Lateral Pelvic Nodal Management and Patterns of Failure in Patients Receiving Short-Course Radiation for Locally Advanced Rectal Cancer.

BACKGROUND: Management of lateral pelvic lymph nodes in locally advanced rectal cancer is controversial, with limited data indicating the optimal approach. In addition, no data exist regarding the treatment of lateral nodes in the setting of short-course radiation and nonoperative intent. OBJECTIVE: To evaluate a novel approach incorporating simultaneous integrated boost to suspicious lateral nodes. DESIGN: A retrospective study. SETTING: This study was conducted at a large tertiary referral center. PATIENTS: Patients treated with radiation therapy and consolidation chemotherapy were included. All primary tumors underwent biopsy confirmation and disease staging with pelvic MRI. INTERVENTIONS: Primary tumors were biopsy proven and staged with pelvic MRI. A subset of lateral pelvic lymph node patients received a simultaneous integrated boost of 35 Gy in 5 fractions. Then, chemotherapy was administered, with the majority receiving modified folinic acid, fluorouracil, and oxaliplatin. Clinical partial response required total mesorectal excision. MAIN OUTCOME MEASURES: Patterns of failure and survival analyses by subgroup were assessed. Outcomes based on receipt of radiation were compared across node status. RESULTS: Between January 2017 and January 2022, 155 patients were treated with short-course chemotherapy, with 121 included in the final analysis. Forty-nine percent of patients underwent nonoperative management. The median follow-up was 36 months and the median age was 58 years. Thirty-eight patients (26%) had positive lateral pelvic lymph nodes. Comparing lateral node status, progression-free survival was significantly worse for patients with positive disease ( p < 0.001), with a trend for worse overall survival. Receipt of nodal boost in patients with lateral nodes resulted in meaningful locoregional control. Nodal boost did not contribute to additional acute or late GI toxicity. LIMITATIONS: Limitations include retrospective nature and lack of lateral node pathology; however, a thorough radiographic review was performed. CONCLUSIONS: Lateral node-positive rectal cancer is correlated with worse oncologic outcomes and higher locoregional failure. Boost to clinically positive lateral nodes is a safe approach in the setting of short course radiation and in those receiving nonoperative intent. See Video Abstract. MANEJO DE LOS GANGLIOS PLVICOS LATERALES Y PATRONES DE FALLA EN PACIENTES QUE RECIBEN RADIACIN DE CICLO CORTO PARA EL CNCER DE RECTO LOCALMENTE AVANZADO: ANTECEDENTES:El manejo de los ganglios linfáticos pélvicos laterales en el cáncer de recto localmente avanzado es controvertido, con datos limitados que indiquen el abordaje óptimo. Además, no existen datos sobre el tratamiento de los ganglios linfáticos laterales en el contexto de la radiación de curso corto y la intención no operatoria.OBJETIVO:Evaluamos un enfoque novedoso que incorpora sobreimpresión integrada simultánea (SIB) a los linfonodos laterales sospechosos.DISEÑO:Este fue un estudio retrospectivo.ESCENARIO:Este estudio se realizó en un gran centro de referencia terciario.PACIENTES:Se incluyeron pacientes tratados con radiación y quimioterapia de consolidación. Todos los tumores primarios se confirmaron mediante biopsia y la enfermedad se estadificó con resonancia magnética pélvica.INTERVENCIONES:Los tumores primarios se confirmaron mediante biopsia y se estadificaron con RM pélvica. Un subconjunto de pacientes con linfonodos pélvicos laterales (LPLN) recibió SIB a 35 Gy en 5 fracciones. Luego, se administró quimioterapia y la mayoría recibió mFOLFOX. La respuesta clínica parcial requirió la escisión total del mesorrecto.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron los patrones de fracaso y los análisis de supervivencia por subgrupo. Los resultados basados en el esquema de radiación se compararon según el estado de los ganglios.RESULTADOS:Entre enero de 2017 y enero de 2022, 155 pacientes fueron tratados con ciclo corto y quimioterapia con 121 incluidos en el análisis final. El 49% se sometió a manejo no operatorio. La mediana de seguimiento fue de 36 meses y la mediana de edad fue de 58 años. 38 pacientes (26%) tuvieron LPLN positivos. Comparando el estado de los ganglios laterales, la supervivencia libre de progresión fue significativamente peor para los pacientes con LPLN positiva ( p < 0,001) con una tendencia a una peor supervivencia global. La recepción de refuerzo nodal en pacientes con nodos laterales dio como resultado un control locorregional significativo. La sobreimpresión ganglionar no contribuyó a la toxicidad GI aguda o tardía adicional.LIMITACIONES:Las limitaciones incluyeron la naturaleza retrospectiva y la falta de patología de los ganglios linfáticos laterales; sin embargo, se realizó una revisión radiográfica exhaustiva.CONCLUSIONES:El cáncer de recto con ganglio lateral positivo se correlaciona con peores resultados oncológicos y mayor fracaso locorregional. La sobreimpresión a los ganglios laterales clínicamente positivos es un enfoque seguro en el contexto de un curso corto y en aquellos que siguen un manejo no operatorio. (Traducción-Dr. Felipe Bellolio ).

Circumferential Resection Margin as Predictor of Nonclinical Complete Response in Nonoperative Management of Rectal Cancer.

BACKGROUND: Short-course radiation therapy and consolidation chemotherapy with nonoperative intent has emerged as a novel treatment paradigm for patients with rectal cancer, but there are no data on the predictors of clinical complete response. OBJECTIVE: Evaluate the predictors of clinical complete response and survival. DESIGN: Retrospective cohort. SETTINGS: National Cancer Institute-designated cancer center. PATIENTS: Patients with stage I to III rectal adenocarcinoma treated between January 2018 and May 2019 (n = 86). INTERVENTIONS: Short-course radiation therapy followed by consolidation chemotherapy. MAIN OUTCOME MEASURES: Logistic regression was performed to assess for predictors of clinical complete response. The end points included local regrowth-free survival, regional control, distant metastasis-free survival, and overall survival. RESULTS: A positive (+) circumferential resection margin by MRI at diagnosis was a significant predictor of nonclinical complete response (OR: 4.1, p = 0.009) when adjusting for CEA level and primary tumor size. Compared to patients with a negative (-) pathologic circumferential resection margin, patients with a positive (+) pathologic circumferential resection margin had inferior local regrowth-free survival (29% vs 87%, p < 0.001), regional control (57% vs 94%, p < 0.001), distant metastasis-free survival (43% vs 95%, p < 0.001), and overall survival (86% vs 95%, p < 0.001) at 2 years. However, the (+) and (-) circumferential resection margin by MRI subgroups in patients who had a clinical complete response both had similar regional control, distant metastasis-free survival, and overall survival of more than 90% at 2 years. LIMITATIONS: Retrospective design, modest sample size, short follow-up, and the heterogeneity of treatments. CONCLUSIONS: Circumferential resection margin involvement by MRI at diagnosis is a strong predictor of nonclinical complete response. However, patients who achieve a clinical complete response after short-course radiation therapy and consolidation chemotherapy with nonoperative intent have excellent clinical outcomes regardless of the initial circumferential resection margin status. See Video Abstract at http://links.lww.com/DCR/C190 . EL MARGEN DE RESECCIN CIRCUNFERENCIAL COMO PREDICTOR NO CLNICO DE RESPUESTA COMPLETA EN EL MANEJO CONSERVADOR DEL CNCER DE RECTO: ANTECEDENTES:La radioterapia de corta duración y la quimioterapia de consolidación en el manejo conservador, han surgido como un nuevo paradigma de tratamiento, para los pacientes con cáncer de recto, lastimosamente no hay datos definitivos sobre los predictores de una respuesta clínica completa.OBJETIVO:Evaluar los predictores de respuesta clínica completa y de la sobrevida.DISEÑO:Estudio retrospectivo de cohortes.AJUSTES:Centro oncológico designado por el NCI.PACIENTES:Adenocarcinomas de recto estadio I-III tratados entre 01/2018 y 05/2019 (n = 86).INTERVENCIONES:Radioterapia de corta duración seguida de quimioterapia de consolidación.PRINCIPALES MEDIDAS DE RESULTADO:Se realizó una regresión logística para evaluar los predictores de respuesta clínica completa. Los criterios de valoración incluyeron la sobrevida libre de recidiva local, el control regional, la sobrevida libre de metástasis a distancia y la sobrevida general.RESULTADOS:Un margen de resección circunferencial positivo (+) evaluado por imagenes de resonancia magnética nuclear en el momento del diagnóstico fue un predictor no clínico muy significativo de respuesta completa (razón de probabilidades/ OR: 4,1, p = 0,009) al ajustar el nivel de antígeno carcinoembrionario y el tamaño del tumor primario. Comparando con los pacientes que presetaban un margen de resección circunferencial patológico negativo (-), los pacientes con un margen de resección circunferencial patológico positivo (+) tuvieron una sobrevida libre de recidiva local (29% frente a 87%, p < 0,001), un control regional (57% frente a 94%, p < 0,001), una sobrevida libre de metástasis a distancia (43% frente a 95%, p < 0,001) y una sobrevida global (86% frente a 95%, p < 0,001) inferior en 2 años de seguimiento. Sin embargo, los subgrupos de margen de resección circunferencial (+) y (-) evaluados por imágenes de resonancia magnética nuclear en pacientes que tuvieron una respuesta clínica completa tuvieron un control regional similar, una sobrevida libre de metástasis a distancia y una sobrevida general >90% en 2 años de seguimiento.LIMITACIONES:Diseño retrospectivo, tamaño modesto de la muestra, seguimiento corto y heterogeneidad de tratamientos.CONCLUSIONES:La afectación del margen de resección circunferencial evaluado por resonancia magnética nuclear al momento del diagnóstico es un fuerte factor predictivo no clínico de respuesta completa. Sin embargo, los pacientes que logran una respuesta clínica completa después de un curso corto de radioterapia y quimioterapia de consolidación como manejo conservador tienen excelentes resultados clínicos independientemente del estado del margen de resección circunferencial inicial. Consulte Video Resumen en http://links.lww.com/DCR/C190 . (Traducción-Dr. Xavier Delgadillo ).

Radiation-Induced Cardiovascular Toxicities.

OPINION STATEMENT: Several seminal papers over the last decade have furthered our recognition of radiation-induced heart disease (RIHD) as an important potential toxicity following radiation therapy (RT) to the chest. Investigators continue to evaluate the subacute and long-term effects of RT. In addition, studies are determining whether certain cardiac substructures are more sensitive to radiation, working to identify risk factors for the development of RIHD, and testing screening and mitigation strategies for RIHD. Multiple groups and expert consensus guidelines have published whole-heart and cardiac substructure dose constraints based on available data and cancer type. The authors recommend readers to familiarize themselves with the guidelines for screening and mitigating RIHD in adults and children, which advocate for cardiovascular risk assessment and reduction before and following RT, as well as cardiovascular imaging at appropriate follow-up intervals for early recognition of subclinical cardiovascular disease. Referrals to cardiology or cardio-oncology can also be helpful in prevention, screening, and mitigation strategies.

A multi-institutional analysis of clinical outcomes and patterns of care of 1p/19q codeleted oligodendrogliomas treated with adjuvant or salvage radiation therapy.

PURPOSE: Practice patterns vary for adjuvant treatment of 1p/19q-codeleted oligodendroglioma patients. This study evaluates the outcomes of adjuvant (aRT) versus salvage radiation therapy (sRT) in a multi-institutional cohort. METHODS: Oligodendroglioma patients with confirmed 1p/19q codeletion who were treated with RT with or without chemotherapy from 2000 to 2017 at four tertiary centers were retrospectively reviewed. Overall survival (OS), post-RT progression-free survival (PFS), freedom-from-RT (FFRT), and radiation necrosis (RN) rates were determined using Kaplan-Meier analyses. OS1/PFS1 were defined from the initial surgery. OS2/PFS2 were defined from the RT start-date. Multivariable analyses (MVAs) of prognostic factors for OS and PFS were performed with Cox regression. RESULTS: One hundred eighty-six patients were identified: 124(67%) received aRT and 62(33%) received sRT; of sRT patients, 58% were observed after surgery while 42% received chemotherapy without aRT. The median time from initial diagnosis to sRT was 61 months, and 74% had reoperations before sRT. sRT had longer OS1 than aRT (94% vs. 69% at 10 years, p = 0.03) and PFS1 (10-year PFS of 80% vs. 68%, p = 0.03), though sRT was not associated with significantly different OS1/PFS1 on MVAs. Chemotherapy did not delay sRT compared to observation and had worse PFS2 (42% vs. 79% at 5 years, p = 0.08). Higher RT dose was not associated with improved clinical outcomes but was associated with higher symptomatic RN rate (15% vs. 0% at 2 years, p = 0.003). CONCLUSIONS: Delaying RT for selected oligodendroglioma patients appears safe. Adjuvant chemotherapy does not delay sRT longer than observation and may be associated with worse PFS after RT.

Minimal acute toxicity from proton beam therapy for major salivary gland cancer.

Introduction: Proton beam therapy (PBT) reduces normal organ dose compared to intensity-modulated radiation therapy (IMRT) for patients with major salivary gland tumors. It is not known whether this dosimetric advantage is clinically meaningful for reducing acute toxicity.Methods: We evaluated treatment parameters and acute toxicity outcomes of patients with major salivary gland cancers enrolled on the Proton Collaborative Group REG001-09 trial (NCT01255748).Results: One-hundred and five patients with a median age of 61 years were included. The majority had parotid (N = 90) versus submandibular gland (N = 15) tumors. The patients were treated across seven institutions in the United States between 2010 and 2017, most commonly in the postoperative setting (70.5%) although a minority were treated definitively (29.5%). Median PBT dose was 66.5 GyE in 33 fractions; only one patient was prescribed less than 50 GyE. Chemotherapy was given concurrently to 20%. Median follow-up was 14.3 months. Acute grade 2 or higher toxicity included nausea (1.5%), dysgeusia (4.8%), xerostomia (7.6%), mucositis (10.5%) and dysphagia (10.5%).Conclusions: PBT should be strongly considered when ipsilateral radiation therapy is indicated for major salivary gland cancer based on a considerably lower incidence of acute grade 2 or higher toxicity in this analysis compared to historical IMRT outcomes.

Evaluation of Cancer Specific Mortality with Surgery versus Radiation as Primary Therapy for Localized High Grade Prostate Cancer in Men Younger Than 60 Years.

PURPOSE: The optimal primary treatment of localized high grade prostate cancer in younger men remains controversial. The objective of this project was to compare the impact of initial radical prostatectomy vs radiation therapy on survival outcomes in young men less than 60 years old with high grade prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed the records of men younger than 60 years in the SEER (Surveillance, Epidemiology and End Results) database who underwent initial surgery or radiation therapy of high grade (Gleason score 8 or greater) localized (N0M0 TNM stage) prostate cancer from 2004 to 2012. Univariate and multivariate Cox proportional hazards regression models were used to examine prostate cancer specific and overall mortality. RESULTS: A total of 2,228 men were identified, of whom 1,459 (65.5%) underwent initial surgery and had a median followup of 43 months and 769 (34.5%) underwent initial external beam radiation therapy with or without brachytherapy and had a median followup of 44 months. On multivariate analysis initial treatment with surgery was associated with improved prostate cancer specific and overall mortality compared with initial radiation treatment (HR 0.37, 95% CI 0.19-0.74, p = 0.005 vs HR 0.41, 95% CI 0.24-0.70, p = 0.001) when controlling for age, biopsy Gleason score, T stage and prostate specific antigen. CONCLUSIONS: Our data showed significant survival differences in young men treated initially with surgery vs external beam radiation therapy of high grade prostate cancer. Future prospective randomized trials are needed to confirm the long-term outcomes of these treatment approaches.

NRG brain tumor specialists consensus guidelines for glioblastoma contouring.

INTRODUCTION: NRG protocols for glioblastoma allow for clinical target volume (CTV) reductions at natural barriers; however, literature examining CTV contouring and the relevant white matter pathways is lacking. This study proposes consensus CTV guidelines, with a focus on areas of controversy while highlighting common errors in glioblastoma target delineation. METHODS: Ten academic radiation oncologists specializing in brain tumor treatment contoured CTVs on four glioblastoma cases. CTV expansions were based on NRG trial guidelines. Contour consensus was assessed and summarized by kappa statistics. A meeting was held to discuss the mathematically averaged contours and form consensus contours and recommendations. RESULTS: Contours of the cavity plus enhancement (mean kappa 0.69) and T2-FLAIR signal (mean kappa 0.74) showed moderate to substantial agreement. Experts were asked to trim off anatomic barriers while respecting pathways of spread to develop their CTVs. Submitted CTV_4600 (mean kappa 0.80) and CTV_6000 (mean kappa 0.81) contours showed substantial to near perfect agreement. Simultaneous truth and performance level estimation (STAPLE) contours were then reviewed and modified by group consensus. Anatomic trimming reduced the amount of total brain tissue planned for radiation targeting by a 13.6% (range 8.7-17.9%) mean proportional reduction. Areas for close scrutiny of target delineation were described, with accompanying recommendations. CONCLUSIONS: Consensus contouring guidelines were established based on expert contours. Careful delineation of anatomic pathways and barriers to spread can spare radiation to uninvolved tissue without compromising target coverage. Further study is necessary to accurately define optimal target volumes beyond isometric expansion techniques for individual patients.

Multi-institutional external validation of a novel glioblastoma prognostic nomogram incorporating MGMT methylation.

A recent nomogram for glioblastoma (GBM) was designed to incorporate methylguanine-DNA methyltransferase (MGMT) methylation status in trial patients receiving temozolomide. Since clinical trial patients are strictly selected, compared to the general population, we performed a multi-institutional, external, independent assessment of the nomogram. Consecutive adult patients with supratentorial GBM diagnosed between June 2007 and December 2014 who initiated TMZ-based concurrent chemoradiotherapy (CRT) and were not enrolled on RTOG 0525 or 0825 were eligible. We collected age, gender, MGMT status, performance status, resection extent, race, and tumor site and Cox regression analysis of overall survival (OS) was conducted with the 1-year nomogram-predicted survival (NPS). The predictive accuracy was quantified by the concordance index (c-index) as well as by separating patients into quintile-groups of the population distribution of NPS and comparing mean NPS and observed OS. Of 514 patients with GBM, 309 had all nomogram factors. Median OS was 18.7 months. NPS and observed OS demonstrated a c-index of 0.695. On univariate analysis, the NPS and all included factors except gender were significant. On multivariable analysis (MVA) the only significant factor for worse survival was lower NPS. When separated into quintile-groups of NPS, the observed survival was slightly better than the predicted survival for all but the worst prognostic group. Our multi-institutional cohort provides independent external validation of a novel GBM nomogram incorporating MGMT methylation status. No individual factor included in the nomogram retained significance on MVA after adjusting for NPS.

Rectal dose to prostate cancer patients treated with proton therapy with or without rectal spacer.

The purpose of this study was to evaluate whether a spacer inserted in the prerectal space could reduce modeled rectal dose and toxicity rates for patients with prostate cancer treated in silico with pencil beam scanning (PBS) proton therapy. A total of 20 patients were included in this study who received photon therapy (12 with rectal spacer (DuraSeal™ gel) and 8 without). Two PBS treatment plans were retrospectively created for each patient using the following beam arrangements: (1) lateral-opposed (LAT) fields and (2) left and right anterior oblique (LAO/RAO) fields. Dose volume histograms (DVH) were generated for the prostate, rectum, bladder, and right and left femoral heads. The normal tissue complication probability (NTCP) for ≥grade 2 rectal toxicity was calculated using the Lyman-Kutcher-Burman model and compared between patients with and without the rectal spacer. A significantly lower mean rectal DVH was achieved in patients with rectal spacer compared to those without. For LAT plans, the mean rectal V70 with and without rectal spacer was 4.19 and 13.5%, respectively. For LAO/RAO plans, the mean rectal V70 with and without rectal spacer was 5.07 and 13.5%, respectively. No significant differences were found in any rectal dosimetric parameters between the LAT and the LAO/RAO plans generated with the rectal spacers. We found that ≥ 9 mm space resulted in a significant decrease in NTCP modeled for ≥grade 2 rectal toxicity. Rectal spacers can significantly decrease modeled rectal dose and predicted ≥grade 2 rectal toxicity in prostate cancer patients treated in silico with PBS. A minimum of 9 mm separation between the prostate and anterior rectal wall yields the largest benefit.

Script-based implementation of automatic grid placement for lattice stereotactic body radiation therapy.

Background and purpose: Spatially fractionated radiation therapy (SFRT) has demonstrated promising clinical response in treating large tumors with heterogeneous dose distributions. Lattice stereotactic body radiation therapy (SBRT) is an SFRT technique that leverages inverse optimization to precisely localize regions of high and lose dose within disease. The aim of this study was to evaluate an automated heuristic approach to sphere placement in lattice SBRT treatment planning. Materials and methods: A script-based algorithm for sphere placement in lattice SBRT based on rules described by protocol was implemented within a treatment planning system. The script was applied to 22 treated cases and sphere distributions were compared with manually placed spheres in terms of number of spheres, number of protocol violations, and time required to place spheres. All cases were re-planned using script-generated spheres and plan quality was compared with clinical plans. Results: The mean number of spheres placed excluding those that violate rules was greater using the script (13.8) than that obtained by either dosimetrist (10.8 and 12.0, p < 0.001 and p = 0.003) or physicist (12.7, p = 0.061). The mean time required to generate spheres was significantly less using the script (2.5 min) compared to manual placement by dosimetrists (25.0 and 29.9 min) and physicist (19.3 min). Plan quality indices were similar in all cases with no significant differences, and OAR constraints remained met on all plans except two. Conclusion: A script placed spheres for lattice SBRT according to institutional protocol rules. The script-produced placement was superior to that of manually-specified spheres, as characterized by sphere number and rule violations.

A Pilot Study of Simulation-Free Hippocampal-Avoidance Whole Brain Radiation Therapy Using Diagnostic MRI-Based and Online Adaptive Planning.

PURPOSE: We aimed to demonstrate the clinical feasibility and safety of simulation-free hippocampal avoidance whole brain radiation therapy (HA-WBRT) in a pilot study (National Clinical Trial 05096286). METHODS AND MATERIALS: Ten HA-WBRT candidates were enrolled for treatment on a commercially available computed tomography (CT)-guided linear accelerator with online adaptive capabilities. Planning structures were contoured on patient-specific diagnostic magnetic resonance imaging (MRI), which were registered to a CT of similar head shape, obtained from an atlas-based database (AB-CT). These patient-specific diagnostic MRI and AB-CT data sets were used for preplan calculation, using NRG-CC001 constraints. At first fraction, AB-CTs were used as primary data sets and deformed to patient-specific cone beam CTs (CBCT) to give patient-matched density information. Brain, ventricle, and brain stem contours were matched through rigid translation and rotation to the corresponding anatomy on CBCT. Lens, optic nerve, and brain contours were manually edited based on CBCT visualization. Preplans were then reoptimized through online adaptation to create final, simulation-free plans, which were used if they met all objectives. Workflow tasks were timed. In addition, patients underwent CT-simulation to create immobilization devices and for prospective dosimetric comparison of simulation-free and simulation-based plans. RESULTS: Median time from MRI importation to completion of "preplan" was 1 weekday (range, 1-4). Median on-table workflow duration was 41 minutes (range, 34-70). NRG-CC001 constraints were achieved by 90% of the simulation-free plans. One patient's simulation-free plan failed a planning target volume coverage objective (89% instead of 90% coverage); this was deemed acceptable for first-fraction delivery, with an offline replan used for subsequent fractions. Both simulation-free and simulation CT-based plans otherwise met constraints, without clinically meaningful differences. CONCLUSIONS: Simulation-free HA-WBRT using online adaptive radiation therapy is feasible, safe, and results in dosimetrically comparable treatment plans to simulation CT-based workflows while providing convenience and time savings for patients.

A Phase 1/2 Study of Disulfiram and Copper With Concurrent Radiation Therapy and Temozolomide for Patients With Newly Diagnosed Glioblastoma.

PURPOSE: This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS: Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry. RESULTS: Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors. CONCLUSIONS: The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation.

Impact of time of day on outcomes after stereotactic radiosurgery for non-small cell lung cancer brain metastases.

BACKGROUND: This study tested the hypothesis that time of day of treatment with stereotactic radiosurgery (SRS) has an effect on local control (LC) and overall survival (OS) in a large cohort of patients with non-small cell lung cancer (NSCLC) brain metastases. METHODS: At Washington University in St. Louis, 437 patients with NSCLC were treated with SRS for NSCLC brain metastases. Receiver operating characteristics analysis was used to identify an optimal cut-point for OS relative to time of day. Kaplan-Meier log-rank statistics, and Cox regression univariate and multivariate analysis were employed to isolate any independent effect of treatment time on OS and LC. Matched-pair analysis was performed to isolate any independent effect of time on OS and LC of day while controlling for confounding variables. RESULTS: Receiver operating characteristics analysis identified a cut-point of 11:41 AM as providing the highest predictive value for OS. On univariate analysis, late SRS was associated with decreased OS, as was age, Karnofsky performance status, risk-stratification schemes, extracranial disease status, and overall burden of brain metastases. On univariate analysis for LC, late SRS was associated with decreased LC, as was burden of brain metastases. On multivariate analysis, only Graded Prognostic Assessment remained predictive of OS, and total number of targets and total tumor volume remained predictive of LC. Matched-pair analysis demonstrated no significant effect of time of day on LC or OS. CONCLUSIONS: Although earlier treatment appears to be associated with improved LC and OS, treatment time fails to remain significant when accounting for confounding variables.

Cost-efficacy of acceleration partial-breast irradiation compared with whole-breast irradiation.

The purpose of this study was to analyze the cost-efficacy of multiple accelerated partial-breast irradiation (APBI) techniques compared with whole breast irradiation (WBI) delivered utilizing 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiation therapy (IMRT). A previously reported matched-pair analysis consisting of 199 patients receiving WBI and 199 patients receiving interstitial APBI formed the basis of this analysis. Cost analyses included a cost minimization analysis, incremental cost- effectiveness ratio (ICER) analysis, and cost per quality adjusted life year (QALY) analysis. Per 1,000 patients treated, the cost savings with the utilization of APBI compared to WBI IMRT is $14.9 million, $10.9 million, $8.8 million, $5.0 million, and $9.7 million for APBI 3D-CRT, APBI IMRT, APBI single-lumen (SL), APBI multi-lumen (ML), and APBI interstitial, respectively. Per 1,000 patients treated, the cost savings with the utilization of APBI compared to WBI 3D-CRT is $6.0 million, $2.0 million, and $0.7 million for APBI 3D-CRT, APBI IMRT, and APBI interstitial, respectively. The cost per QALY for APBI SL, APBI ML, and APBI interstitial compared with APBI 3D-CRT are $12,273, $66,032, and $546, respectively. When incorporating non-medical costs and cost of recurrences the cost per QALY was $54,698 and $49,009 for APBI ML compared with APBI 3D-CRT. When compared to WBI IMRT, all APBI techniques are cost-effective based on cost minimization, ICER, and QALY analyses. When compared to WBI 3D-CRT, external beam APBI techniques represent a more cost-effective approach based on cost minimization with brachytherapy representing a cost-effective approach based on cost per QALY.

Treatment efficacy with accelerated partial breast irradiation (APBI): final analysis of the American Society of Breast Surgeons MammoSite(®) breast brachytherapy registry trial.

BACKGROUND: The purpose of this study was to examine data on treatment efficacy, cosmesis and toxicities for the final analysis of the American Society of Breast Surgeons MammoSite(®) breast brachytherapy registry trial. METHODS: A total of 1,449 cases of early-stage breast cancer underwent breast conserving therapy. The single-lumen MammoSite(®) device was used to deliver accelerated partial breast irradiation (APBI) (34 Gy in 3.4 Gy fractions). Of these, 1,255 cases (87 %) had invasive breast cancer (IBC) and 194 cases had DCIS. Median follow-up was 63.1 months with 45 % of all patients having follow-up of 6 years or longer. RESULTS: There were 41 cases (2.8 %) that developed an ipsilateral breast tumor recurrence (IBTR) for a 5-year actuarial rate of 3.8 % (3.7 % for IBC and 4.1 % for DCIS). Tumor size (odds ratio [OR] = 1.1, p = 0.03) and estrogen receptor negativity (OR = 3.0, p = 0.0009) were associated with IBTR, while a trend was noted for positive margins (OR = 2.0, p = 0.06) and cautionary/unsuitable status compared with suitable status (OR = 1.8, p = 0.07). The percentage of patients with excellent/good cosmetic results at 60, 72, and 84 months was 91.3, 90.5, and 90.6 %, respectively. The overall rates of fat necrosis and infections remained low at 2.5 and 9.6 % with few late toxicity events beyond 2 years. The overall symptomatic seroma rate was 13.4 and 0.6 % beyond 2 years. CONCLUSIONS: The final analysis of treatment efficacy, cosmesis, and toxicity from the American Society of Breast Surgeons MammoSite(®) breast brachytherapy registry trial confirms previously noted excellent results and compares favorably with other forms of APBI with similar follow-up and to outcomes seen in selected patients treated with whole breast irradiation.

A pilot phase Ib study to evaluate tadalafil to overcome immunosuppression during chemoradiotherapy for IDH-wild-type glioblastoma.

Background: Myeloid-derived suppressor cells (MDSCs) are critical regulators of immunosuppression and radioresistance in glioblastoma (GBM). The primary objective of this pilot phase Ib study was to validate the on-target effect of tadalafil on inhibiting MDSCs in peripheral blood and its safety when combined with chemoradiotherapy in GBM patients. Methods: Patients with newly diagnosed IDH-wild-type GBM received radiation therapy (RT) and temozolomide (TMZ) combined with oral tadalafil for 2 months. A historical cohort of 12 GBM patients treated with RT and TMZ was used as the comparison group. The ratio of MDSCs, T cells, and cytokines at week 6 of RT compared to baseline were analyzed using flow cytometry. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Tadalafil was well tolerated with no dose-limiting toxicity among 16 evaluable patients. The tadalafil cohort had a significantly lower ratio of circulating MDSCs than the control: granulocytic-MDSCs (mean 0.78 versus 3.21, respectively, P = 0.01) and monocytic-MDSCs (1.02 versus 1.96, respectively, P = 0.006). Tadalafil increased the CD8 ratio compared to the control (1.99 versus 0.70, respectively, P < 0.001), especially the PD-1-CD8 T cells expressing Ki-67, CD38, HLA-DR, CD28, and granzyme B. Proinflammatory cytokine IL-1ß was also significantly increased after tadalafil compared to the control. The tadalafil cohort did not have significantly different PFS and OS than the historical control. Conclusions: Concurrent tadalafil is well tolerated during chemoradiotherapy for GBM. Tadalafil is associated with a reduction of peripheral MDSCs after chemoradiotherapy and increased CD8 T-cell proliferation and activation.

A pilot study of same-day MRI-only simulation and treatment with MR-guided adaptive palliative radiotherapy (MAP-RT).

We conducted a prospective pilot study evaluating the feasibility of same day MRI-only simulation and treatment with MRI-guided adaptive palliative radiotherapy (MAP-RT) for urgent palliative indications (NCT#03824366). All (16/16) patients were able to complete 99% of their first on-table attempted fractions, and no grades 3-5 toxicities occurred.

Prospective In Silico Evaluation of Cone-Beam Computed Tomography-Guided StereoTactic Adaptive Radiation Therapy (CT-STAR) for the Ablative Treatment of Ultracentral Thoracic Disease.

Purpose: We conducted a prospective, in silico study to evaluate the feasibility of cone-beam computed tomography (CBCT)-guided stereotactic adaptive radiation therapy (CT-STAR) for the treatment of ultracentral thoracic cancers (NCT04008537). We hypothesized that CT-STAR would reduce dose to organs at risk (OARs) compared with nonadaptive stereotactic body radiation therapy (SBRT) while maintaining adequate tumor coverage. Methods and Materials: Patients who were already receiving radiation therapy for ultracentral thoracic malignancies underwent 5 additional daily CBCTs on the ETHOS system as part of a prospective imaging study. These were used to simulate CT-STAR, in silico. Initial, nonadaptive plans (PI) were created based on simulation images and simulated adaptive plans (PA) were based on study CBCTs. 55 Gy/5 fractions was prescribed, with OAR constraint prioritization over PTV coverage under a strict isotoxicity approach. PI were applied to patients' anatomy of the day and compared with daily PA using dose-volume histogram metrics, with selection of superior plans for simulated delivery. Feasibility was defined as completion of the end-to-end adaptive workflow while meeting strict OAR constraints in ≥80% of fractions. CT-STAR was performed under time pressures to mimic clinical adaptive processes. Results: Seven patients were accrued, 6 with intraparenchymal tumors and 1 with a subcarinal lymph node. CT-STAR was feasible in 34 of 35 simulated fractions. In total, 32 dose constraint violations occurred when the PI was applied to anatomy-of-the-day across 22 of 35 fractions. These violations were resolved by the PA in all but one fraction, in which the proximal bronchial tree dose was still numerically improved through adaptation. The mean difference between the planning target volume and gross total volume V100% in the PI and the PA was -0.24% (-10.40 to 9.90) and -0.62% (-11.00 to 8.00), respectively. Mean end-to-end workflow time was 28.21 minutes (18.02-50.97). Conclusions: CT-STAR widened the dosimetric therapeutic index of ultracentral thorax SBRT compared with nonadaptive SBRT. A phase 1 protocol is underway to evaluate the safety of this paradigm for patients with ultracentral early-stage NSCLC.

Pre-radiotherapy ctDNA liquid biopsy for risk stratification of oligometastatic non-small cell lung cancer.

The optimal treatment for patients with oligometastatic non-small cell lung cancer (NSCLC) remains unclear. Some patients with oligometastatic disease can experience prolonged remission after locally consolidative radiation therapy (RT), while others harbor micrometastatic disease (below current limits of detection by imaging) that may benefit from further prioritization of systemic therapy. To better risk-stratify this population and identify the patients most likely to benefit from locally consolidative radiation therapy, we performed a multi-institutional cohort study of patients with oligometastatic NSCLC undergoing liquid biopsy analysis of circulating tumor DNA (ctDNA). Among this real-world cohort of 1,487 patients undergoing analysis (using the Tempus xF assay), a total of 1,880 ctDNA liquid biopsies along with paired clinical data were obtained across various timepoints. Approximately 20% (n=309) of patients had ctDNA obtained prior to RT and after their diagnosis of oligometastatic disease. Samples were de-identified and analyzed for mutational burden and variant frequencies of detectable deleterious (or likely deleterious) mutations in plasma. Patients with undetectable ctDNA before RT had significantly improved progression-free survival and overall survival compared to patients with detectable ctDNA prior to RT. In patients that received RT, 598 pathogenic (or likely deleterious) variants were identified. ctDNA mutational burden pre-RT and ctDNA maximum variant allele frequency (VAF) pre-RT were both significantly inversely correlated with both progression-free (P = 0.0031 for mutational burden, P = 0.0084 for maximum VAF) and overall survival (P = 0.045 for mutational burden, P = 0.0073 for maximum VAF). Patients without detectable ctDNA prior to RT had significantly improved progression-free survival (P = 0.004) and overall survival (P = 0.03) compared to patients with detectable ctDNA prior to RT. These data suggest that in patients with oligometastatic NSCLC, pre-radiotherapy ctDNA analysis can potentially identify the patients most likely to benefit from locally consolidative RT and experience prolonged progression-free and overall survival. Similarly, ctDNA may be useful to identify those patients with undiagnosed micrometastatic disease, in whom it may be appropriate to prioritize systemic therapy.

Pre-radiotherapy ctDNA liquid biopsy for risk stratification of oligometastatic non-small cell lung cancer.

The optimal treatment paradigm for patients with oligometastatic non-small cell lung cancer (NSCLC) remains unclear. Some patients with oligometastatic disease experience prolonged remission after locally consolidative radiation therapy (RT), while others harbor micrometastatic disease (below limits of detection by imaging) and benefit from systemic therapy. To risk-stratify and identify the patients most likely to benefit from locally consolidative RT, we performed a multi-institutional cohort study of 1487 patients with oligometastatic NSCLC undergoing liquid biopsy analysis of circulating tumor DNA (ctDNA). In total, 1880 liquid biopsies were performed and approximately 20% of patients (n = 309) had ctDNA measured prior to RT and after their diagnosis of oligometastatic disease. Patients with undetectable ctDNA (pathogenic or likely pathogenic variants in plasma using the Tempus xF assay) before RT had significantly improved progression-free survival (PFS) (P = 0.004) and overall survival (OS) (P = 0.030). ctDNA maximum variant allele frequency (VAF) pre-RT and ctDNA mutational burden pre-RT were both significantly inversely correlated with PFS (maximum VAF P = 0.008, mutational burden P = 0.003) and OS (maximum VAF P = 0.007, mutational burden P = 0.045). These findings were corroborated by multivariate Cox proportional hazards models that included eight additional clinical and genomic parameters. Overall, these data suggest that in patients with oligometastatic NSCLC, pre-RT ctDNA can potentially identify the patients most likely to benefit from locally consolidative RT and experience prolonged PFS and OS. Similarly, ctDNA may be useful to identify undiagnosed micrometastatic disease where it may be appropriate to prioritize systemic therapies.