First-site-metastasis pattern in patients with inoperable stage III NSCLC treated with concurrent chemoradiotherapy with or without immune check-point inhibition: a retrospective analysis.

PURPOSE: The aim of this study was to investigate a first-site-metastasis pattern (FSMP) in unresectable stage III NSCLC after concurrent chemoradiotherapy (cCRT) with or without immune checkpoint inhibition (ICI). METHODS: We defined three patient subgroups according to the year of initial multimodal treatment: A (2011-2014), B (2015-2017) and C (2018-2020). Different treatment-related parameters were analyzed. Observed outcome parameters were brain metastasis-free survival (BMFS), extracranial distant metastasis-free survival (ecDMFS) and distant metastasis-free survival (DMFS). RESULTS: 136 patients treated between 2011 and 2020 were included with ≥ 60.0 Gy total dose and concurrent chemotherapy (cCRT); thirty-six (26%) received ICI. Median follow-up was 49.7 (range:0.7-126.1), median OS 31.2 (95% CI:16.4-30.3) months (23.4 for non-ICI vs not reached for ICI patients, p = 0.001). Median BMFS/ecDMFS/DMFS in subgroups A, B and C was 14.9/16.3/14.7 months, 20.6/12.9/12.7 months and not reached (NR)/NR/36.4 months (p = 0.004/0.001/0.016). For cCRT+ICI median BMFS was 53.1 vs. 19.1 months for cCRT alone (p = 0.005). Median ecDMFS achieved 55.2 vs. 17.9 (p = 0.003) and median DMFS 29.5 (95% CI: 1.4-57.6) vs 14.93 (95% CI:10.8-19.0) months (p = 0.031), respectively. Multivariate analysis showed that age over 65 (HR:1.629; p = 0.036), GTV ≥ 78 cc (HR: 2.100; p = 0.002) and V20 ≥ 30 (HR: 2.400; p = 0.002) were negative prognosticators for BMFS and GTV ≥ 78 cc for ecDMFS (HR: 1.739; p = 0.027). After onset of brain metastasis (BM), patients survived 13.3 (95% CI: 6.4-20.2) months and 8.6 months (95% CI: 1.6-15.5) after extracranial-distant-metastasis (ecDM). Patients with ecDM as FSMP reached significantly worse overall survival of 22.1 (range:14.4-29.8) vs. 40.1 (range:18.7-61.3) months (p = 0.034) in the rest of cohort. In contrast, BM as FSMP had no impact on OS. CONCLUSION: This retrospective analysis of inoperable stage III NSCLC patients revealed that age over 65, V20 ≥ 30 and GTV ≥ 78 cc were prognosticators for BMFS and GTV ≥ 78 cc for ecDMFS. ICI treatment led to a significant improvement of BMFS, ecDMFS and DMFS. ecDM as FSMP was associated with significant deterioration of OS, whereas BM as FSMP was not.

Deep Learning and Registration-Based Mapping for Analyzing the Distribution of Nodal Metastases in Head and Neck Cancer Cohorts: Informing Optimal Radiotherapy Target Volume Design.

We introduce a deep-learning- and a registration-based method for automatically analyzing the spatial distribution of nodal metastases (LNs) in head and neck (H/N) cancer cohorts to inform radiotherapy (RT) target volume design. The two methods are evaluated in a cohort of 193 H/N patients/planning CTs with a total of 449 LNs. In the deep learning method, a previously developed nnU-Net 3D/2D ensemble model is used to autosegment 20 H/N levels, with each LN subsequently being algorithmically assigned to the closest-level autosegmentation. In the nonrigid-registration-based mapping method, LNs are mapped into a calculated template CT representing the cohort-average patient anatomy, and kernel density estimation is employed to estimate the underlying average 3D-LN probability distribution allowing for analysis and visualization without prespecified level definitions. Multireader assessment by three radio-oncologists with majority voting was used to evaluate the deep learning method and obtain the ground-truth distribution. For the mapping technique, the proportion of LNs predicted by the 3D probability distribution for each level was calculated and compared to the deep learning and ground-truth distributions. As determined by a multireader review with majority voting, the deep learning method correctly categorized all 449 LNs to their respective levels. Level 2 showed the highest LN involvement (59.0%). The level involvement predicted by the mapping technique was consistent with the ground-truth distribution (p for difference 0.915). Application of the proposed methods to multicenter cohorts with selected H/N tumor subtypes for informing optimal RT target volume design is promising.

Deep learning for automatic head and neck lymph node level delineation provides expert-level accuracy.

Background: Deep learning-based head and neck lymph node level (HN_LNL) autodelineation is of high relevance to radiotherapy research and clinical treatment planning but still underinvestigated in academic literature. In particular, there is no publicly available open-source solution for large-scale autosegmentation of HN_LNL in the research setting. Methods: An expert-delineated cohort of 35 planning CTs was used for training of an nnU-net 3D-fullres/2D-ensemble model for autosegmentation of 20 different HN_LNL. A second cohort acquired at the same institution later in time served as the test set (n = 20). In a completely blinded evaluation, 3 clinical experts rated the quality of deep learning autosegmentations in a head-to-head comparison with expert-created contours. For a subgroup of 10 cases, intraobserver variability was compared to the average deep learning autosegmentation accuracy on the original and recontoured set of expert segmentations. A postprocessing step to adjust craniocaudal boundaries of level autosegmentations to the CT slice plane was introduced and the effect of autocontour consistency with CT slice plane orientation on geometric accuracy and expert rating was investigated. Results: Blinded expert ratings for deep learning segmentations and expert-created contours were not significantly different. Deep learning segmentations with slice plane adjustment were rated numerically higher (mean, 81.0 vs. 79.6, p = 0.185) and deep learning segmentations without slice plane adjustment were rated numerically lower (77.2 vs. 79.6, p = 0.167) than manually drawn contours. In a head-to-head comparison, deep learning segmentations with CT slice plane adjustment were rated significantly better than deep learning contours without slice plane adjustment (81.0 vs. 77.2, p = 0.004). Geometric accuracy of deep learning segmentations was not different from intraobserver variability (mean Dice per level, 0.76 vs. 0.77, p = 0.307). Clinical significance of contour consistency with CT slice plane orientation was not represented by geometric accuracy metrics (volumetric Dice, 0.78 vs. 0.78, p = 0.703). Conclusions: We show that a nnU-net 3D-fullres/2D-ensemble model can be used for highly accurate autodelineation of HN_LNL using only a limited training dataset that is ideally suited for large-scale standardized autodelineation of HN_LNL in the research setting. Geometric accuracy metrics are only an imperfect surrogate for blinded expert rating.

Transient Enlargement in Meningiomas Treated with Stereotactic Radiotherapy.

To investigate the occurrence of pseudoprogression/transient enlargement in meningiomas after stereotactic radiotherapy (RT) and to evaluate recently proposed volumetric RANO meningioma criteria for response assessment in the context of RT. Sixty-nine meningiomas (benign: 90%, atypical: 10%) received stereotactic RT from January 2005-May 2018. A total of 468 MRI studies were segmented longitudinally during a median follow-up of 42.3 months. Best response and local control were evaluated according to recently proposed volumetric RANO criteria. Transient enlargement was defined as volumetric increase ≥20% followed by a subsequent regression ≥20%. The mean best volumetric response was -23% change from baseline (range, -86% to +19%). According to RANO, the best volumetric response was SD in 81% (56/69), MR in 13% (9/69) and PR in 6% (4/69). Transient enlargement occurred in only 6% (4/69) post RT but would have represented 60% (3/5) of cases with progressive disease if not accounted for. Transient enlargement was characterized by a mean maximum volumetric increase of +181% (range, +24% to +389 %) with all cases occurring in the first year post-RT (range, 4.1-10.3 months). Transient enlargement was significantly more frequent with SRS or hypofractionation than with conventional fractionation (25% vs. 2%, p = 0.015). Five-year volumetric control was 97.8% if transient enlargement was recognized but 92.9% if not accounted for. Transient enlargement/pseudoprogression in the first year following SRS and hypofractionated RT represents an important differential diagnosis, especially because of the high volumetric control achieved with stereotactic RT. Meningioma enlargement during subsequent post-RT follow-up and after conventional fractionation should raise suspicion for tumor progression.

Shift of radiotherapy use during the first wave of the COVID-19 pandemic? An analysis of German inpatient data.

OBJECTIVE: To assess the change in inpatient radiotherapy related to COVID-19 lockdown measures during the first wave of the pandemic in 2020. METHODS: We included cases hospitalized between January 1 and August 31, 2018-2020, with a primary ICD-10 diagnosis of C00-C13, C32 (head and neck cancer, HNC) and C53 (cervical cancer, CC). Data collection was conducted within the Medical Informatics Initiative. Outcomes were fractions and admissions. Controlling for decreasing hospital admissions during holidays, calendar weeks of 2018/2019 were aligned to Easter 2020. A lockdown period (LP; 16/03/2020-02/08/2020) and a return-to-normal period (RNP; 04/05/2020-02/08/2020) were defined. The study sample comprised a control (admission 2018/19) and study cohort (admission 2020). We computed weekly incidence and IR ratios from generalized linear mixed models. RESULTS: We included 9365 (CC: 2040, HNC: 7325) inpatient hospital admissions from 14 German university hospitals. For CC, fractions decreased by 19.97% in 2020 compared to 2018/19 in the LP. In the RNP the reduction was 28.57% (p < 0.001 for both periods). LP fractions for HNC increased by 10.38% (RNP: 9.27%; p < 0.001 for both periods). Admissions for CC decreased in both periods (LP: 10.2%, RNP: 22.14%), whereas for HNC, admissions increased (LP: 2.25%, RNP: 1.96%) in 2020. Within LP, for CC, radiotherapy admissions without brachytherapy were reduced by 23.92%, whereas surgery-related admissions increased by 20.48%. For HNC, admissions with radiotherapy increased by 13.84%, while surgery-related admissions decreased by 11.28% in the same period. CONCLUSION: Related to the COVID-19 lockdown in an inpatient setting, radiotherapy for HNC treatment became a more frequently applied modality, while admissions of CC cases decreased.

Implementation of a dedicated 1.5 T MR scanner for radiotherapy treatment planning featuring a novel high-channel coil setup for brain imaging in treatment position.

PURPOSE: To share our experiences in implementing a dedicated magnetic resonance (MR) scanner for radiotherapy (RT) treatment planning using a novel coil setup for brain imaging in treatment position as well as to present developed core protocols with sequences specifically tuned for brain and prostate RT treatment planning. MATERIALS AND METHODS: Our novel setup consists of two large 18-channel flexible coils and a specifically designed wooden mask holder mounted on a flat tabletop overlay, which allows patients to be measured in treatment position with mask immobilization. The signal-to-noise ratio (SNR) of this setup was compared to the vendor-provided flexible coil RT setup and the standard setup for diagnostic radiology. The occurrence of motion artifacts was quantified. To develop magnetic resonance imaging (MRI) protocols, we formulated site- and disease-specific clinical objectives. RESULTS: Our novel setup showed mean SNR of 163 ± 28 anteriorly, 104 ± 23 centrally, and 78 ± 14 posteriorly compared to 84 ± 8 and 102 ± 22 anteriorly, 68 ± 6 and 95 ± 20 centrally, and 56 ± 7 and 119 ± 23 posteriorly for the vendor-provided and diagnostic setup, respectively. All differences were significant (p > 0.05). Image quality of our novel setup was judged suitable for contouring by expert-based assessment. Motion artifacts were found in 8/60 patients in the diagnostic setup, whereas none were found for patients in the RT setup. Site-specific core protocols were designed to minimize distortions while optimizing tissue contrast and 3D resolution according to indication-specific objectives. CONCLUSION: We present a novel setup for high-quality imaging in treatment position that allows use of several immobilization systems enabling MR-only workflows, which could reduce unnecessary dose and registration inaccuracies.

The Distribution of Pelvic Nodal Metastases in Prostate Cancer Reveals Potential to Advance and Personalize Pelvic Radiotherapy.

BACKGROUND: Traditional clinical target volume (CTV) definition for pelvic radiotherapy in prostate cancer consists of large volumes being treated with homogeneous doses without fully utilizing information on the probability of microscopic involvement to guide target volume design and prescription dose distribution. METHODS: We analyzed patterns of nodal involvement in 75 patients that received RT for pelvic and paraaortic lymph node metastases (LNs) from prostate cancer in regard to the new NRG-CTV recommendation. Non-rigid registration-based LN mapping and weighted three-dimensional kernel density estimation were used to visualize the average probability distribution for nodal metastases. As independent approach, the mean relative proportion of LNs observed for each level was determined manually and NRG and non-NRG levels were evaluated for frequency of involvement. Computer-automated distance measurements were used to compare LN distances in individual patients to the spatial proximity of nodal metastases at a cohort level. RESULTS: 34.7% of patients had pelvic LNs outside NRG-consensus, of which perirectal was most common (25.3% of all patients) followed by left common iliac nodes near the left psoas major (6.7%). A substantial portion of patients (13.3%) had nodes at the posterior edge of the NRG obturator level. Observer-independent mapping consistently visualized high-probability hotspots outside NRG-consensus in the perirectal and left common iliac regions. Affected nodes in individual patients occurred in highly significantly closer proximity than at cohort-level (mean distance, 6.6 cm vs. 8.7 cm, p < 0.001). CONCLUSIONS: Based on this analysis, the common iliac level should extend to the left psoas major and obturator levels should extend posteriorly 5 mm beyond the obturator internus. Incomplete coverage by the NRG-consensus was mostly because of perirectal involvement. We introduce three-dimensional kernel density estimation after non-rigid registration-based mapping for the analysis of recurrence data in radiotherapy. This technique provides an estimate of the underlying probability distribution of nodal involvement and may help in addressing institution- or subgroup-specific differences. Nodal metastases in individual patients occurred in highly significantly closer proximity than at a cohort-level, which supports that personalized target volumes could be reduced in size compared to a "one-size-fits-all" approach and is an important basis for further investigation into individualized field designs.