Larger Planning Target Volume Research Articles

GLIOBLASTOMA IN THE UK POST WHO CNS 5: INITIAL fiNDINGS FROM THE HISTO-MOL GBM COLLABORATIVE

Abstract AIMS The 2021 World Health Organisation Classification (WHO CNS5) incorporated molecular diagnostic features for glioblastoma for the first time. The Histo-Mol GBM collaborative is conducting a retrospective cohort study evaluating the outcomes of patients prospectively diagnosed with WHO CNS5 IDH wild type glioblastoma. METHOD Biopsy confirmed glioblastoma patients diagnosed between 01/01-31/12/2021 were identified. Demographic, tumour, treatment, and survival data were collected. Descriptive statistics and Kaplan-Meier method were used to describe the cohort and for survival analysis respectively, assessed from surgery date. RESULTS So far, 363 glioblastoma patients were included from 13 centres (range: 11-61 patients/centre). Median age was 63.0, 65.8% were male, 77.4% had an ECOG performance status of 0-1 at diagnosis, and 28/333 had a molecular glioblastoma (8.4%). Biopsy was performed in 106/363 patients (29.2%), and gross total resection in 50/363 (13.8%). Adjuvant radiotherapy was performed in 290/363 (79.9%), and 71/290 (24.5%) had an additional pre-radiotherapy MRI with rapid early progression identified in 30/71 patients (42.3%). 128/269 (47.6%) patients received 2nd line treatment; most commonly systemic therapy (91/128, 71.1%) followed by re-resection (27/128, 21.1%). Second line systemic therapy was primarily lomustine (48/81, 52.7%). Median progression free survival was 7.7 months and median overall survival (OS) was 11.6 months. Median OS was 16.9 months with conventional fractionation chemoradiotherapy (n=169/363, 46.6%), 10.4 months with hypofractionated chemoradiotherapy (n=64/363, 17.6%), and 2.3 months with no oncological treatment (n=57/363, 15.7%). On univariate analysis age, gender, performance status, multifocality, MGMT promoter methylation, surgery extent, radiotherapy type (none, palliative, hypofractionated, conventional fractionation), larger planning target volume (PTV), receiving concurrent temozolomide, and receiving adjuvant temozolomide were statistically significant. On multivariate analysis age, and receiving concurrent temozolomide remained significant. CONCLUSION We describe the initial findings from a large real-world cohort of glioblastoma patients prospectively diagnosed according to WHO CNS5. Survival compares favourably with the practice changing phase 3 clinical trial outcomes.

Deep learning-based optimization of field geometry for total marrow irradiation delivered with volumetric modulated arc therapy.

Total marrow (lymphoid) irradiation (TMI/TMLI) is a radiotherapy treatment used to selectively target the bone marrow and lymph nodes in conditioning regimens for allogeneic hematopoietic stem cell transplantation. A complex field geometry is needed to cover the large planning target volume (PTV) of TMI/TMLI with volumetric modulated arc therapy (VMAT). Five isocenters and ten overlapping fields are needed for the upper body, while, for patients with large anatomical conformation, two specific isocenters are placed on the arms. The creation of a field geometry is clinically challenging and is performed by a medical physicist (MP) specialized in TMI/TMLI. To develop convolutional neural networks (CNNs) for automatically generating the field geometry of TMI/TMLI. The dataset comprised 117 patients treated with TMI/TMLI between 2011 and 2023 at our Institute. The CNN input image consisted of three channels, obtained by projecting along the sagittal plane: (1) average CT pixel intensity within the PTV; (2) PTV mask; (3) brain, lungs, liver, bowel, and bladder masks. This "averaged" frontal view combined the information analyzed by the MP when setting the field geometry in the treatment planning system (TPS). Two CNNs were trained to predict the isocenters coordinates and jaws apertures for patients with (CNN-1) and without (CNN-2) isocenters on the arms. Local optimization methods were used to refine the models output based on the anatomy of the patient. Model evaluation was performed on a test set of 15 patients in two ways: (1) by computing the root mean squared error (RMSE) between the CNN output and ground truth; (2) with a qualitative assessment of manual and generated field geometries-scale: 1=not adequate, 4=adequate-carried out in blind mode by three MPs with different expertise in TMI/TMLI. The Wilcoxon signed-rank test was used to evaluate the independence of the given scores between manual and generated configurations (p<0.05 significant). The average and standard deviation values of RMSE for CNN-1 and CNN-2 before/after local optimization were 15±2/13±3mm and 16±2/18±4mm, respectively. The CNNs were integrated into a planning automation software for TMI/TMLI such that the MPs could analyze in detail the proposed field geometries directly in the TPS. The selection of the CNN model to create the field geometry was based on the PTV width to approximate the decision process of an experienced MP and provide a single option of field configuration. We found no significant differences between the manual and generated field geometries for any MP, with median values of 4versus 4 (p=0.92), 3versus 3 (p=0.78), 4versus 3 (p=0.48), respectively. Starting from October 2023, the generated field geometry has been introduced in our clinical practice for prospective patients. The generated field geometries were clinically acceptable and adequate, even for an MP with high level of expertise in TMI/TMLI. Incorporating the knowledge of the MPs into the development cycle was crucial for optimizing the models, especially in this scenario with limited data.

Prognostic significance of alterations in fibrinogen level and fibrinogen-to-lymphocyte ratio after radiotherapy on survival outcomes in glioblastoma.

Fibrinogen (FIB) plays an important role in tumor initiation, progression, and metastasis, but its clinical significance in glioblastoma has not been studied. We intend to explore the prognostic value by retrospectively analyzing the changes in FIB and fibrinogen-to-lymphocyte ratio (FLR) in glioblastoma patients before and after radiotherapy, and study the impact of radiotherapy on them. This study retrospectively included 104 patients who were newly diagnosed with glioblastoma between February 2017 and February 2022 and analysed their clinical data from before to after radiotherapy. The cut-off values for FLR and FIB were calculated using a receiver operating characteristic curve. For inter-group comparisons, the Mann-Whitney U or t-test was applied. The prognostic importance of FIB and FLR was evaluated using the Kaplan-Meier curve and the Cox regression model. Spearman correlation coefficients were calculated to evaluate the association of FIB and FLR with radiotherapy-related dose-volume parameters. The mean progression-free survival (PFS) and overall survival (OS) of the high FIB and high FLR groups were significantly lower than those of the low FIB and low FLR groups (P<0.05). Larger planning target volume (PTV), mean brain dose, and mean brainstem dose were independent prognostic factors for poor PFS and OS in patients with glioblastoma. FLR was a unique and very accurate predictor for the prognosis of glioblastoma, and FIB rise after radiation was a predictive sign of poor survival. Both PTV volume and dose volume for involved organs could significantly affect the FIB and FLR values in patients with glioblastoma.

Stereotactic body radiotherapy with volumetric intensity-modulated arc therapy and flattening filter-free beams: dosimetric considerations.

The present study comparatively evaluates the impact of energy-matched flattening filter-free (FFF) photon beams with different energy levels on the physical-dosimetric quality of lung and liver stereotactic body radiotherapy (SBRT) treatment plans. For this purpose, 54different lung and liver lesions from 44patients who had already received SBRT combined with volumetric modulated arc therapy (VMAT) were included in this retrospective planning study. Planning computed tomography scans already available were used for the renewed planning with 6MV, 6MV-FFF, 10MV, and 10MV-FFF under constant planning objectives. The treatment delivery data, dosimetric distributions, and dose-volume histograms as well as parameters such as the conformity index and gradient indices were the basis for the evaluation and comparison of treatment plans. Asignificant reduction of beam-on time (BOT) was achieved due to the high dose rates of FFF beams. In addition, we showed that for FFF beams compared to flattened beams of the same energy level, smaller planning target volumes (PTV) require fewer monitor units (MU) than larger PTVs. An equal to slightly superior target volume coverage and sparing of healthy tissue as well as organs at risk in both lung and liver lesions were found. Significant differences were seen mainly in the medium to lower dose range. We found that FFF beams together with VMAT represent an excellent combination for SBRT of lung or liver lesions with shortest BOT for 10MV-FFF but significant dose savings for 6MV-FFF in lung lesions.

Histopathologically confirmed radiation-induced damage of the brain – an in-depth analysis of radiation parameters and spatio-temporal occurrence

BackgroundRadiation-induced damage (RID) after radiotherapy (RT) of primary brain tumors and metastases can be challenging to clinico-radiographically distinguish from tumor progression. RID includes pseudoprogression and radiation necrosis; the latter being irreversible and often associated with severe symptoms. While histopathology constitutes the diagnostic gold standard, biopsy-controlled clinical studies investigating RID remain limited. Whether certain brain areas are potentially more vulnerable to RID remains an area of active investigation. Here, we analyze histopathologically confirmed cases of RID in relation to the temporal and spatial dose distribution.MethodsHistopathologically confirmed cases of RID after photon-based RT for primary or secondary central nervous system malignancies were included. Demographic, clinical, and dosimetric data were collected from patient records and treatment planning systems. We calculated the equivalent dose in 2 Gy fractions (EQD22) and the biologically effective dose (BED2) for normal brain tissue (α/β ratio of 2 Gy) and analyzed the spatial and temporal distribution using frequency maps.ResultsThirty-three patients were identified. High-grade glioma patients (n = 18) mostly received one normofractionated RT series (median cumulative EQD22 60 Gy) to a large planning target volume (PTV) (median 203.9 ccm) before diagnosis of RID. Despite the low EQD22 and BED2, three patients with an accelerated hyperfractionated RT developed RID. In contrast, brain metastases patients (n = 15; 16 RID lesions) were often treated with two or more RT courses and with radiosurgery or fractionated stereotactic RT, resulting in a higher cumulative EQD22 (median 162.4 Gy), to a small PTV (median 6.7 ccm). All (n = 34) RID lesions occurred within the PTV of at least one of the preceding RT courses. RID in the high-grade glioma group showed a frontotemporal distribution pattern, whereas, in metastatic patients, RID was observed throughout the brain with highest density in the parietal lobe. The cumulative EQD22 was significantly lower in RID lesions that involved the subventricular zone (SVZ) than in lesions without SVZ involvement (median 60 Gy vs. 141 Gy, p = 0.01).ConclusionsAccelerated hyperfractionated RT can lead to RID despite computationally low EQD22 and BED2 in high-grade glioma patients. The anatomical location of RID corresponded to the general tumor distribution of gliomas and metastases. The SVZ might be a particularly vulnerable area.

A feasibility study of adaptive radiation therapy for postprostatectomy prostate cancer

Postoperative prostate radiotherapy requires large planning target volume (PTV) margins to account for motion and deformation of the prostate bed. Adaptive radiation therapy (ART) can incorporate image-guidance data to personalize PTVs that maintain coverage while reducing toxicity. We present feasibility and dosimetry results of a prospective study of postprostatectomy ART. Twenty-one patients were treated with single-adaptation ART. Conventional treatments were delivered for fractions 1 to 6 and adapted plans for the remaining 27 fractions. Clinical target volumes (CTVs) and small bowel delineated on fraction 1 to 4 CBCT were used to generate adapted PTVs and planning organ-at-risk (OAR) volumes for adapted plans. PTV volume and OAR dose were compared between ART and conventional using Wilcoxon signed-rank tests. Weekly CBCT were used to assess the fraction of CTV covered by PTV, CTV D99, and small bowel D1cc. Clinical metrics were compared using a Student's t-test (p < 0.05 significant). Offline adaptive planning required 1.9 ± 0.4 days (mean ± SD). ART decreased mean adapted PTV volume 61 ± 37 cc and bladder wall D50 compared with conventional treatment (p < 0.01). The CTV was fully covered for 96% (97%) of fractions with ART (conventional). Reconstructing dose on weekly CBCT, a nonsignificant reduction in CTV D99 was observed with ART (94%) compared to conventional (96%). Reduced CTV D99 with ART was significantly correlated with large anterior-posterior rectal diameter on simulation CT. ART reduced the number of fractions exceeding our institution's small bowel D1c limit from 14% to 7%. This study has demonstrated the feasibility of offline ART for post-prostatectomy cancer. ART facilitates PTV volume reduction while maintaining reasonable CTV coverage and can reduce the dose to adjacent normal tissues.

Abscopal effect in metastatic breast cancer treated with stereotactic body radiotherapy in the absence of immunotherapy.

In this study, we aimed to assess the abscopal effect (AE) after CyberKnife stereotactic body radiotherapy (SBRT) in metastatic breast cancer patients without immunotherapy. We reviewed breast cancer patients who received SBRT with a fraction size of ≥ 6 Gy for metastatic lesions between July 2008 and December 2021. We selected patients who had at least one measurable extracranial lesion in addition to SBRT target lesions and were not treated with immunotherapy. A total of 40 SBRT cases from 34 patients were included in the analysis. The AE was defined as occurring before the overall progression of the disease, regardless of the use of systemic treatment. The median follow-up duration was 16.4 months. Among 40 SBRT cases, the AE was observed in 10 (25.0%) with a median interval of 2.1 months. Of these lesions, 70.0% did not progress for one year. In multivariate logistic regression analysis, no change in systemic treatment after SBRT was significantly associated with an increase in the AE (odds ratio [OR] = 1.428, 95% confidence interval [CI] = 1.108 - 1.841, p = 0.009). A post-SBRT neutrophil-to-lymphocyte ratio (NLR) of < 2 marginally increased the AE (OR = 1.275, 95% CI = 0.998 - 1.629, p = 0.060). However, a high SBRT dose and large planning target volume did not (p = 0.858 and 0.152, respectively) in univariate analysis. One out of four patients experienced the AE after SBRT in the absence of immunotherapy. The AE could occur more frequently when systemic treatment remains unchanged, and patients have a low NLR after SBRT.

Seizure outcomes following single-fraction versus hypofractionated radiosurgery for brain metastases: a single-center experience.

Although seizures are a relatively common phenomenon in the setting of brain metastases (BMs), there are no discrete recommendations regarding the use of antiepileptic drugs (AEDs) in this population, either in general or in the context of treatment. The authors' aim was to better understand the underlying pathological factors as well as the therapeutic techniques that may lead to seizures following the radiosurgical treatment of BMs with the goal of guiding appropriate AED prophylaxis. Adult patients with BMs diagnosed from 2013 to 2020 at a single academic institution and treated with radiation therapy were included in this study. The authors evaluated factors associated with the incidence of seizures throughout the disease course, with a focus on seizures in the 90-day period following stereotactic radiosurgery (SRS). Four hundred forty-four patients with newly diagnosed BMs were identified, 10% of whom had seizures at the time of presentation and 28% of whom had a seizure at any point during the study period. Tumor histology was significantly associated with initial seizure risk. AED use was highly variable. In the 90-day post-SRS period, the summed total planning target volume (PTV) was independently predictive of post-SRS seizures, regardless of the fractionation scheme (single fraction vs hypofractionated) and other clinical factors. The number of supratentorial BMs was not predictive of post-SRS seizures. PTV is a superior predictor of post-SRS seizures relative to the number of supratentorial BMs, as it serves as a volumetric proxy for intracranial disease burden. A larger PTV, alongside tumor histology and prior seizure history, should be considered in the decision-making process for AED use following radiosurgery.

Ultra Low-Dose Radiation for Extranodal Marginal Zone Lymphoma of the Lung

Definitive radiation treatment (RT) for extranodal marginal zone lymphoma (ENMZL) of mucosal associated lymphoid tissue historically involves treatment to 24-30 Gy. There is increasing data supporting the use of ultra-low dose RT as part of a response-adapted approach in the treatment of orbital and gastric ENMZL. With this approach, patients receive initial treatment with 4 Gy, and additional RT is considered for those with persistent or locally progressive disease. However limited data to date assesses the efficacy of 4 Gy in the management of ENMZL of the lung. We performed an IRB-approved retrospective review of 17 patients with ENMZL of the lung treated with 4 Gy between 7/2015 and 12/2022 with response assessed after RT. Clinical/treatment characteristics, response, and toxicity were extracted from medical records. Statistics were performed using Mann-Whitney U and Fisher's Exact Test. Eight patients (47%) were female, 15 (88%) white, and 1 (6%) Hispanic. Median age at RT was 66 (interquartile range (IQR) 59-77). All had disease limited to the lung at diagnosis and 15 had stage IE disease. Four patients (24%) were diagnosed incidentally on screening/surveillance imaging in the absence of symptoms. Sixteen patients received 4 Gy in 2 fractions, while one patient received a single fraction of 4 Gy. Median SUVmax prior to RT was 4.5 (IQR 3.2-7.2). Median planning target volume (PTV) was 74 cc (IQR 47-130cc). Six patients (35%) had respiratory symptoms prior to RT, which improved or resolved in 3 (50%). A larger PTV was associated with improvement in symptoms following RT with a median PTV of 266 cc (IQR 171-402) in those who experienced improvement vs. 64 cc (IQR 42-100) in those who did not (p = 0.032). One patient experienced toxicity following RT with pleuritic chest pain, which resolved with corticosteroids. At a median follow-up of 15 months following RT (IQR 7-43 months), the overall response rate (ORR) was 100% (CR, n = 15; PR, n = 2). Fourteen patients had follow-up PET/CT, of whom 13 had a complete metabolic response (CMR) at a median of 3 months following RT (IQR 3-5 months). Two additional patients had a complete response (CR) on CT while one had a partial response on CT. Achieving a CR was not associated with SUV prior to RT (p = 0.50) or PTV size (p = 0.62). In patients with stage IE disease, the ORR rate was 100% and there have been no distant failures to date. Fifteen of 17 patients were alive at last follow-up; two passed away of unrelated causes (one from Alzheimer's disease and one from recurrent squamous cell carcinoma). Ultra-low dose radiation of 4 Gy is associated with excellent local control in the management of ENMZL of the lung and is very well tolerated. Four Gy was effective for local control and symptom palliation even for larger tumors and is an effective initial therapy as part of a response-adapted approach even in limited stage patients.

A Risk Prediction Model for Severe Radiation Induced Lymphopenia in Patients with Pancreatic Cancer Treated with Concurrent Chemoradiotherapy

In pancreatic cancer, radiation induced lymphopenia (RIL) is associated with a poor prognosis. However, normal tissue complication probability (NTCP) models predicting RIL in pancreatic cancer treated with concurrent chemoradiotherapy (CCRT) have yet to be developed. This study aims to develop a least absolute shrinkage and selection operator (LASSO)-based multivariate NTCP model to predict severe RIL in patients with pancreatic cancer during CCRT and to validate the model internally. We retrospectively reviewed patients with localized pancreatic cancer who underwent CCRT using three-dimensional conformal radiation therapy from 2013 to 2021. The exclusion criteria were patients with distant metastasis; patients who did not complete RT due to tumor progression; patients who did not have absolute lymphocyte count (ALC) data available before or during RT. An ALC of < 0.5 K/μL during CCRT was defined as severe RIL. A NTCP model of severe RIL was developed by LASSO-based multivariate analysis. We used age, sex, Karnofsky performance status, maximum tumor size, carbohydrate antigen 19-9 level before RT, ALC before RT, volume of planning target volume (PTV), and dosimetric parameters for surrounding organs (including spleen, vertebrae, liver, bilateral kidneys, gastrointestinal tracts) as variables for LASSO. In addition, internal validation was performed by the bootstrap method. The predictive performance of the model was evaluated by the area under the curve (AUC) of the receiver operating characteristic curve and scaled Brier score. Of the 131 patients included in the study, the median age was 68 years (range, 42-84), and 55% were male. The median ALC before RT was 1.37 K/µL (0.52-3.50). The median PTV volume was 315.4 ml (86.3-1079.3). The median dose of radiotherapy was 50.4 Gy (16.2-50.4), with 1.8 Gy per fraction. Combination chemotherapy was S-1 in 99 cases (75.6%) and gemcitabine in 32 cases (24.4%). Induction chemotherapy before CCRT was performed in 39 patients (29.8%). Severe RIL was observed in 84 (63.6%) patients. The LASSO showed that low baseline ALC (p = 0.0002), large PTV volume (p < 0.0001), and a large kidney V5 defined as the percentage of bilateral kidneys receiving 5 Gy or more (p = 0.0338) were selected as parameters of the prediction model for severe RIL (AUC = 0.917) and scaled Brier score was 0.511. As a result of internal validation by the bootstrap method, the average AUC was 0.918 (95% confidence interval, 0.849-0.954). Severe RIL occurred frequently during CCRT for pancreatic cancer, and a NTCP model for severe RIL developed and validated internally in this study showed good predictive performance. External validation is needed before this NTCP model can be used as a benchmark for treatment planning to reduce the risk of severe RIL and for considering future treatment approaches.

Toxicity and Outcomes of Moderately Hypofractionated Radiation for Prostate Cancer With Seminal Vesicle Involvement

The aim of this study was to assess the toxicity and outcomes following treatment of prostate cancer with seminal vesicle involvement (SVI) evident on magnetic resonance imaging or clinical examination with moderately hypofractionated radiation therapy (MHRT). Forty-one patients treated with MHRT to the prostate and 1 or both seminal vesicles from 2013 to 2021 at a single institution were identified and propensity score matched to 82 patients treated during the same period with prescription dose given to the prostate alone. Dosimetry of the planning target volume, bladder, and rectum were compared. Urinary and bowel toxicity were scored by National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Clinical outcomes including freedom from biochemical recurrence, prostate cancer-specific survival, and overall survival were assessed. Of the 41 patients identified with SVI, 26.8% had SVI by clinical examination and 95.1% had high-risk prostate cancer. Compared with the cohort without SVI, treatment plans to include SVI had a larger planning target volume (152.2 vs 109.9 cc; P < .001), maximum point dose (107.9% vs 105.8%; P < .001), and volume receiving 100% of the prescription dose (143.1 vs 95.9 cc; P < .001). No difference in bladder dosimetric variables between cohorts was observed, but there was an increase in the rectal maximum point dose (103.9% vs 102.8%; P=.030) and rectal volume receiving 100% of the prescription dose (1.8 vs 1.2 cc; P=.016). Despite these differences, there was no difference in the cumulative incidence of grade 2+ urinary (hazard ratio [HR], 0.73; 95% CI, 0.39-1.35; P=.31) or bowel (HR, 0.35; 95% CI, 0.04-3.03; P=.34) toxicity. Freedom from biochemical recurrence (HR, 0.47; 95% CI, 0.16-1.38; P=.17), prostate cancer-specific survival (HR, 0.31; 95% CI, 0.04-2.49; P=.31), and overall survival (HR, 0.35; 95% CI, 0.10-1.16; P=.09) also did not differ with or without SVI, respectively. Treatment of SVI to prescription dose with MHRT for localized prostate cancer does not increase bowel or urinary toxicity. Similar clinical outcomes were also observed with or without SVI.

Association Between Lymphopenia and Survival Outcomes in Esophageal Carcinoma Patients Receiving Combined Immunotherapy and Chemoradiotherapy.

To investigate the association between absolute lymphocyte count (ALC) nadir and survival outcomes in esophageal squamous cell carcinoma (ESCC) patients who received definitive chemoradiotherapy (CRT) combined with anti-PD-1 immunotherapy, as well as to explore clinical characteristics and dosimetric parameters that affect ALC nadir during CRT. Patients with ESCC (n = 602) who underwent definitive CRT were analyzed, of whom 166 received combined anti-PD-1 immunotherapy and CRT. Changes in ALC and survival were compared between patients with and without immunotherapy. Propensity score matching (PSM) was performed to minimize the effects of confounding factors. Low ALC was defined as nadir of <0.33 × 103 cells/μL during CRT (top tertile). Univariate and multivariate logistic regression were used to identify predictors of low ALC nadir. Patients with immunotherapy had significantly higher ALC in the first 3 weeks during CRT and higher ALC nadir than those without. Overall survival was more favorable in patients with immunotherapy both before and after PSM. After a median follow-up of 12.1 months, patients with low ALC during CRT had a worse progression-free survival (PFS) (P = .026). In multivariate analysis, low ALC remained a significant prognostic factor for PFS. Planning target volume (PTV) and heart V5 were revealed to be independent predictors of low ALC. The addition of anti-PD-1 immunotherapy to definitive CRT could mitigate the decline of ALC during radiotherapy and might prolong survival. Low ALC nadir was correlated to worse PFS, larger PTV, and higher heart V5 in patients receiving combined immunotherapy and CRT.

Utilization and Factors Precluding Receipt of Checkpoint Inhibitor Consolidation for Stage III NSCLC in a Large US Academic Health System

ObjectivesWe sought to determine the proportion of patients with stage III non–small cell lung cancer (NSCLC) who initiate consolidation durvalumab or other immune checkpoint inhibitors (ICIs) after concurrent chemoradiotherapy (cCRT), as well as reasons for nonreceipt and prognostic implications. Materials and MethodsWe retrospectively identified consecutive patients with unresectable stage III NSCLC treated with definitive cCRT between October 2017 and December 2021 within a large US academic health system. Patients either received consolidation ICIs (ICI group) or did not (no-ICI group). Baseline characteristics and overall survival (OS) of the groups were assessed. Factors predictive of ICI nonreceipt were evaluated using logistic regression. ResultsOf 333 patients who completed cCRT, 229 (69%) initiated consolidation ICIs; 104 (31%) did not. Reasons for ICI nonreceipt included progressive disease post-cCRT (N = 31, 9%), comorbidity or intercurrent illness (N = 25, 8%), cCRT toxicity (N = 23, 7%; 19/23 pneumonitis), and EGFR/ALK alteration (N = 14, 4%). The no-ICI group had worse performance status and a higher rate of baseline pulmonary comorbidity. Larger planning target volume was associated with post-cCRT progressive disease, and higher lung radiation dose with cCRT toxicity. Median OS was 16 months in the no-ICI group and 34.4 months in the ICI group. In the no-ICI group, OS was superior among those with EGFR/ALK alterations (median 44.5 months) and worst among those with progressive disease (median 5.9 months, P < 0.001). Conclusion31% of patients who completed cCRT for stage III NSCLC did not receive consolidation ICIs. Survival amongst these patients is poor, especially for those with progressive disease post-cCRT.

Proton and Carbon Ion Radiation Therapy Decreased Severe Lymphopenia by Reducing Thoracic Vertebra and Aortic Doses in Non-Small Cell Lung Cancer Versus Intensity Modulated Radiation Therapy

Lymphopenia is a common adverse effect of radiotherapy (RT). Little is known about the difference in lymphopenia between intensity-modulated (photon) radiation therapy (IMRT) and proton and carbon ion radiotherapy (PCIRT). This study aimed to investigate lymphopenia differences between IMRT and PCIRT in non-small cell lung cancer (NSCLC). Clinical and dosimetric parameters were collected from 343 patients who received definitive IMRT or PCIRT for NSCLC. Severe lymphopenia (SRL) was defined as an absolute lymphocyte count (ALC) ≤0.5*103 cells/μL. Overall survival (OS) was analyzed using the Kaplan-Meier method. Propensity score matching was performed between the IMRT and PCIRT groups. LASSO analysis was used to select appropriate dosimetric parameters. Univariate and multivariate logistic regression analyses were conducted to identify the predictors of SRL. Compared to the IMRT group, the PCIRT group was less likely to develop SRL (p <0.001). Compared with non-SRL group, SRL group showed significant association with poorer OS, with median survival time of 29.2 vs. 15.0 months (p = 0.046). IMRT was an independent risk factor of SRL (p = 0.004). A lower ALC before RT (p = 0.030) and larger planning target volume (PTV) (p = 0.002) were also significant independent risk factors for SRL. Moreover, the majority of dosimetric parameters of organ at risks in PCIRT were lower than those in IMRT (p <0.001). Thoracic vertebra V5 (p =0.002) and aorta V5 (p =0.026) were identified as independent risk predictors of SRL after adding dosimetric parameters to the regression model. Compared with IMRT, PCIRT could reduce the SRL incidence, possibly by limiting thoracic vertebra and aortic doses, and SRL was associated with poor outcomes in NSCLC patients.

Radiation Re-Planning for Stage III Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> The primary objective of this study was to identify factors associated with unexpected radiation therapy (RT) re-planning in Stage III non-small cell lung cancer (NSCLC). These factors may help predict which patients are more likely to require adaptive radical radiotherapy. <h3>Materials/Methods</h3> Stage III NSCLC patients treated in a single institution with radical intent RT from January 1, 2016, to December 31, 2019 were analyzed. Descriptive statistics were performed, including the frequency of RT re-planning and reason for re-planning. Logistic regression analysis was used to identify predictive factors associated with re-planning. Variables significant on univariate modelling, with a P value < 0.05, were selected for multivariate modelling. <h3>Results</h3> There were 144 patients with Stage III NSCLC who met study criteria. Eighteen percent (n=26) of these patients required re-planning. The most common reason for re-planning was due to volume changes (target shift or enlargement) on cone beam computed tomography (CBCT) (n=20, 77%), followed by failure to meet planning constraints (n=6, 23%). On univariate analysis, patients with a larger superior -inferior (SI) dimension of the primary and nodal planning target volume (PTV) was associated with a higher incidence of re-planning [Odds ratio (OR) 1.17, 95% CI 1.03-1.35 p = 0.02). Larger PTV (primary and nodal) was also associated with higher incidence of re-planning on univariate analysis [(OR) 2.48, 95% CI 1.21-5.38, p=0.02). On multivariable analysis, only larger PTV (primary and nodal) was statistically predictive of re-planning. <h3>Conclusion</h3> A larger SI dimension of the PTV, as well as larger PTV are associated with a higher odds ratio of re-planning. Target volume changes (tumor shift or enlargement) were the most common reasons for unanticipated re-planning. These PTV characteristics predict those stage III lung cancer targets most likely to require adaptive radiotherapy.

Risk Factors for Progression and Toxicity after Preoperative Radiosurgery for Resected Brain Metastases: A PROPS-BM Multicenter Cohort Study

<h3>Purpose/Objective(s)</h3> Preoperative (preop) stereotactic radiosurgery (SRS) is a feasible alternative to postoperative (postop) SRS with potential benefits in adverse radiation effect (ARE) and meningeal disease (MD) compared to postop SRS. The goal of this study was to determine risk factors for progression and toxicity after preop SRS in an expanded multicenter cohort. <h3>Materials/Methods</h3> Patients with brain metastases (BM) from solid cancers, of which at least 1 lesion was treated with preop SRS and underwent planned resection were included from 6 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included classically radiosensitive or non-solid cancers and prior or planned whole brain radiotherapy (WBRT). SRS dose, fractionation, and interval between preop SRS and surgery was per individual institutional protocol. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Radiographic MD was categorized as nodular (nMD) or classical "sugarcoating" (cMD). <h3>Results</h3> The cohort consisted of 378 patients with 389 preop SRS treated index lesions. Most patients (61.1%) had a single BM, underwent gross total resection (GTR, 95.4%), and had non-small cell lung (NSCLC, 47.9%), breast (16.1%), or melanoma (11.4%) cancer. Median dose was 15 Gy in 1 fraction to a median gross tumor volume (GTV) of 10.1 cc. Median interval between preop SRS and surgery was 2 days. Median cranial imaging follow-up interval was 9.5 months overall and 17.5 months for alive patients. The 2-year cavity local recurrence (LR) rate was 14.5%. Multivariable analysis (MVA) for LR demonstrated subtotal resection (STR, vs. GTR), single fraction SRS (vs. fractionated), larger GTV, gastrointestinal (GI) primary (vs. NSCLC), active systemic disease, and piecemeal resection (vs. en bloc) to be associated with higher risk of LR. Of note, interval between preop SRS and surgery was not significant. The 2-year any grade ARE rate was 7.7%. MVA for ARE demonstrated only larger planning target volume (PTV) margin expansion as associated with higher risk of ARE. The 2-year rate of MD was 5.6%. Most MD (76%) was classical type, with the remainder being nodular type. MVA for MD demonstrated STR (vs. GTR) and breast or melanoma histology (vs. NSCLC) as associated with higher risk of MD. Of note, posterior fossa location and type of surgical resection were not significant. <h3>Conclusion</h3> Preop SRS demonstrates overall excellent rates of cavity LR, ARE, and MD in this expanded multicenter cohort study. We have identified several tumor and treatment factors that are significantly associated with risk of cavity LR, ARE, and MD after treatment with preop SRS. Minimizing likelihood of STR and treating with fractionated preop SRS for larger higher risk tumors may lead to improved outcomes. A randomized trial of preop versus postop SRS is currently being designed (NRG BN012).

Initial Experience Using Daily Artificial Intelligence-Assisted Adaptive Radiotherapy on Cone-Beam CT for Bladder Cancer

<h3>Purpose/Objective(s)</h3> Adaptive radiation therapy (ART) provides a method to observe daily changes in the patient's internal anatomy and revise the radiation plan. In patients undergoing radiation for bladder cancer, changes in the bladder contour due to bladder filling result in significant changes in the radiation dose distribution potentially reducing the target coverage. Large margins are required in order to account for these anatomic changes, increasing the dose to the nearby organs at risk (OARs). Daily ART is an attractive method for bladder cancer in an attempt to reduce treatment margins. Herein we report our initial experience using commercially available, online adaptive platform with Artificial Intelligence (AI)-assisted workflows on daily cone-beam computed tomography (CBCT) for bladder cancer. <h3>Materials/Methods</h3> 9 consecutive patients eligible for bladder conserving radiotherapy underwent CT-simulation (CT-sim) and planned for ART. Clinical Target Volume included the bladder and proximal prostatic urethra +/- pelvic lymph nodes with an additional 0.5-1cm margin for the planning target volume (PTV). Fractionation schemas utilized included 64Gy/32 fractions, 55Gy/20 fractions, and 36Gy/6 fractions. A reference IMRT plan was created and approved using institutional target goals and OAR constraints. For treatment, the patient was aligned and CBCT acquired. The CT-sim was registered to the CBCT using deformable registration and a synthetic CT scan was generated. AI-based auto-contour and structure deformation of OARs and Targets on CBCT were reviewed and edited by the treating physician. 2 plans were generated including, a CT sim-based plan with deformed structures (scheduled) and a re-optimized plan (adaptive) of which both plans evaluated and the best one approved and delivered. Statistical analyses were performed comparing PTV coverage and OAR constraints between adaptive versus scheduled plans and a dosimetric comparison of ART compared to non-ART large-margin (1.5cm) treatment. <h3>Results</h3> 174 comparative adaptive and scheduled plans were generated of which the adaptive plan was chosen in 91.0% of sessions. V95 PTV mean coverage was improved with adaptation 97.0% versus 86.9% (p<.001). Average PTV volume change during ART was 16.4% (Range:0.4%-98.0%). All completed ART courses met institutional OAR constraints. With adaptation, there was a mean decrease in rectal V45%, V75%, V100% by 6% (95% CI 4.2%-7.6%, p<.003), 2.3% (95% CI 1.6%-3%, p<.003), 0.7% (95% CI 0.5%-0.8%, p<.001) respectively, and an increase in bowel V85%, V90% by 0.5% (95% CI 0.3%-0.8%, p<.04), 0.6% (95% CI 0.4%-0.8%, p<.01), respectively. Compared to a plan with large margins, there was a significant reduction in all bowel and rectal parameters with daily ART and smaller PTV margins. <h3>Conclusion</h3> Daily AI-assisted ART using CBCT for bladder cancer appears feasible and may potentially improve the therapeutic index by reducing the need for large PTV margins while ensuring acceptable target coverage.

A Systematic Review and Meta-analysis of the Impact of Radiation-Related Lymphopenia on Outcomes in High-Grade Gliomas.

Supriya MallickIntroduction Malignant gliomas are the most common primary malignant brain tumors and are typically treated with maximal safe surgical resection followed by chemoradiation. One of the unintended effects of radiation is depletion of circulating lymphocyte pool, which has been correlated with inferior overall survival outcomes. Methods A comprehensive and systematic searches of the PubMed, Cochrane Central, and Embase databases were done to assess the studies that have reported radiation-related lymphopenia in high-grade gliomas. Hazard ratios (HRs), odds ratios (OR), and mean differences were represented with Forest plots comparing patients with severe lymphopenia and no severe lymphopenia. Review Manager Version 5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark) was used for the analysis. Results Nineteen studies were included in the final systematic review and 12 studies were included in the meta-analysis. The odds of developing severe lymphopenia were 0.39 (95% CI:0.19, 0.81, I 2 = 94%, p = 0.01). Patients with severe lymphopenia were at increased risk of death with a pooled HR = 2.19 (95% CI: 1.70, 2.83, I 2 = 0%, p <0.00001) compared to patients with no severe lymphopenia. The mean difference in survival between patients with severe lymphopenia and no severe lymphopenia was -6.72 months (95% CI: -8.95, -4.49, I 2 = 99%, p <0.00001), with a better mean survival in the no severe lymphopenia group. Conclusion Radiation-induced severe lymphopenia was associated with poor overall survival and increased risk of death. Photon therapy, larger planning target volume, higher brain dose, higher hypothalamus dose, and female gender were associated with increased risk of severe lymphopenia.

Stereotactic Body Radiotherapy for Renal Cell Carcinoma: Oncological and Renal Function Outcomes

AimsTo evaluate oncological and renal function outcomes of stereotactic body radiotherapy (SBRT) for medically inoperable patients with localised renal cell carcinoma. Materials and methodsConsecutive patients treated with curative intent SBRT (30–45 Gy in five fractions or 42 Gy in three fractions) were included. Data on local control (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), distant metastasis, impact on estimated glomerular filtration rate (eGFR) and proportional ipsilateral and contralateral renal functions (measured through renal scans) were collected. Univariate and multivariable analyses were conducted to determine association of variables with oncological and renal function outcomes. ResultsSeventy-four patients were analysed. The median follow-up was 27.8 months (interquartile range 17.6–41.7). Fifty-seven per cent had tumours ≥ T1b. One-, 2- and 4-year cumulative incidence of local failure was 5.85, 7.77 and 7.77%, respectively. The cumulative incidence of distant metastasis at 2 years was 4.24%. On multivariable analysis, a lower planning target volume (PTV) mean dose (P = 0.019) and a larger PTV (P = 0.005) were significantly associated with the risk of developing local failure. A lower PTV maximum dose (P = 0.039) was significantly associated with the risk of developing distant metastasis. The median change in global eGFR (ml/min) from pre-SBRT levels was –7.0 (interquartile range –14.5 to –1.0) at 1 year and –11.5 (interquartile range –19.5 to –4.0) at 2 years. The proportion of ipsilateral (differential) renal function decreased over time from 47% of overall renal function pre-SBRT to 36% at 2 years, whereas the proportion of contralateral renal function correspondingly improved. On multivariable analysis, a higher volume of uninvolved renal cortex (P < 0.0001) was significantly associated with a smaller decrease in eGFR over time. ConclusionIn this large institutional cohort, oncological outcomes of renal cell carcinoma treated with SBRT were favourable and a longitudinal decline in renal function in the ipsilateral kidney and compensatory increase in the contralateral kidney were observed. Clinical and dosimetric factors were significantly associated with oncological and renal function outcomes.

Dosimetric impact of phase shifts on Radixact Synchrony tracking system with patient-specific breathing patterns.

PurposeThe Synchrony tracking system of Radixact is capable of real‐time tumor tracking by building a correlation model between external light‐emitting diodes on the patient's chest and an internal marker. A phase shift between the chest wall and a lung tumor has been reported. Hence, this study focused on evaluating the accuracy of the tracking system, especially under a patient‐specific breathing pattern with respiratory phase shifts.MethodsA phantom containing fiducial markers was placed on a moving platform. The intrinsic delivery accuracy was verified with a patient‐specific breathing pattern. Three patient‐specific breathing patterns were then implemented, for which phase shifts, φ, were introduced. Phase shifts with +0.3 s and +1 s were tested for dosimetric aspects, whereas ±0.3, ±0.6, and ±0.8 s shifts were used for tracking accuracy. The resultant dose distributions were analyzed by γ comparison. Dose profiles in the superior‐inferior and lateral directions were compared. Logfiles of the tracking information were extracted from the system and compared with the input breathing pattern. The root mean square (RMS) difference was used to quantify the consistency.ResultsWhen the φ value was as large as 1 s, a severe inconsistency was observed. The target was significantly underdosed, down to 89% of the originally planned dose. γ analysis revealed that the failed portion was concentrated in the target region. The RMS of the tracking difference was close to 1 mm when φ was ±0.3 s and approximately 4 mm when φ was ±0.8 s. Tracking errors increased with an increase in the degree of phase shifts.ConclusionPhase shifts between the patient chest wall and the internal target may hamper treatment delivery and jeopardize treatment using Synchrony Tracking. Hence, a larger planning target volume (PTV) may be necessary if a large phase shift is observed in a patient, especially when an external surrogate shows a lag in motion when compared with the tumor.