Mean Body Dose Research Articles

Stereotactic body radiation therapy for prostate cancer: a dosimetric comparison of IMRT and VMAT using flattening filter and flattening filter-free beams.

This retrospective study was performed to evaluate plan quality and treatment delivery parameters of stereotactic body radiation therapy (SBRT) for prostate cancer. The study utilized different isocentric modulated techniques: intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) using 6 MV flattening filter (FF) and 10 MV flattening filter-free beams (FFF). Fifteen retrospective prostate cancer patients were selected for this study. Sixty plans were created with an SBRT-prescribed dose of 36.25Gy delivered in five fractions. Planning target volume (PTV) coverage, plan quality indices, doses delivered to organs at risk (OARs), and treatment delivery parameters were compared for all plans. It turned out that VMAT plans, particularly those using the FFF beam, provided superior target conformality and a steeper dose gradient as compared to IMRT plans. Additionally, VMAT plans showed better OARs sparing compared to IMRT plans. However, IMRT plans delivered a lower maximum dose to the target than VMAT plans. Importantly, the VMAT plans resulted in reduced treatment delivery parameters, including beam on time (BOT), monitor unit (MU), and modulation factor (MF), compared to IMRT plans. Furthermore, a statistically significant difference was observed in BOT and mean body dose between FF and FFF beams, with FFF beams showing superior performance. Considering all results, VMAT using 10 MV (FFF) is suggested for treating prostate cancer patients with SBRT. This offers the fastest delivery in addition to maintaining the highest plan quality.

Impact of radiation dose to the immune cells in stage IV non-small cell lung cancer in the era of immunotherapy.

e20608 Background: Thoracic radiotherapy now is widely accepted in advanced lung cancer. It is not only been used as palliative therapy but also been involved in Systemic treatments in advanced lung cancer, especially in immune era. However, radiotherapy impairs immune system which can be evaluated by estimated dose of radiation to immune cells (EDRIC). Here, we sought to examine the prognostic impact of the EDRIC in advanced NSCLC in the context of immunotherapy, and to identify the factors influencing EDRIC in this population. Methods: We retrospectively enrolled patients with stage IV NSCLC who had received first-line immunotherapy and thoracic radiation therapy. EDRIC is a specific formulation using a model developed by Jin et al and improved by Ladbury et al, calculated using radiation fraction, mean lung dose (MLD), mean heart dose (MHD), and mean body dose (MBD). Spearman’s rank correlation was used to assess the correlation between variables.Associations between EDRIC [analyzed continuously and categorically (<5.7Gy vs ≥5.7Gy)] and overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and Cox proportional methods. Results: We conducted a retrospectively analysis of 152 patients with stage IV NSCLC patients. GTV (r = 0.2023, p = 0.0137), PTV (r = 0.4139, p < 0.0001) and N (r = 0.1897, p = 0.0193) stage showed a positive correlation with EDRIC. Negative correlations of lymphocyte nadir with EDRIC (r = -0.3172, p < 0.0001), during/pre lymphocyte nadir with EDRIC (r = -0.2102, p = 0.0093), during/post lymphocyte nadir with EDRIC (r = -0.2750, p = 0.0006) were found. Median PFS was shorter among the EDRIC ≥5.7Gy group (10.2months vs 18.6months; p < 0.0001). Median OS was also shorter among the EDRIC ≥5.7Gy group (19.8 months vs 30.2months; p = 0.024). For ORR (38% vs 46%; p = 0.413) and DCR (84% vs 92%; p = 0.304), there was no statistical significance between EDRIC≥5.7Gy and EDRIC < 5.7Gy. Analyzed as a continuous variable, EDRIC was the only factor associated with worse PFS (HR = 1.001, p = 0.018) and OS (HR = 1.002, p = 0.001) in multivariate analysis. Conclusions: In the era of immunotherapy, EDRIC is an independent predictor for PFS and OS in advanced NSCLC, warranting investigation into techniques to optimize radiation dose to the immune compartment.

A New Treatment Planning Method for Efficient Proton ARC Therapy with Direct Minimization of Number of Energy Jumps

The optimization of energy layer distributions is crucial for efficient proton ARC therapy: on one hand, a sufficient number of energy layers is needed to ensure the plan quality; on the other hand, an excess number of energy jumps can substantially slow down the treatment delivery. This work will develop a new treatment plan optimization method with direct minimization of number of energy jumps (NEJ), which will be shown to outperform state-of-the-art methods in both plan quality and delivery efficiency. The proposed method jointly optimizes the plan quality and minimizes the NEJ. To minimize NEJ, (1) the proton spots x is summed per energy layer to form the energy vector y; (2) y is binarized via sigmoid transform into y1; (3) y1 is multiplied with a predefined energy order vector via dot product into y2; (4) y2 is filtered through the finite-differencing kernel into y3 in order to identify NEJ; (5) only the NEJ of y3 is penalized, while x is optimized for plan quality. The solution algorithm to this new method is based on iterative convex relaxation. The new method is validated in comparison with state-of-the-art methods called energy sequencing (ES) method and energy matrix (EM) method. In terms of delivery efficiency, the new method had fewer NEJ, less energy switching time, and generally less total delivery time. In terms of plan quality, the new method had smaller optimization objective values, lower normal tissue dose, and generally better target coverage. A head-and-neck case is provided in the table with the following dosimetric parameters: planning objective value F; conformity index CI; homogeneity index HI; mean dose of larynx DOAR; mean body dose Dbody; the unit of dose is Gy. We have developed a new treatment plan optimization method with direct minimization of NEJ, and demonstrated that this new method outperformed state-of-the-art methods (ES and EM) in both plan quality and delivery efficiency.

The Correlation Between Lymphocyte Nadir and Radiation Therapy for Soft Tissue Sarcoma: Defining Key Dosimetric Parameters and Outlining Clinical Significance

The objectives of this study were to identify key dosimetric parameters associated with postradiation therapy lymphopenia and uncover any effect on clinical outcomes. This was a retrospective review of 69 patients (between April 2010 and January 2023) who underwent radiation therapy (RT) as a part of curative intent for soft tissue sarcoma (STS) at a single academic institution. All patients with treatment plans available to review and measurable absolute lymphocyte count (ALC) nadir within a year after completion of RT were included. Median follow-up was 22 months after the start of RT. A decrease in lymphocyte count was noted as early as during treatment and persisted at least 3 months after the completion of RT. On multivariable linear regression, the strongest correlations with ALC nadir were mean body dose, body V10 Gy, mean bone dose, bone V10 Gy, and bone V20 Gy. Five-year overall survival was 60% and 5-year disease-free survival was 44%. Advanced T-stage, chemotherapy use, use of intensity-modulated RT, lower ALC nadir, and the development of grade ≥2 lymphopenia at nadir were associated with worse overall survival and disease-free survival. Post-RT lymphopenia was associated with worse outcomes in STS. There were associations between higher body V10 Gy and bone V10 Gy and lower post-RT ALC nadir, despite the varying sites of STS presentation, which aligns with the well-known radiosensitivity of lymphocyte cell lines. These findings support efforts to reduce treatment-related hematopoietic toxicity as a way to improve oncologic outcomes. Additionally, this study supports the idea that the effect of radiation on lymphocyte progenitors in the bone marrow is more significant than that on circulating lymphocytes in treatments with limited involvement of the heart and lung.

Dosimetric Effect of Thymus and Thoracic Duct on Radiation-Induced Lymphopenia in Patients With Primary Lung Cancer Who Received Thoracic Radiation

Radiation-induced lymphopenia is a well-recognized factor for tumor control and survival in patients with cancer. This study aimed to determine the role of radiation dose to the thymus and thoracic duct on radiation-induced lymphopenia. Patients with primary lung cancer treated with thoracic radiation therapy between May 2015 and February 2020 with whole blood count data were eligible. Clinical characteristics, including age, gender, histology, stage, chemotherapy regimen, radiation dosimetry, and absolute lymphocyte count (ALC) were collected. The thymus and thoracic duct were contoured by one investigator for consistency and checked by one senior physician. The primary endpoint was radiation-induced decrease in lymphocytes, defined as the difference in ALC (DALC) before and after radiation therapy. The data of a total of 116 consecutive patients were retrospectively retrieved. Significant correlations were found between DALC and several clinical factors. These factors include stage, chemotherapy or concurrent chemoradiation, biologically effective dose (BED), mean lung dose, mean body dose, effective dose to immune cells (EDIC), mean thymus dose (MTD), and mean thoracic duct dose (MTDD) (all P < .05). Ridge regression showed that DALC = 0.0063 × BED + 0.0172 × EDIC + 0.0002 × MTD + 0.0147 × MTDD + 0.2510 (overall P = .00025 and F = 5.85). The combination model has the highest area under the curve of 0.77 (P < .001) when fitting the logistic regression model on DALC categorized as binary endpoint. The sensitivity and specificity of the combined model were 89% and 58%, respectively. This study demonstrated for the first time that radiation doses to the thymus and thoracic duct are strongly associated with radiation-induced lymphopenia patients with lung cancer. Further validation studies are needed to implement thymus and thoracic duct as organs at risk.

High weekly integral dose and larger fraction size increase risk of fatigue and worsening of functional outcomes following radiotherapy for localized prostate cancer.

We hypothesized that increasing the pelvic integral dose (ID) and a higher dose per fraction correlate with worsening fatigue and functional outcomes in localized prostate cancer (PCa) patients treated with external beam radiotherapy (EBRT). The study design was a retrospective analysis of two prospective observational cohorts, REQUITE (development, n=543) and DUE-01 (validation, n=228). Data were available for comorbidities, medication, androgen deprivation therapy, previous surgeries, smoking, age, and body mass index. The ID was calculated as the product of the mean body dose and body volume. The weekly ID accounted for differences in fractionation. The worsening (end of radiotherapy versus baseline) of European Organisation for Research and Treatment of Cancer EORTC) Quality of Life Questionnaire (QLQ)-C30 scores in physical/role/social functioning and fatigue symptom scales were evaluated, and two outcome measures were defined as worsening in ≥2 (WS2) or ≥3 (WS3) scales, respectively. The weekly ID and clinical risk factors were tested in multivariable logistic regression analysis. In REQUITE, WS2 was seen in 28% and WS3 in 16% of patients. The median weekly ID was 13.1 L·Gy/week [interquartile (IQ) range 10.2-19.3]. The weekly ID, diabetes, the use of intensity-modulated radiotherapy, and the dose per fraction were significantly associated with WS2 [AUC (area under the receiver operating characteristics curve) =0.59; 95% CI 0.55-0.63] and WS3 (AUC=0.60; 95% CI 0.55-0.64). The prevalence of WS2 (15.3%) and WS3 (6.1%) was lower in DUE-01, but the median weekly ID was higher (15.8 L·Gy/week; IQ range 13.2-19.3). The model for WS2 was validated with reduced discrimination (AUC=0.52 95% CI 0.47-0.61), The AUC for WS3 was 0.58. Increasing the weekly ID and the dose per fraction lead to the worsening of fatigue and functional outcomes in patients with localized PCa treated with EBRT.

Early onset of severe lymphopenia during definitive radiotherapy correlates with mean body dose and predicts poor survival in cervical cancer.

BACKGROUND: Lymphopenia during definitive radiotherapy (RT) has been shown to reduce survival in patients with cervical cancer. However, there are few studies on the significance of onset time of lymphopenia during RT in patients with cervical cancer.OBJECTIVE: This study aimed to exam the prognostic significance of early onset of severe lymphopenia (EOSL) during definitive RT in patients with cervical cancer.METHODS: Newly diagnosed cervical cancer patients treated with definitive RT from January 2015 to December 2019 were eligible for this retrospective study. EOSL was defined as first onset of grade 3–4 lymphopenia 3 weeks from the start of RT. Mean body dose (MBD) was the mean radiation dose absorbed by the body during the whole course of external beam RT (EBRT) and was directly obtained from the dose volume histogram (DVH) of the EBRT planning. Logistic regression analysis and restricted cubic spline (RCS) models were applied to assess relationships between clinicopathological factors and EOSL. Survival analysis was performed using Kaplan-Meier curves and log-rank test. A COX regression model was developed to predict overall survival (OS).RESULTS: A total of 104 patients were included and 59.6% had EOSL. MBD ( 0.04), concurrent cisplatin ( 0.011), and pre-RT absolute lymphocyte count (ALC) ( 0.001) were associated with EOSL. A linear relationship ( for non-linearity 0.803) between MBD and risk of EOSL was found. Patients with EOSL had decreased OS (2-yr 75.1% vs 91.1%, 0.021) and progression-free survival (PFS) (2-yr 71.2% vs 83.7%, 0.071). An OS prediction COX model was developed with C-index of 0.835 and AUC of 0.872.CONCLUSIONS: EOSL during definitive RT correlates with MBD and predicts poor survival in patients with cervical cancer.

CLR 131 (Iopofosine I-131) Treatment in Triple Class Refractory and Beyond Multiple Myeloma Patients: Preliminary Efficacy and Safety Results from the Phase 2 Clover-1 Trial

Background: Phospholipid ethers (PLE) provide a novel mechanism to target tumor cells. Tumor cells contain increased amounts of lipid rafts in their cell membranes, which are thought to enhance signaling and resist apoptosis. Phospholipid drug conjugates (PDC) are specifically designed to have high affinity for lipid rafts which upon binding results in trans-membrane inversion with the ability to deliver an attached therapeutic directly to the cytosol. Iopofosine I-131 (formerly identified as CLR 131) is a novel PDC delivering I-131 as a targeted tumor cell radiotherapy. Iopofosine I-131 is being examined in relapsed or refractory multiple myeloma (RRMM) patients through an open-label, Phase 2 trial, CLOVER-1 (NCT02952508).Methods: The primary objective of this study is to determine the safety and efficacy of Iopofosine I-131 in heavily pretreated MM patients. Eligibility criteria for MM patients include progression or relapsed disease that is refractory to at least 1 proteasome inhibitor and 1 immunomodulatory agent unless intolerable/ineligible to receive such agents with no upper limit to the number of prior lines of therapy. Iopofosine I-131 is administered in up to 4 IV infusions (15-20 min) over 3 months, with doses given 1-2 weeks apart each cycle for a maximum of 2 cycles, along with dexamethasone 40 mg weekly (20 mg in patients > 75), for up to 12 weeks. Following iopofosine I-131 administration, no other antineoplastic or targeted therapy was given until clinically indicated by the investigator. Adverse events (AEs) are graded by NCI-CTCAE v4.03; responses are assessed by the 2016 International Myeloma Working Group criteria.Results: Eleven patients with at least triple class refractory (immunomodulatory agent, proteasome inhibitor and monoclonal antibody) MM have been enrolled in this Phase 2 study with data current as of 28 May 2021. Patients had a median age of 72 (range 34-77), mean prior regimens of 7.2 (range 3-17) and received a mean total body dose of 75.4 mCi (range 59.7-118.7) of iopofosine I-131. The overall response rate (ORR) was 45.5% (5/11), the clinical benefit rate (CBR) was 72.7% (8/11) and disease control rate (DCR) was 100%. Median progression free survival (PFS) was 3.4 months. In a subset of patients who are quad/penta drug refractory, efficacy increased with an ORR of 80.0% (4/5) and CBR of 100% (5/5).The primary treatment emergent AEs in patients with MM included cytopenias (87.5%), in line with prior experience with iopofosine I-131. The most commonly observed cytopenias included Grade 3 or 4 thrombocytopenia (62.5%), anemia (62.5%), neutropenia (62.5%) and decreased white blood cell count (50%). There were no infusion-related reactions or AEs.Conclusions: Initial results for iopofosine I-131 show efficacy with a promising ORR of 45.5% and a CBR or 72.7% in heavily pretreated triple class refractory multiple myeloma patients. Interestingly, iopofosine I-131 showed its highest efficacy in patients that were quad/penta drug refractory with ORR of 80%, highlighting its potential as a later line therapy. Iopofosine I-131 is a novel cancer radiotherapeutic that may provide benefit to patients that are refractory/unresponsive to traditional MM therapies. CLOVER-1 is actively enrolling MM patients that are at least triple class refractory across the United States. DisclosuresAilawadhi: AbbVie: Consultancy; Pharmacyclics: Consultancy, Research Funding; Ascentage: Research Funding; Cellectar: Research Funding; GSK: Consultancy, Research Funding; Genentech: Consultancy; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Sanofi: Consultancy; Medimmune: Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Xencor: Research Funding; Takeda: Consultancy; Beigene: Consultancy. Stiff: CRISPR: Consultancy; Gamida-Cell, Atara, Amgen, Incyte, Takeda, Macrogenetics, Eisai: Research Funding; Cellectar: Research Funding. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Cull: Aptevo: Research Funding. Friend: Cellectar: Current Employment. Longcor: Cellectar: Current Employment. Oliver: Cellectar: Current Employment.

Pre-Treatment Immune-Related Markers Predict Disease Outcomes in Non-Small Cell Lung Cancer Patients Treated With Chemoradiation and Durvalumab

Immune-related markers from the peripheral blood and radiation dose to the immune system have been associated with outcomes in locally-advanced non-small cell lung cancers (LA-NSCLC) patients treated with concurrent chemoradiation (cCRT). We assessed if the neutrophil-to-lymphocyte ratio (NLR), and risk scores from two dose models (Estimated Dose of Radiation to Immune Cells (EDRIC) and the RTOG 0617 overall survival (OS) model including cardiopulmonary dose) are also associated with outcomes in patients treated with cCRT and durvalumab.Consecutive LA-NSCLC patients treated with platinum-based cCRT and at least one dose of durvalumab between November 2017 and December 2019 were evaluated. The pre-cCRT and pre-durvalumab NLR were calculated using samples most proximal to RT and durvalumab start (NLRpre-cCRT, NLRDurvalumab). Mean body dose, mean heart dose and mean lung dose (MLD) were extracted to calculate EDRIC; atria D45, mean of the hottest 5% of the ventricle dose (MOH5), pericardium MOH55 and MLD were used to calculate OS risk scores from the 0617 model. Progression-free survival (PFS) was defined from the start of cCRT. NLRpre-cCRT, NLRDurvalumab, risk scores from the two dose models, and patient characteristics (stage, age, PD-L1, ECOG status) were associated with PFS using bootstrapped Cox proportional hazards modeling. A Bonferroni-corrected P≤0.006 was considered statistically significant.A total of 105 patients with a median follow-up of 20 months (IQR: 13-27) were included. Median age was 67 years, 60% were male, and 45% were ECOG 1. Most patients had adenocarcinoma histology (n = 64) and stage IIIB/IIIC disease (n = 71). PD-L1 expression was available for 75% of patients, of which 66% had PD-L1 expression ≥1%. Patients were treated with a median of 7 (IQR: 2-12) months of durvalumab that started a median of 7 (5-9) weeks from end of cCRT. Twenty-eight (27%) patients discontinued durvalumab due to toxicity after a median of 2 (IQR: 1-4) months. In total, 41 patients had a progression event at a median of 8 (IQR: 6-11) months. The 12- and 18-months PFS estimates were 69% (95% CI: 60-78%) and 62% (52-72%), respectively. The median NLRpre-cCRT was 3.4 (IQR: 2.2-4.7), NLRDurvalumab was 5.5 (IQR: 3.6-7.4). The median risk score for EDRIC was 5.3 (IQR: 3.9-6.6) and 0.82 (IQR: 0.62-1.1) for the 0617 model. Among the investigated variables only NLRpre-cCRT reached significance in predicting PFS (HR: 1.10, 95% CI 1.05-1.16, P = 0.0002). Further, NLRpre-cCRT was not strongly correlated with age, stage, PD-L1 expression or ECOG status (Spearman's rho range: -0.22, 0.22).This study represents the first effort focusing on immune-related markers and dose models in LA-NSCLC treated with cCRT and durvalumab and finds the pre-cCRT NLR as the best predictor of disease outcomes.

Association Between Neurocognitive Outcomes and Radiation Dose to the Corpus Callosum and Hippocampus in Children With Medulloblastoma Treated on a Phase III Study

<h3>Purpose/Objective(s)</h3> To characterize the association between neurocognitive outcomes and radiation dose to the corpus callosum and the hippocampus in children with medulloblastoma treated on a phase III study. <h3>Materials/Methods</h3> Patients aged 3 to 21 years with medulloblastoma were treated at a single institution on a phase III risk-adapted study. Craniospinal radiation dose was 23.4 Gy for average-risk patients (M0 and GTR/NTR) and 36-39.6 Gy for high-risk patients (M+ or STR). All patients were treated with photons and received 55.8 Gy to the tumor bed using a 1cm clinical target volume margin. Metastasis > 0.5 cm received 50.4-54 Gy. Patients underwent age-appropriate cognitive testing at baseline (prior to completion of radiation) and yearly for 5 years. Neurocognitive scores were reported as standard deviations (SD) derived from age-standardized normative samples. Mixed effects models were used to estimate the longitudinal trends in neurocognitive scores. Reliable change index was used to identify patients whose scores declined significantly from baseline to last follow-up. Logistic regression was used to identify variables associated with a significant decline in neurocognitive outcomes. <h3>Results</h3> One hundred and twenty-four patients were eligible for analysis. The median neurocognitive follow-up was 59.4 months. Decline in processing speed was associated with mean dose to the corpus callosum genu (slope: -.166 points/year/Gy, <i>P</i> < .001), body (slope: -.176 points/year/Gy, <i>P</i> < .001) and splenium (slope: -.115 points/year/Gy, <i>P</i> < .001), after adjusting for age and sex. Of the 90 patients with baseline processing speed scores, 21 (19%) demonstrated significant decline at last follow up. Patients with a mean corpus callosum genu and body dose of ≥40 Gy were at a four to seven-fold increased odds of experiencing significant decline compared to those with a mean dose of < 40 Gy (genu: OR: 7.47, 95% CI: 2.64 - 21.12, <i>P</i> < .001; body: OR: 4.47, 95% CI: 1.65 - 12.11, <i>P</i> = .003). Decline in associative memory was associated with mean right hippocampal dose (slope: -.11 points/year/Gy, <i>P</i> = .013) and left hippocampal dose (slope: -.109 points/year/Gy, <i>P</i> = .019), after adjusting for age and sex. Of 98 patients with baseline memory scores, 11 (11%) demonstrated significant decline at last follow up. Patients with a mean hippocampal dose of ≥50 Gy were at a five to seven-fold increased odds of experiencing significant decline compared to those with mean dose < 50 Gy (right hippocampus: Odds Ratio [OR]: 7.21, 95% Confidence Interval [CI]: 1.98 – 27.46, <i>P</i> = .004; left hippocampus: OR: 5.17, 95% CI: 1.38 – 19.36, <i>P</i> = .015). <h3>Conclusion</h3> For children with medulloblastoma, increasing radiation dose to the corpus callosum and hippocampus is associated with decreased performance on tests of processing speed and memory, respectively. During radiation plan optimization, careful consideration should be given to minimizing dose to these structures while achieving appropriate tumor bed coverage.

Treatment free remission (TFR) and overall response rate (ORR) results in patients with relapsed/refractory Waldenstrom’s macroglobulinemia (WM) treated with CLR 131.

7561 Background: Phospholipid ethers (PLE) provide a novel mechanism to specifically target tumor cells leveraging high lipid raft content in their cell membranes. PLE/phospholipid drug conjugates are specifically designed to have high affinity to lipid rafts which upon binding results in trans-membrane flipping with the ability to deliver an attached warhead directly to the cytosol. CLR 131 (I-131-CLR1404) is a novel PLE molecule armed with I-131 resulting in targeted tumor cell radiotherapy which is being examined in relapsed or refractory WM through an open-label, Phase 2 trial, CLOVER-1 (NCT02952508). Methods: The primary objective of this study is to determine the efficacy and safety of CLR 131 in select B-cell malignancies. Eligibility criteria for WM pts include receipt of at least 2 prior treatment regimens unless ineligible to receive standard agents and have measurable disease: either IgM or extramedullary disease. CLR 131 is administered in up to 4 IV infusions (15-20 min) over 3 months. Adverse events (AEs) are graded by NCI-CTCAE v4.03; responses are assessed by the VIth WM Criteria for Response Assessment [Owen 2013]. Results: 6 pts with WM were enrolled in the study with data current as of 8 Jan 2021. The median age was 69 (range 54-81) with 4 females and 2 males who had a median of 2 prior regimens (range 1-5) and received a mean total body dose of 92.76 mCi CLR 131. 3 of 6 patients were MYD88 wild type (WT) of which 2 were dual WT (MYD88 WT &amp; CXCR4 WT). The overall response rate (ORR) was 100% and the major response rate (MRR) was 83%, including 1 pt with a CR, 4 PR, and 1 MR. For those pts who were dual WT, the MRR was 100% and 1 pt who was MYD88 WT (CXCR4 is unknown) had a complete response. The median time to initial response was 48 days. Median duration of response (DOR) and treatment free remission (TFR) have not been reached; ongoing mean DOR is 335 days and mean TFR is 384 days. 100% of MYD88 WT patients have exceeded 6.5 months of follow up with average TFR of 18.1 months. The primary treatment emergent AEs in pts with WM included fatigue and cytopenias, in line with prior experience with CLR 131 in other B-cell malignancies. The most commonly observed cytopenias included Grade 3 or 4 thrombocytopenia (100%), neutropenia (83%), anaemia (66%) and decreased white blood cell count (33%). Of note, no cases of bleeding or febrile neutropenia were observed. Conclusions: Initial results for CLR 131 show efficacy across multiple WM patient genotypes including dual WT patients with durable DOR and TFR after 2 to 4 infusions. CLR 131 represents a novel and promising approach to the treatment of MYD88 WT patients who have a historical median time to progression of 1.3 years. These encouraging data led to the pivotal global CLOVER-WaM trial (N=50) in WM patients who have failed or had a suboptimal response to a Bruton Tyrosine Kinase inhibitor. CLOVER-WaM is currently enrolling. Clinical trial information: NCT02952508.

Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio associations with heart and body dose and their effects on patient outcomes in locally advanced non-small cell lung cancer treated with definitive radiotherapy.

BackgroundInflammation plays a vital role in tumor growth and progression and can be affected by radiotherapy (RT) and chemotherapy. We sought to investigate the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), and their associations with dosimetric factors in locally advanced non-small cell lung cancer (LA-NSCLC).MethodsIn this retrospective study, subjects consisted of 244 patients who had received definitive RT ± chemotherapy for LA-NSCLC between 2012 and 2016. Absolute lymphocyte count (ALC), NLR and PLR recorded at pretreatment, during RT and post-RT were analyzed. Multivariable analysis (MVA) was performed to correlate clinical factors and inflammatory biomarkers with progression-free survival (PFS) and overall survival (OS) using a Cox regression model. Relationships between NLR or PLR with OS and PFS were evaluated with Kaplan-Meier analysis and compared with log-rank test results. Multiple stepwise linear regression was used to assess the associations between dosimetric factors and NLR or PLR.ResultsThe median PFS and OS for all patients were 8.6 and 15.8 months, respectively. On MVA for PFS and OS, higher 1-month post-RT start NLR [hazard ratio (HR) 1.049; 95% CI: 1.018–1.080; P=0.001] or higher 1-month post-RT start PLR (HR 1.001; 95% CI: 1.000–1.002; P<0.001) was associated with inferior PFS. Higher 1-month post-RT start NLR (HR 1.040; 95% CI: 1.013–1.069; P=0.004) or PLR (HR 1.001; 95% CI: 1.001–1.002; P<0.001) was also an independent predictor of OS. ALCmin, baseline NLR and PLR were not associated with treatment outcomes. Multiple stepwise linear regression analysis confirmed that baseline NLR (P<0.001), heart V20 (P<0.001), heart V40 (P<0.001), and mean body dose (MBD) were significantly associated with 1-month post-RT start NLR. Also, baseline PLR (P<0.001) and MBD (P<0.001) were significantly associated with 1-month post-RT start PLR.ConclusionsHigher NLR and PLR during treatment were associated with worse patient outcomes, and heart dose or body dose was correlated with NLR or PLR in advanced NSCLC patients treated with definitive RT.

Dosimetric analysis of lymphopenia during chemoradiotherapy for esophageal cancer.

BackgroundLymphopenia during chemoradiation (CRT) for esophageal cancer (EC) can adversely affect clinical outcomes. We sought to explore an association between lymphopenia and dosimetric parameters during CRT for EC.MethodsAfter IRB approval, we retrospectively reviewed 54 patients treated with either definitive or neoadjuvant CRT for EC. Absolute lymphocyte count was recorded weekly during CRT up and graded according to the common terminology of adverse events (CTCAE) version 4.0. Dose volume histograms (DVH) parameters were collected based on vertebral body, body dose, dose to peripheral lymphocytes, and spleen. Logistic regression correlated Grade 4 toxicity with DVH parameters and linear regression analysis correlated absolute lymphocyte nadir counts with DVH parameters. Receiver operator curves (ROC) were constructed to define dosimetric thresholds.ResultsThere were a total of 21 Grade 4 events (38.8%) of lymphopenia. Increasing vertebral volume receiving ≥10 Gy (OR 1.1, P=0.04), ≥20 Gy (OR 1.1, P=0.03), ≥30 Gy (OR 1.1, P=0.012), or mean body dose (OR 1.04, P=0.032) were correlated with Grade 4 lymphopenia on multivariable logistic regression. The dosimetric parameters most predictive of Grade 4 toxicity via a ROC analysis included absolute vertebral volume receiving 10 Gy >289 cc, 20 Gy ≥270 cc, and vertebral volumes receiving 30 Gy ≥197 cc. On multivariable linear regression increasing volume receiving 20 Gy (Beta −0.004, P=0.001), 30 Gy (Beta −0.005, P=0.0046), and mean body dose (Beta −0.002, P=0.001) all correlated with absolute lymphocyte nadir.ConclusionsLymphopenia, a known negative prognostic factor in EC, is closely correlated with the volume of vertebral bodies receiving radiation during CRT for EC. Dosimetric sparing of the vertebral bodies may result in better outcomes.

Surgeon's and patient's radiation exposure during percutaneous thoraco-lumbar pedicle screw fixation: A prospective multicenter study of 100 cases.

Percutaneous pedicle screw fixations (PPSF) are increasingly used in spine surgery, minimizing morbidity through less muscle breakdown but at the cost of intraoperative fluoroscopic guidance that generates high radiation exposure. Few studies have been conducted to measure them accurately. The objective of our study is to quantify, during a PPSF carried out in different experimented centers respecting current radiation protection recommendations, this irradiation at the level of the surgeon and the patient. We have prospectively included 100 FPVP procedures for which we have collected radiation doses from the main operator. For each procedure, the doses of whole-body radiation, lens and extremities were measured. Our results show a mean whole body, extremity and lens exposure dose per procedure reaching 1.7±2.8μSv, 204.7±260.9μSv and 30.5±25.9μSv, respectively. According to these values, the exposure of the surgeon's extremities and lens will exceed the annual limit allowed by the International Commission on Radiological Protection (ICRP) after 2440 and 4840 procedures respectively. Recent European guidelines will reduce the maximum annual exposure dose from 150 to 20mSv. The number of surgical procedures to not reach the eye threshold, according to our results, should not exceed 645 procedures per year. Pending the democratization of neuronavigation systems, the use of conventional fluoroscopy exposes the eyes in the first place. Therefore they must be protected by leaded glasses. IV, case series.

MicroCT imaging dose to mouse organs using a validated Monte Carlo model of the small animal radiation research platform (SARRP)

The goal of this work was to establish imaging dose to mouse organs with a validated Monte Carlo (MC) model of the image-guided Small Animal Radiation Research Platform (SARRP) and to investigate the effect of scatter from the internal walls on animal therapy dose determination. A MC model of the SARRP was built in the BEAMnrc code and validated with a series of homogeneous and heterogeneous phantom measurements. A segmented microCT scan of a mouse was used in DOSXYZnrc to determine mouse organ microCT imaging doses to 15–35 g mice for the SARRP pancake (mouse lying on couch) and standard (mouse standing on couch) imaging geometries for 40–80 kVp tube voltages. Imaging dose for off-center positioning shifts and maintaining image noise across tube voltages were also calculated. Half-value layer (HVL) measurements for the 220 kVp therapy beam in the presence of the SARRP shielding cabinet were modeled in BEAMnrc and compared to the 100 cm source-to-detector distance (SDD) in the scatter free, narrow-beam geometry recommended by the American Association of Physicists in Medicine Task Group 61 (AAPM TG-61). For a 60 kVp, 0.8 mA, and 60 s scan protocol, maximum mean organ imaging doses to boney and non-boney structures were 10.5 cGy and 3.5 cGy, respectively, for an average size 20 g mouse. Current-exposure combinations above 323, 203, 147, 116, and 95 mAs for 40–80 kVp tube voltages, respectively, will increase body doses above 10 cGy. MicroCT mean body dose was 18% lower in pancake compared to standard imaging geometry. An 11% difference in measured HVL at a 50 cm SDD was found compared to MC simulated HVL for the AAPM TG-61 recommended scatter free geometry at a 100 cm SDD. This change in HVL resulted in a 0.5% change in absorbed dose to water calculations for the treatment beam.

Improved dose homogeneity using electronic compensation technique for total body irradiation.

In total body irradiation (TBI) utilizing large parallel‐opposed fields, the manual placement of lead compensators has conventionally been used to compensate for the varying thickness throughout the body. The goal of this study is to pursue utilizing the modern electronic compensation (E‐comp) technique to more accurately deliver dose to TBI patients. Bilateral parallel‐opposed TBI treatment plans were created using E‐comp for 15 patients for whom CT data had been previously acquired. A desirable fluence pattern was manually painted within each field to yield a uniform dose distribution. The conventional compensation technique was simulated within the treatment planning system (TPS) using a field‐in‐field (FIF) method. This allows for a meaningful evaluation of the E‐comp technique in comparison to the conventional method. Dose–volume histograms (DVH) were computed for all treatment plans. The mean total body dose using E‐comp deviates from the prescribed dose (4 Gy) by an average of 2.4%. The mean total body dose using the conventional compensation deviates from the prescribed dose by an average of 4.5%. In all cases, the mean body dose calculated using E‐comp technique deviates less than 10% from that of conventional compensation. The average reduction in maximum dose using E‐comp compared to that of the conventional method was 30.3% ± 6.6% (standard deviation). In all cases, the s‐index for the E‐comp technique was lower (10.5% ± 0.7%) than that of the conventional method (15.8% ± 4.4%), indicating a more homogenous dose distribution. In conclusion, a large reduction in maximum body dose can be seen using the proposed E‐comp technique while still producing a mean body dose that accurately complies with the prescription dose. Dose homogeneity was quantified using s‐index which demonstrated a reduction in hotspots with E‐comp technique. Electronic compensation technique is capable of more accurately delivering a total body dose compared to conventional methods.

High lymphocyte count during neoadjuvant chemoradiotherapy is associated with improved pathologic complete response in esophageal cancer

Background and purposeNeoadjuvant chemoradiation (nCRT) can reduce tumor infiltrating lymphocytes. We examined absolute lymphocyte count (ALC) nadir during nCRT for esophageal cancer (EC) and pathologic complete response (pCR). Materials and methodsPatients with stage I–IVA EC (n = 313) treated 2007–2013 with nCRT followed by surgery were analyzed. ALC was obtained before, during/weekly, and one month after CRT. pCR was defined as no viable tumor cells at surgery. High ALC was defined as nadir of ≥0.35 × 103/μL (highest tertile). Comparison of continuous and categorical variables by pCR was assessed by ANOVA and Pearson’s chi-square. Univariate/multivariate logistic regression was used to assess predictors of pCR and high ALC nadir. ResultsEighty-nine patients (27.8%) achieved a complete pathological response (pCR). For patients with pCR, median ALC nadir was significantly higher than those without (0.35 × 103/μL vs 0.29 × 103/μL, p = 0.007). Patients maintaining high ALC nadir had a higher pCR rate (OR1.82, 95%CI 1.08–3.05, p = 0.024). Predictors of high ALC included treatment with proton therapy vs. IMRT (OR4.18, 95%CI 2.34–7.47, p < 0.001), smoking at diagnosis (OR2.80, 95%CI 1.49–5.25, p = 0.001), early stage I–II disease (OR2.33, 95%CI 1.32–4.17, p = 0.005), and SCC histology (OR3.70, 95%CI 1.01–14.29, p = 0.048). Mean body dose (MBD) was inversely related to high ALC nadir (OR0.77 per Gy, 95%CI 0.70–0.84, p < 0.001). ConclusionA higher ALC level during nCRT is associated with a higher rate of pCR for esophageal cancer patients undergoing trimodality therapy.

Weekly Integral Dose and Use of Lipid Lowering Drugs Are Associated With Worsening of Functional Outcomes in Prostate Cancer Patients Treated With IMRT

IMRT allows the delivery of highly conformal doses to target, but increases body integral dose due to irradiation of a larger volume of tissue at lower doses. We previously showed that higher weekly integral pelvic dose (weekID) was associated with adverse functional outcomes at RT end in patients (pts) with localized prostate cancer treated with IMRT (RO 2016). This analysis aimed to model worsening of functional and nonfunctional items from EORTC QLQ-C30, all plausibly related to fatigue. Patients from two prospective multicentric trials were evaluated, involving either conventional (78 Gy, 2 Gy/Fr) or hypo-fractionated (HF) (60-75.2 Gy, 2.35-3 Gy/Fr) RT alone, without lymph node irradiation. Collected clinical factors were: comorbidities, drugs, hormone therapies, previous surgeries, smoking, age, BMI. Integral dose was calculated as the product of mean body dose and body volume. WeekID was used to properly consider different fractionations. Worsening (RT end vs baseline) of EORTC QLQ-C30 scores in Physical/Role/Social Functioning scales and Fatigue was evaluated: 2 point worsening was considered for subscales including >2 items, 1 point worsening for 2 items subscales. Outcome measures for the analysis were defined as worsening in at least 2 (Wrs2) or 3 (Wrs3) subscales. Models incorporating weekID and clinical factors were developed using multivariable logistic regression (MVL). Complete data for 254 pts were available. The table summarizes the cohorts. The MVL for Wrs2 included weekID (OR = 1.05, continuous variable) and use of lipid lowering drugs (LLD, OR = 1.5). Calibration was good: slope = 1.01 (Rˆ2 = 0.80) in the development cohort and 1.05 (Rˆ2 = 0.90) in the validation dataset. The model for Wrs3 included the same factors (weekID OR = 1.06 and LLD OR = 2.3) with calibration slopes of 1.05 (Rˆ2 = 0.96) and 0.72 (Rˆ2 = 0.70), in the development and validation cohorts, respectively. Worsening of functional and non-functional quality of life symptoms was significantly associated with use of lipid lowering drugs and weekID, suggesting a higher impairment effect of hypofractionation in the acute phase (possible fraction size related inflammatory response or effect on blood cell counts). The effect of lipid lowering drugs is interesting, as they were found to be a risk factor for urinary toxicity in a large population (Palorini R&O 2016). These drugs are usually prescribed for vasculopathies: the present result thus bolsters the clue that pts with potential microangiopathic disease exhibit a possible enhanced sensitivity to RT-induced damage.

Lymphocyte Nadir and Esophageal Cancer Survival Outcomes After Chemoradiation Therapy

Host immunity may affect the outcome in patients with esophageal cancer. We sought to identify factors that influenced absolute lymphocyte count (ALC) nadir during chemoradiation therapy (CRT) for esophageal cancer (EC) and looked for clinically relevant associations with survival. 504 patients with stage I-III EC (2007-2013) treated with neoadjuvant or definitive CRT with weekly ALC determinations made during treatment were analyzed. Grade of lymphopenia from ALC nadir during CRT was based on Common Terminology Criteria for Adverse Events version 4.0. Associations of ALC nadir with survival were examined using multivariate Cox proportional hazards analysis (MVA) and competing risks regression analysis. The median follow-up time was 36months. The incidences of grade 1, 2, 3, and 4 ALC nadir during CRT were 2%, 12%, 59%, and 27%, respectively. The impact was lymphocyte-specific because this was not seen for monocyte or neutrophil count. On MVA, grade 4 ALC nadir (G4 nadir) was significantly associated with worse overall and disease-specific survival outcomes. Predictors of G4 nadir included distal tumor location, definitive CRT, taxane/5-fluorouracil chemotherapy, and photon-based radiation type (vs proton-based). Radiation type strongly influenced the mean body dose exposure, which was a strong predictor for G4 nadir (odds ratio 1.22 per Gray, P<.001). G4 nadir during CRT for EC was associated with poor outcomes, suggesting a role of host immunity in disease control. This observation provides a rationale to prospectively test chemotherapeutic and radiation treatment strategies that may have a lower impact on host immunity.

Comparative dosimetric analysis of IMRT and VMAT (RapidArc) in brain, head and neck, breast and prostate malignancies

Purpose: Intensity modulated radiotherapy (IMRT) in the recent past has established itself as a gold standard for organs at risk (OAR) sparing, target coverage and dose conformity. With the advent of a rotational treatment technology such as volumetric modulated arc therapy (VMAT), an inter-comparison is warranted to address the advantages and disadvantages of each technique. Methods: Twenty patients were selected retrospectively from our patient database. Sites included were brain, head and neck, chest wall, and prostate, with five patients for each site. For all the selected patients, both the IMRT and VMAT treatment plans were generated. Plan comparison was done in terms of OAR dose, dose homogeneity index (HI), dose conformity index (CI), target coverage, low isodose volumes, monitor units (MUs), and treatment time. Results: The VMAT showed better sparing of “parotids minus planning target volume (PTV)”, spinal cord and head of femur as compared to the IMRT. The lung V 40 for VMAT was lower, whereas the lung V 10 , contralateral lung mean dose, contralateral breast mean dose and mean body dose were lower with IMRT for chest wall cases. Both the VMAT and IMRT achieved comparable HI except for the brain site, where IMRT scored over VMAT. The CI achieved by the IMRT and VMAT were similar except for chest wall cases, whereas the VMAT achieved better dose conformity. The target coverage was comparable with both the plans. The VMAT clearly scored over IMRT in terms of average MUs (486 versus 812 respectively) and average treatment time (2.54 minutes versus 5.54 minutes) per treatment session. Conclusion: The VMAT (RapidArc) has a potential to generate treatment plans for various anatomical sites which are comparable with the corresponding IMRT plans in terms of OAR sparing and plan quality parameters. The VMAT significantly reduces treatment time as compared to the IMRT, thus VMAT can increase the throughput of a busy radiotherapy department.