusable, 1: major edits, 2: minor edits, 3: acceptable). The distribution of the fitted delineation parameters varied systematically across physicians, especially in the CTV contours near the brainstem and ventricles. The best-performing classification model identified physician-specific CTV delineation starting points with 80% accuracy and Cohen's Kappa score of 0.68. CONCLUSION:Our parametric CTV delineation system effectively captures and quantifies physician contouring practices. The model can be used in a contour quality assurance program to promote consensus-building and CTV standardization across physician practices.
OBJECTIVES:To describe metastatic characteristics and outcomes in patients with de novo metastatic (cM1) head and neck squamous cell carcinoma (HNSCC). METHODS:cM1 HNSCC patients diagnosed between 2001 and 2024 were reviewed. Metastatic characteristics and management patterns were collected, including the timing of locoregional radiotherapy (LR-RT) relative to first-line systemic therapy. Overall survival (OS) was estimated using the Kaplan-Meier method, and multivariable Cox regression analyses (MVA) identified prognostic factors. RESULTS:Among 10,273 newly diagnosed HNSCC cases, 222 (2.2%) had cM1 disease (HPV-associated: 48/2593 [1.9%]; HPV-independent: 174/7680 [2.3%]). cM1 characteristics were similar between HPV-associated and HPV-independent disease, including oligometastatic presentation (1-5 lesions; 31% vs 43%, p = 0.21) and frequency of lung-only metastases (83% vs 77%, p = 0.46), although mediastinal involvement was more common in HPV-associated disease (40% vs 23%, p = 0.034). LR-RT was delivered to 191 (86%) patients: 127 (57%) as sole treatment, 55 (25%) before, and 9 (4%) after first-line systemic therapy. After median follow-up of 25 months, median OS was 7 months (6.0-8.8). On MVA, LR-RT (HR 0.49 [0.32-0.75]), HPV-associated disease (HR 0.62 [0.43-0.88]), ECOG 0-1 (HR 0.63 [0.47-0.86]), first-line immunotherapy (HR 0.52 [0.33-0.82]), and lung-only metastases (HR 0.67 [0.48-0.95]) were associated with longer OS. Among patients receiving LR-RT, a radiation dose ≥ 50 Gy was associated with improved OS (HR 0.53 [0.34-0.83]). CONCLUSIONS:cM1 HNSCC has a poor prognosis, highlighting a substantial unmet need. First-line immunotherapy and LR-RT, particularly with ≥ 50 Gy, were associated with improved OS and warrant prospective evaluation.
Progression-free survival treats biologically and clinically distinct progression events equivalently, limiting its interpretability in oligometastatic radiotherapy trials. Across 21 randomized trials, event-level reporting was frequently absent, and none described how post-radiotherapy imaging was adjudicated within PFS. Pragmatic reporting standards could improve interpretation without requiring new endpoints or altered trial design.
PURPOSE:To evaluate the survival benefit of adding pelvic radiotherapy (RT) to chemotherapy and to identify patient subgroups most likely to benefit from pelvic RT. MATERIALS AND METHODS:A multicentre retrospective study was conducted in Japan and included patients with newly diagnosed stage IVB (FIGO 2018) cervical cancer treated with chemotherapy alone or chemotherapy plus pelvic RT between 2016 and 2020. Patients were classified into the CT group (chemotherapy-alone) or PRT group (chemotherapy plus pelvic RT). Propensity score matching (PSM) was applied using age, histology, T stage, N stage, metastatic pattern, and number of metastatic lesions. Overall survival (OS) represented the primary endpoint; progression-free survival (PFS) and late adverse events constituted the secondary endpoints. RESULTS:Among 343 patients, the PRT group showed significantly longer OS than the CT group following PSM (median OS: 25.0 vs. 18.0 months; hazard ratio [HR], 0.58; 95% confidence intervals [CI], 0.42-0.79; p < 0.001). PFS was also significantly improved in the PRT group (HR, 0.65; 95% CI, 0.48-0.87; p = 0.002). The longer OS in the PRT group was seen across metastatic patterns, although this was less evident in early T stages (≤ T2). Brachytherapy was independently associated with improved OS in the PRT group. Grade ≥ 3 gastrointestinal toxicity was more frequent in the PRT group. CONCLUSION:In this nationwide, real-world study, definitive-dose pelvic RT combined with chemotherapy was associated with improved survival in selected patients with stage IVB cervical cancer. Prospective randomised trials are warranted to validate these findings.
PURPOSE:Translating FLASH radiotherapy into clinical practice is limited by technological challenges in achieving highly conformal dose delivery. A hybrid approach, combining ultra-high dose rate (UHDR) and conventional dose rate (CDR) irradiation, could potentially improve dose conformity, but biological validation is required. This study presents the first investigation into the biological response to hybrid UHDR/CDR regimens, evaluating normal tissue sparing in murine models and assessing its dependence on the UHDR dose. METHODS AND MATERIALS:Two murine models were utilized: BALB/c mice evaluated for radiation dermatitis following localized hindlimb irradiation, and C57BL/6 mice evaluated for gastrointestinal (GI) toxicity following whole-abdomen irradiation. The hybrid irradiation protocol consisted of an initial UHDR boost (10 or 20 Gy for skin; 10 or 14 Gy for abdomen), a one-minute beam-off interval, and escalating CDR doses. Irradiation was delivered using prototype electron FLASH irradiators. Normal tissue complication probability (NTCP) curves were generated to determine the median toxic dose (TD50) and dose modifying factors (DMF), comparing hybrid treatments against reference split-dose regimens delivered entirely at CDR. RESULTS:Hybrid irradiation effectively preserved the normal tissue sparing characteristic of the FLASH effect, though the magnitude of protection was highly dependent on the proportion of the UHDR boost. In the skin model, the 20 Gy UHDR boost yielded a DMF of 1.26, which decreased to 1.14 when the boost was reduced to 10 Gy. For GI toxicity, the 14 Gy UHDR boost demonstrated a tissue-sparing effect with a DMF of 1.09. However, reducing the UHDR boost to 10 Gy in the abdominal model resulted in complete overlap with the CDR reference curve, eliminating the sparing effect (DMF = 1.00). CONCLUSIONS:The FLASH normal tissue sparing effect is partially maintained when UHDR radiation is combined with CDR radiation in a hybrid protocol, with the degree of sparing relying heavily on the overall UHDR dose contribution. While these biological findings support hybrid UHDR/CDR regimens as a promising approach for the clinical implementation of FLASH-RT, the achievable dose conformity has yet to be practically validated.
PURPOSE:The efficacy and safety of TPF-induced chemotherapy(IC) combined with concurrent chemoradiotherapy(CCRT) compared to CCRT and sequential PF-adjuvant chemotherapy(AC) lack phase III randomized controlled clinical trials for evaluation, so the comparative efficacy and safety between the two approaches remain unclear. METHODS AND MATERIALS:This randomized clinical phase III trial recruited patients from May 2018 to July 2021,at 4 institutions in China(NCT03574324), 266 patients were enrolled and randomly assigned to either the IC or AC groups. The IC group received TPF followed by CCRT, while the AC group received CCRT followed by PF. We are reporting on the primary outcome of progression-free survival (PFS) and secondary endpoints of overall survival(OS), locoregional relapse-free survival(LRFS), distant metastasis-free survival(DMFS), and toxicity profile. RESULTS:The 3-year PFS was similar between the two groups, with 79 % for the IC group and 74.5 % for the AC group (P = 0.454) at a median follow-up of 39 months. Similar findings were observed, with no significant disparities in OS, LRFS, and DMFS between the two treatment cohorts. Both groups had similar compliance rates for radiotherapy and chemotherapy. However, the IC group experienced fewer grade toxic effects during CCRT, such as nausea/vomiting, swallowing, and dryness (101[77.10 %] vs. 114[89.06 %] patients,40 [30.53 %]vs56 [43.75 %] patients and 58 [44.27 %]vs86 [67.19 %] patients, respectively). However,3-4 grade leukopenia and neutrophilia patients were increased(58 [44.27 %]vs28 [21.88 %] patients and 78 [59.54 %]vs24 [18.75 %]) in the IC group. CONCLUSIONS:In this randomized clinical trial, IC did not improve 3-year PFS for LA-NPC patients and increased hematological toxicity. Still, the advantage of it is that it did reduce the incidence rates of nausea/vomiting, swallowing, and dry mouth during radiotherapy.
This review provides a succinct up-to-date discussion of required and achievable accuracy in MV photon beam and particle therapy, focusing on technology and techniques reflecting today's general clinical practice for radical radiotherapy. The major advances in recent decades have enabled a new degree of geometric and dosimetric precision to be achieved. These are related to dosimetry standards, imaging for treatment planning, dose calculation algorithms and approaches, fluence-modulated techniques facilitating conformality optimisation, image guidance (IG), IG-enabled adaptive and motion management methods and volume-based dose prescription concepts. In addition, evolving quality assurance methodologies have contributed substantially to improve the dosimetric accuracy. Consequently, in state-of-the-art radiotherapy the emphasis has shifted from accuracy of reference (prescription) dose delivery to accuracy of spatial dose distribution delivery, with greater focus on geometric uncertainties. The relationship between delivered dose and the resulting biological effect is examined, to consider the clinical impact of radiotherapy accuracy. Developments in required and achievable accuracy for photon beams are discussed, including insights from audits and patient specific quality assurance. Based on the steeper dose-response relations, the dosimetric accuracy requirements are still similar to those in the late 1980's, but the geometric accuracy demands have become significantly more stringent. In optimal conditions, radiotherapy practice can achieve these standards, but this necessitates a continued strong focus on treatment precision and quality. Robust quality assurance programmes, evolving in step with conceptual and methodological radiotherapy developments, remain essential to meet the accuracy requirements. As regards particle therapy, there are some significant uncertainty differences to photon therapy, but the models and clinical data are not yet sufficiently detailed to confidently predict differences in accuracy requirements compared to photon beam therapy.
BACKGROUND AND PURPOSE:Preoperative stereotactic body radiotherapy (SBRT) has emerged as a precision locoregional strategy for early luminal breast cancer, yet no quantitative meta-analysis exists in this subtype. We aimed to estimate the pooled pathological complete response (pCR) rate, identify its predictors through meta-regression, and characterise safety and cosmetic outcomes. MATERIALS AND METHODS:A systematic review and meta-analysis of prospective trials of preoperative SBRT in patients with clinical stage T1-T2 N0-N1 luminal (ER-positive, HER2-negative) breast cancer was conducted following PRISMA 2020 guidelines. Random-effects models with REML estimation were fitted on logit-transformed proportions. Univariable meta-regression analyses examined absorbed dose (BED_4), irradiation-to-surgery interval, fractionation, technique, and biological tumor characteristics as covariates. RESULTS:Eleven prospective studies (428 patients) were included. Eight trials (N = 277) reported pCR data, yielding a pooled pCR rate of 21.4 % (95 % CI: 12.1-35.1 %; I2 = 77.0 %). The irradiation-to-surgery interval was the sole statistically significant predictor of pCR (β = +0.045 per week; p < 0.001; R2 = 98.9 %), whilst BED_4, fractionation, and technique showed no independent association. Pooled late grade ≥ 3 toxicity was 5.9 % (95 % CI: 3.7-9.1 %) and excellent or good cosmesis was achieved in 88.3 % of patients (95 % CI: 79.4-93.6 %). CONCLUSION:Preoperative SBRT achieves a clinically meaningful pCR rate in early luminal breast cancer, with acceptable toxicity and preserved cosmesis. The irradiation-to-surgery interval is the dominant modifiable predictor of pathological response. Randomized trials prospectively optimizing this interval in the luminal subtype are warranted.
PURPOSE:To investigate whether advanced registration methods for dose accumulation lead to meaningful differences in online adaptive radiotherapy (OART) to aid in-treatment dose adaptation (ITDA). In ITDA, fraction dose is adjusted when anatomy is favorable to shorten treatment or increase target dose. METHODS AND MATERIALS:Twenty-five patients with abdominal-pelvic lymph node oligometastases were retrospectively included. 5 x 9 Gy OART was simulated. Gastrointestinal organ (GIO) segments were propagated and doses accumulated using five techniques: DVH summation, rigid registration, image-based and hybrid deformable registration, and Thin Plate Spline Robust Point Matching (TPS-RPM). Metrics included: Dice, Hausdorff distance (HD-99%), mean surface distance (MSD), and accumulated GIO V20Gy3, D0.5cc, and D2.0cc, and respective robustness. The most accurate method was compared to DVH summation for ITDA. RESULTS:Geometric accuracy increased significantly with registration complexity. TPS-RPM achieved the highest accuracy (median Dice 0.98, HD-99% 1.4 mm, MSD 0.25 mm) with lowest variability, and yielded significantly lower accumulated GIO doses compared to DVH summation (D0.5cc 25.5 Gy vs 26.9 Gy and V20Gy3 5.4 cc vs 5.9 cc). Nonetheless, ITDA outcomes were identical or similar between the approaches. Fractions were reduced by 17%. PTV V100% and PTV D95% increased significantly. Only PTV D95% differed. CONCLUSION:Although advanced registration methods improve geometric accuracy and predict lower accumulated GIO doses, differences in fraction reduction or target dose were absent or minimal with ITDA compared to DVH summation. DVH summation therefore remains practical and efficient for this application, avoiding unnecessary complexity without compromising outcomes.
BACKGROUND:Radon, a naturally occurring radioactive noble gas, remains an established component of European balneological medicine in the management of inflammatory diseases. Similarly, X-ray-based radiotherapy, known as low-dose radiation therapy (LDRT), is used. However, the use of both radon therapy and LDRT, remains controversial, even though it was used in some countries to treat patients during the COVID-19 pandemic. This raises the question of the effectiveness of LDRT, especially against inflammatory lung diseases. Previously, we could show in mice that X-ray LDRT has anti-inflammatory and immunosuppressive effects in the management of pneumonia. Our study presented here aimed to assess the effect of radon inhalation on murine pneumonia induced by intratracheal administration of lipopolysaccharide (LPS). METHODS:Mice were treated with either radon or dexamethasone, the latter being the standard of care for inflammatory diseases. RESULTS:Both treatments improved clinical signs, general health condition and lung architecture in mice with LPS-induced pneumonia. Mechanistically, both treatments downregulated inflammatory pathways and promoted those related to tissue repair and integrity. In both treatment groups, the Th1-proinflammatory response was suppressed and a Th2-anti-inflammatory one was promoted. Interestingly, radon inhalation promoted the anti-inflammatory 'alternative' activation profile of lung macrophages. Furthermore, the assessment of the potential of radon to induce oncogene expression and thereby to increase the risk of cancer development following exposure, showed significant downregulation of oncogenes. CONCLUSIONS:In sum, our data provides indications for the effective use of radon in treatment of pneumonia as an alternative for patients who are refractory to dexamethasone treatment or unable to receive corticosteroids due to contraindications.
INTRODUCTION:Regional nodal irradiation (RNI) is associated with breast cancer-related lymphedema (BCRL), yet varying definition of extensive RNI among radiation oncologists leads to the inconsistencies in risk assessment. Recently, the axillary-lateral thoracic junction (ALTJ) has been proposed as a potential organ-of-interest, but its role remains controversial. This study investigates the predictive role of ALTJ dose-volumetric parameters in BCRL development. METHODS AND MATERIALS:We identified patients with breast cancer who underwent surgery and adjuvant radiotherapy (2018 - 2020). BCRL was defined as newly developed upper arm lymphedema after radiotherapy, with International Society of Lymphology stage ≥ 2. Following retrospective ALTJ contouring, multivariable Cox regression and Random Survival Forest models were developed using clinical factors and ALTJ dosimetric parameters. Model performance was evaluated via Harrell's C-index and 24-month landmark analysis. RESULTS:We investigated 722 patients with a median follow-up of 30 months. 283 (39.2%) underwent axillary lymph node dissection (ALND). In multivariate Cox regression, along with ALND, ALTJ V35Gy > 50% was associated with an increased risk BCRL (p = 0.003, HR 3.07), whereas binary RNI status wasn't (p = 0.363). When comparing multivariable prognostic frameworks, Model B (incorporating ALTJ V35Gy) demonstrated a more favorable statistical fit than Model A (incorporating RNI). While Model B yielded a numerically higher C-index (0.753 vs. 0.749), this gain was not statistically significant. CONCLUSIONS:This study highlights the significance of the ALTJ as an organ-of-interest in breast cancer patients who underwent radiotherapy. Incorporating ALTJ dosimetric parameters into predictive models enhances prognostic accuracy, addressing the limitations of variable RNI field definitions.
