12011 Background: NRG-CC003, a phase II/III study, randomized 393 patients with small cell lung cancer to prophylactic cranial irradiation (PCI) with or without Hippocampal Avoidance (HA). “Hopefulness” is a cognitive construct based on 3 components: goals; pathways to reach those goals; and agency (i.e., motivation to embark on the pathway). Hope can be measured with validated instruments. Since hope is cognitive in nature, the existence of a “hope center” in the brain -- most likely in the hippocampus -- has been hypothesized. One exploratory objective of NRG-CC003 posited that if hope levels (measured pre- and post-PCI) were better maintained in patients randomized to PCI+HA (in comparison to patients treated by PCI without hippocampal protection), then the hippocampus would, indeed, be implicated as part of the mechanism of hopefulness. Methods: In both arms, PCI consisted of 10 fractions of 2.5 Gy. The Adult Hope Scale (AHS) was administered at time-zero and at 6-months. With regard to patient reported outcome (PRO) measures, the EORTC QLQ-C30 was administered at baseline and then at 3, 6-, 12-, 18- and 24-month intervals. Comparisons of AHS scores by arm were made using Wilcoxon-Mann-Whitney tests, and correlation of AHS with EORTC QLQ-C30 by Pearson correlation coefficients. Results: Approximately 95% of patients completed the AHS at baseline and 67% filled out the questionnaire at 6-months which paralleled the completion rates of the conventional tools for QOL and neurocognition that were employed in the study. When comparing hope levels (change from baseline to 6 months) there was no significant difference (p > 0.05) between the two arms of the trial (PCI vs PCI + HA). There was a significant correlation for the components of hopefulness with QOL; specifically, between change in agency score and QLQ-C30 global health status (p < 0.0001) as well as between change in pathways score and QLQ-C30 global health status (p = 0.022). Conclusions: It is feasible to study hopefulness in the context of prospective trials conducted within the NCTN. The hippocampus could not be implicated as a critical structure in a central pathway that coordinates hopefulness. Whether these data categorically refute the “hope-hippocampal hypothesis” will be discussed vis-à-vis several caveats (e.g., selection of AHS; presence of sufficient cognitive reserve post-irradiation; adequacy of the dose-delta between the 2 arms to cause differential levels of damage to the purported hope center). For the first time, a validated tool prospectively established a relationship between hope and quality of life among patients with cancer. Given previous NRG studies correlating QOL with oncologic endpoints (e.g., local control and survival), modelling will be carried out to determine if hope mediates, results from, or is associated with these endpoints. Clinical trial information: NCT02635009 .

Background Patients with locally advanced non-small-cell lung cancer (NSCLC) who undergo concurrent chemotherapy and radiotherapy often experience synergistic toxicity, and local regional control rates remain poor. We assessed the activity and safety outcomes of primary tumour stereotactic body radiotherapy (SBRT) followed by conventional chemoradiotherapy to the lymph nodes and consolidation immunotherapy in patients with unresectable locally advanced NSCLC. Methods In this multicentre, single-arm, phase 2 trial, patients aged 18 years and older were enrolled at eight regional cancer centres in North Carolina and South Carolina, USA. Patients were eligible if they had stage II-III, unresectable, locally advanced NSCLC (any histology), with peripheral or central primary tumours that were 7 cm or smaller, excluding central tumours within 2 cm of involved nodal disease, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients who had previously received systemic therapy or radiotherapy were excluded. Participants received SBRT to the primary tumour (50-54 Gy in three to five fractions) followed by standard radiotherapy (planned up to 60 Gy in 30 2 Gy fractions) to the involved lymph nodes with concurrent platinum doublet chemotherapy (either paclitaxel 50 mg/m2 intravenously plus carboplatin area under the curve mg/mL per min every 7 days for a total of six 1-week cycles or etoposide 50 mg/m2 intravenously on days 1-5 and days 29-33 plus cisplatin 50 mg/m2 intravenously on days 1, 8, 29, and 36 for two cycles of 4 weeks). An amendment to the protocol (Dec 11, 2017) permitted the administration of consolidation durvalumab at the discretion of the treating investigator. An additional protocol amendment on Jan 13, 2021, directed patients without disease progression after chemoradiotherapy to receive consolidation durvalumab (10 mg/kg intravenously on day 1 and day 15 of a 4-week cycle for up to 12 cycles or 1500 mg intravenously on day 1 of a 4-week cycle for up to 12 cycles). The primary endpoint was 1-year progression-free survival (per Response Evaluation Criteria in Solid Tumours version 1.1), assessed in all participants who received at least one fraction of SBRT and had radiological follow-up data up to 1 year. A 1-year progression-free survival rate of greater than 60% was required to reject the null hypothesis and show significant improvement in 1-year progression-free survival. One-sided exact binomial tests were used to compare the primary endpoint versus the historical control 1-year progression-free survival rate used to determine the sample size. Safety was assessed in all patients who received at least one fraction of SBRT. This study is registered with ClinicalTrials.gov, NCT03141359, and is closed to accrual. Findings Between May 11, 2017, and June 27, 2022, 61 patients were enrolled and received at least one dose of fractionated SBRT, of whom 59 were evaluable for the primary endpoint. Median age was 67 years (IQR 61-72), 28 (46%) of 61 were female, 33 (54%) were male, 51 (84%) were White, seven (11%) were Black, and three (5%) were of other or unknown race. Of the 61 patients enrolled, 47 received at least one dose of consolidation durvalumab. As of data cutoff (July 12, 2023), median follow-up was 295 months (IQR 149-471). 1-year progression-free survival was 627% (90% CI 512-732; one-sided p=039, compared with the historical control rate), with 37 of 59 evaluable participants progression free and alive 1 year after enrolment (n=14 progressed, n=8 died). The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (nine [15%] of 61 patients), decreased white blood cell count (five [8%]), and anaemia (four [7%]). Treatment-related serious adverse events occurred in 11 (18%) of 61 patients, which included lung infection (three [5%]), pneumonitis (two [3%]), decreased neutrophil count (two [3%]), febrile neutropenia (two [3%]), and dyspnoea, hypoxia, respiratory failure, sinus tachycardia, bronchial infection, and acute kidney injury (each in one [2%] patient). Treatment-related deaths occurred in four (7%) of 61 patients (one each of respiratory failure, respiratory failure and dyspnoea, lung infection, and pneumonitis). Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Purpose We report the financial toxicity and quality-of-life outcomes of our prospective phase 1 dose-escalation study of 5-fraction stereotactic partial breast irradiation (S-PBI) for early-stage breast cancer. Materials and Methods Women with unifocal in situ or invasive epithelial histologies, clinical stages 0, I, or II with tumor size < 3 cm treated with lumpectomy were enrolled in our phase 1 5-fraction S-PBI dose-escalation trial. Our institutionally generated questionnaire on the “Patient Perspective Cost and Convenience of Care” and the EuroQol 5-Dimension 5-level questionnaire were administered to patients treated at follow-up. Results Between 2010 and 2015, 68 of the 75 patients who enrolled and completed treatment on trial completed at least some component of either the EuroQol 5-Dimension 5-level questionnaire or the “Patient Perspective Cost and Convenience of Care” questionnaire. Nearly all patients reported very high satisfaction with their treatment overall, particularly the shortened length of treatment. Over half of the patients reported some level of financial toxicity (FT) despite a significantly shortened treatment time. Patients who reported any FT were significantly younger than patients with no financial burden of treatment (means 59.2 and 63.7, respectively, P = .03). There was no difference in those who reported any level of FT based on patient race, ethnicity, marital, or employment status. This S-PBI regimen did not significantly affect quality of life over a 4-year follow-up. Conclusions These patient-reported outcomes suggest that the use of accelerated partial breast irradiation may offer low FT rates in breast cancer care, particularly for disadvantaged patient groups.

Background: These are the efficacy and toxicity outcomes of a prospective phase II trial of primary tumor stereotactic body radiation (SBRT) followed by conventional chemoradiation to the lymph nodes and consolidation immunotherapy in patients with unresectable locally advanced non-small cell lung cancer (LA NSCLC). Methods: Eligible patients included stages II-III LA NSCLC with peripheral primary tumors ≤7 cm or centrally-based tumors with ≥2 cm separation from involved nodal disease. Patients received SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by standard radiation (60 Gy in 30 fractions) to the involved lymph nodes with concurrent platinum-doublet chemotherapy. Trial amendment allowed patients without disease progression after chemoradiation to receive consolidation durvalumab. The primary endpoint was 1-year progression-free survival (PFS). Frequencies and proportions were used for reporting this primary endpoint, adverse events, and patterns of failure. Time to event endpoints, including PFS and overall survival (OS), were estimated using Kaplan Meier (KM) methods. Findings: 61 patients across 8 centers were enrolled, including 59 evaluable for the primary objective, with a median follow-up of 48.1 months. Overall grade 3 or higher toxicity related to SBRT and/or mediastinal radiation was 13·1%, with three patients (5%) developing grade 3 pneumonitis. KM-estimated PFS at 1-year for all patients was 62.8%, median PFS was 25·3 months (95% CI: 11·5, 54·1), and median OS was 47·1 months. Of the 61 patients enrolled, 47 received at least one dose of consolidation durvalumab. The KM-estimated 1-year PFS for patients who received durvalumab was 69·6%. Interpretation: SBRT to the primary tumor followed by conventional chemoradiation to the involved lymph nodes and consolidation immunotherapy was well tolerated and showed improved 1-year PFS compared to prior conventional chemoradiation trials for inoperable LA NSCLC. These findings serve as the basis for the randomized phase III study NRG Oncology LU008 (NCT05624996).Trial Registration: The trial is registered with ClinicalTrials.gov, NCT03141359.Funding: This research was supported by AstraZeneca and Atrium Health Levine Cancer.Declaration of Interest: The authors have no potential competing interests to report.Ethical Approval: This was an open-label, single-arm, phase II study approved by our Institutional Review Board and monitored by our institutional data and safety monitoring committee. All participants provided written informed consent to participate. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice at eight different centers within North and South Carolina all within the Levine Cancer Institute Atrium Health network. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice and approved by the IRB of the Levine Cancer Institute Atrium Health network (IRB approval number Pro00021247).

Purpose/Objective(s) Outcomes remain poor for unresectable LA-NSCLC treated with concurrent chemoradiation followed by immunotherapy. The primary tumor is the most common site of non-metastatic failure, and local failure (LF) is associated with overall survival (OS). While local control (LC) and OS have improved by increasing the biological effective dose with SBRT in early-stage NSCLC, SBRT use in LA-NSCLC has largely been limited to primary tumor boost after chemoradiation, which has high morbidity. A recent phase II trial of SBRT to the primary tumor and chemoradiation to involved lymph nodes demonstrated lower rates of pulmonary and cardiac toxicities relative to historical controls, while improving LC, progression-free survival (PFS), and OS. We hypothesize that replacing conventionally fractionated radiotherapy with SBRT to the primary tumor followed by concurrent chemoradiation to the mediastinum will be associated with lower rates of toxicity and improved QOL, while also improving LC, PFS, and OS. Materials/Methods LU008 is a phase III randomized trial in stage II-III NSCLC conducted by NRG Oncology (NCT05624996). Inclusion criteria include node-positive stage II-III NSCLC, medically inoperable or surgery declined, identified primary tumor ≤7 cm, ECOG performance status (PS) 0-2, and ≤4 cycles of systemic therapy prior to registration. Key exclusion includes central primary tumor location that is <2cm from involved nodal disease. Patients are randomized to chemoradiation to all disease (60/2 Gy) (control arm) or SBRT to the primary (BED ≥100 Gy in 3-5 fractions) followed by chemoradiation to nodal disease (60/2 Gy) (experimental arm). Standard concurrent chemotherapy regimens are allowed in both arms. Maintenance therapy is pragmatic, with most patients expected to receive durvalumab for up to 12 months. The primary objectives are to compare OS and PFS. Secondary objectives are to compare response rate, LC, patterns of failure, pulmonary function changes, QOL, and toxicity. Exploratory objectives include biospecimen analyses, regional lung ventilation, and proton vs. photon differences. Real-time pre-treatment reviews are conducted. Results LU008 was activated nationally on 5/10/23. As of 3/1/24, 30 patients have been accrued, and 266 sites have the trial open to accrual. Final target accrual is 474 subjects, with an expected 9.5 accruals per month after a 6-month ramp up. Conclusion LU008 is a thoracic NCI National Clinical Trial Network (NCTN) trial with highly pragmatic eligibility criteria, with no lab/PFT cutoffs, no CT chest/MRI brain/lab time windows, no exclusions for actionable mutations, and allowing ECOG PS 2. LU008 is the only phase III NCTN trial accruing for inoperable LA-NSCLC and may change the standard of care in inoperable LA-NSCLC by improving LC, PFS, and OS. Funding: Grants U10CA180868 (NRG Operations), U10CA180822 (NRG SDMC), UG1CA189867 (NCORP), U24CA196067 (NRG Specimen Bank), U24CA180803 (IROC) from the National Cancer Institute (NCI).

Purpose/Objective(s) Stereotactic body radiation therapy (SBRT) for peripheral lung tumors can result in high radiation doses to surrounding ribs. Pre-clinical studies have shown single fraction doses of 2-10 Gy increase osteoclast activity and lead to bone loss. We conducted a randomized, double-blind, placebo-controlled trial to evaluate whether early suppression of osteoclast activity could mitigate SBRT-induced rib fractures. Materials/Methods Between July 2019 and February 2022, 84 patients were enrolled. Eligible patients had lung tumors within 2 cm of chest wall and were randomized 1:1 to receive either a single dose of risedronate (150mg) or placebo delivered 7 to 21 days before SBRT (48-60 Gy in 3-10 fractions). Chest wall pain (CWP) was graded using modified CTCAE v5 assessed every 3 months after SBRT up to 1 year. Following a minimum period of one year post drug administration, a thoracic radiologist assessed all accessible imaging follow-up for fracture incidence. Results Seventy-six patients (38 placebo 38 risedronate) with 81 treated lung lesions were included in this analysis with a median follow-up of 26.3 months with a maximum of 43.4 months. Follow-up was measured from the end date of SBRT to the date of last available CT chest or date fracture detection. A total of 25 patients (33%) developed rib fractures. Median (range) values for rib (dose in EQD2, a/b = 3) and chest wall (3 cm thickness) structures are as follows: rib D0.03cc, 215 Gy (range = 52-373); rib D2cc, 101 (26-252); chest wall V30, 20 cc (0.5-314). There was no significant difference in fracture rates between risedronate and placebo groups - 13 risedronate group (34.2%) vs 12 in placebo arm (31.6%) (p = 0.2). Among those who fractured, the median time to fracture was 14.2 mo (95% CI = 9.8 - 16.9 mo) [range 5.9 - 43.4 mo] with 9 patients developing fracture within 1 year from the end of SBRT. Patients receiving risedronate had a significantly lower rate of grade 2+ CWP within 1 year post SBRT completion compared to patients who received placebo: 18% versus 42% respectively (P = 0.045), Among patients who did not develop a detectable fracture, the rate of G2+ CWP was (12 % vs 34.6% P = 0.06) favoring the risedronate arm, and similarly among those who did develop fractures, the incidence of G2+ CWP was 31% vs 58% (p = 0.17). Conclusion For patients receiving SBRT for peripheral lung tumors, the use of prophylactic risedronate, when compared to placebo, did not reduce the incidence of treatment-induced rib fractures. The use of risedronate, however, lowered the risk of G2+ CWP. The suggested protective impact of risedronate against G2 or higher CWP may point to a nerve and osteoclast cross talk mechanism contributing to the development of SBRT-induced CWP. Alternatively, risedronate may have partially reduced osteoclast activity, preventing the accumulation of microfractures that could have contributed to pain. Further investigations into the appropriate dose and type of antiresorptive agent to specifically counteract bone loss and prevent pain or fracture after thoracic SBRT are warranted

Purpose The schedule of cisplatin concurrent with definitive radiation for squamous carcinoma of the head and neck remains controversial. Most institutions deliver either a high-dose “bolus” schedule once every 3 weeks or a low-dose weekly schedule. We compared these 2 schedules via a simplified network meta-analysis with a common comparator. Methods and Materials We performed a PRISMA–concordant systematic review to identify randomized controlled trials comparing cisplatin with cetuximab for nonmetastatic, locoregionally advanced squamous carcinoma of the head and neck treated with definitive radiation. Trials incorporating primary surgery or induction therapy were excluded. Patient survival times were extracted on a per-event basis from the published curves using a digitizer and validated against published point estimates and hazard ratios (HRs). Survival was compared using random effects Cox regression under a frequentist framework. Toxicity and secondary endpoints were analyzed qualitatively. The Cochrane method assessed the risk of bias. The analysis plan was preregistered with the Open Science Foundation. Results Five randomized trials were identified, including 1678 patients. There was no statistical difference in overall survival between weekly and bolus regimens (HR, 0.90; 95% CI, 0.53-1.52, P = .345). This Cox model suggested that for the average patient in the cohort, the absolute difference in 5-year overall survival between weekly and bolus regimens was +1.2% (95% CI, −6.1%-+5.9%, P = .345). Secondary endpoints and toxicity were not obviously different by regimen, qualitatively. Conclusions The cetuximab trials provide indirect data suggesting that the differences between cisplatin schedules are subtle.

Planning the joint SBRT-IMRT plan in the cases of a significant target overlap requires a careful approach, but is feasible with the proposed guideline and should be achievable for any center electing to participate in the NRG LU-008 trial.

Purpose: Stereotactic radiosurgery (SRS) immobilization with an open face mask is more comfortable and less invasive than frame based, but concerns about intrafraction motion must be addressed. Surface-guided radiation therapy (SGRT) is an attractive option for intrafraction patient monitoring because it is continuous, has submillimeter accuracy, and uses no ionizing radiation. The purpose of this study was to investigate the dosimetric consequences of uncorrected intrafraction patient motion detected during frameless linac-based SRS.Methods and Materials: Fifty-five SRS patients were monitored during treatment using SGRT between January 1, 2017, and September 30, 2020. If SGRT detected motion >1 mm, imaging was repeated and the necessary shifts were made before continuing treatment. For the 25 patients with intrafraction 3-dimensional vector shifts of & GE;1 mm, we moved the isocenter in the planning system using the translational shifts from the repeat imaging and recalculated the plans to determine the dosimetric effect of the shifts. Planning target volume (PTV) coverage, minimum gross tumor volume (GTV) dose (relative and absolute), and normal brain V12 were evaluated. Wilcoxon signed rank tests were used to compare planned and simulated dosimetric parameters and median 2 sample tests were used to investigate these differences between cone and multileaf collimator (MLC) plans. Results: For simulated plans, V12 increased by a median of 0.01 cc (P = .006) and relative GTV minimum dose and PTV coverage decreased by a median of 15.8% (P < .001) and 10.2 % (P < .001), respectively. Absolute minimum GTV dose was found to be significantly lower in the simulated plans (P < .001). PTV coverage decreased more for simulated cone plans than for simulated MLC plans (11.6% vs 4.7%, P = .011) but median V12 differences were found to be significantly larger for MLC plans (-0.34 cc vs-0.01 cc, P = .011). Differences in GTV minimum dose between cone and MLC plans were not statistically significant.Conclusions: SGRT detected clinically meaningful intrafraction motion during frameless SRS, which could lead to large underdoses and increased normal brain dose if uncorrected.& COPY; 2023 The Authors. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Purpose/Objective(s) Prior randomized trials have demonstrated neurocognitive function (NCF) benefits of HA during whole-brain radiotherapy for non-SCLC brain metastases. NRG CC003 sought to evaluate whether HA confers similar neuroprotection and non-inferior intracranial relapse (ICR) risk following PCI for SCLC. Materials/Methods SCLC patients (pts) were stratified by age, stage and planned memantine use, and randomized to PCI or HA-PCI (25Gy in 10 fractions). Standardized NCF tests of Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Tests (TMT), and Controlled Oral Word Association (COWA) were performed at baseline, 3, 6, 12, 18 and 24 months (mos). The primary endpoints were 12-mo ICR (phase II) and 6-mo HVLT-R Delayed Recall (DR) failure, defined as decline using the reliable change index (phase III). To detect a 14.5% reduction in 6-mo HVLT-DR failure, 196 analyzable pts were required for 80% power and one-sided α=0.05. Phase III sample size was increased to 392 pts for non-compliance and death. Secondary endpoints were first failure in any NCF test and failure in other NCF tests. NCF failure was analyzed using Fisher's exact test and mixed effects models. Cumulative incidence estimated time to NCF failure (death without NCF failure was competing risk); between-arm comparison tested using Cox proportional hazards model. Results From 12/2015-6/2022, 392 pts were randomized; study closed from 10/2017-7/2020 for phase IIR analysis. Median age was 64. 70% had limited stage; 47% used memantine. Median follow-up was 14.9 mos (all pts) and 24 mos (alive pts). Grade≥3 toxicity did not differ. HA-PCI had non-inferior 12-mo ICR rate (PCI 14.8% vs. HA-PCI 14.2%, p<0.0001 to rule out inferiority). 6-mo HVLT-R DR deterioration was not significant (PCI 30.0% vs. HA-PCI 26.0%, p=0.31). Addition of HA to PCI prevented NCF failure (adjusted HR=0.77, 95% confidence interval (CI): 0.61-0.98, p=0.03). Memantine use trended to increased NCF failure (adjusted HR=1.26, 95% CI: 0.99-1.59, p=0.062); test for interaction between HA and memantine use was non-significant. HA-PCI arm had higher COWA scores at baseline (mean: PCI 31.9 vs. HA-PCI 34.4, p=0.019) and exhibited greater deterioration in COWA over time (estimate -0.259, p=0.042). There were no differences in overall survival (adjusted HR=0.83, 95% CI: 0.63-1.09, p=0.19). Conclusion While the study did not meet its HVLT-DR failure primary endpoint, HA during PCI prevents NCF failure with non-inferior ICR risk and similar survival. The NCF benefit of HA was independent of non-significant higher NCF failure risk with memantine use. Worse verbal word fluency, assessed using COWA, following HA-PCI requires further investigation given baseline between-arm imbalance in COWA scores. Supported by grants UG1CA189867 (NCORP) and U24CA180803 (IROC) from the NCI. Prior randomized trials have demonstrated neurocognitive function (NCF) benefits of HA during whole-brain radiotherapy for non-SCLC brain metastases. NRG CC003 sought to evaluate whether HA confers similar neuroprotection and non-inferior intracranial relapse (ICR) risk following PCI for SCLC. SCLC patients (pts) were stratified by age, stage and planned memantine use, and randomized to PCI or HA-PCI (25Gy in 10 fractions). Standardized NCF tests of Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Tests (TMT), and Controlled Oral Word Association (COWA) were performed at baseline, 3, 6, 12, 18 and 24 months (mos). The primary endpoints were 12-mo ICR (phase II) and 6-mo HVLT-R Delayed Recall (DR) failure, defined as decline using the reliable change index (phase III). To detect a 14.5% reduction in 6-mo HVLT-DR failure, 196 analyzable pts were required for 80% power and one-sided α=0.05. Phase III sample size was increased to 392 pts for non-compliance and death. Secondary endpoints were first failure in any NCF test and failure in other NCF tests. NCF failure was analyzed using Fisher's exact test and mixed effects models. Cumulative incidence estimated time to NCF failure (death without NCF failure was competing risk); between-arm comparison tested using Cox proportional hazards model. From 12/2015-6/2022, 392 pts were randomized; study closed from 10/2017-7/2020 for phase IIR analysis. Median age was 64. 70% had limited stage; 47% used memantine. Median follow-up was 14.9 mos (all pts) and 24 mos (alive pts). Grade≥3 toxicity did not differ. HA-PCI had non-inferior 12-mo ICR rate (PCI 14.8% vs. HA-PCI 14.2%, p<0.0001 to rule out inferiority). 6-mo HVLT-R DR deterioration was not significant (PCI 30.0% vs. HA-PCI 26.0%, p=0.31). Addition of HA to PCI prevented NCF failure (adjusted HR=0.77, 95% confidence interval (CI): 0.61-0.98, p=0.03). Memantine use trended to increased NCF failure (adjusted HR=1.26, 95% CI: 0.99-1.59, p=0.062); test for interaction between HA and memantine use was non-significant. HA-PCI arm had higher COWA scores at baseline (mean: PCI 31.9 vs. HA-PCI 34.4, p=0.019) and exhibited greater deterioration in COWA over time (estimate -0.259, p=0.042). There were no differences in overall survival (adjusted HR=0.83, 95% CI: 0.63-1.09, p=0.19). While the study did not meet its HVLT-DR failure primary endpoint, HA during PCI prevents NCF failure with non-inferior ICR risk and similar survival. The NCF benefit of HA was independent of non-significant higher NCF failure risk with memantine use. Worse verbal word fluency, assessed using COWA, following HA-PCI requires further investigation given baseline between-arm imbalance in COWA scores. Supported by grants UG1CA189867 (NCORP) and U24CA180803 (IROC) from the NCI.

PURPOSE:Stereotactic body radiation therapy (SBRT) has been used with high effectiveness in early-stage non-small cell lung cancer (NSCLC) but has not been studied extensively in locally advanced NSCLC. We conducted a phase 2 study delivering SBRT to the primary tumor followed by conventionally fractionated chemoradiation to the involved lymph nodes for patients with node-positive locally advanced NSCLC. This manuscript serves as both a guide to planning techniques used on this trial and the subsequent phase 3 study, NRG Oncology LU-008, and to report patient dosimetry and toxicity results. METHODS AND MATERIALS:We initiated a phase 2 multicenter single arm study evaluating SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by conventionally fractionated chemoradiation to 60 Gy in 2 Gy fractions with doublet chemotherapy to the involved lymph nodes for patients with stage III or unresectable stage II NSCLC. Patients eligible for adjuvant immunotherapy received up to 12 months of durvalumab. We report a detailed guide for the entire treatment process from computed tomography simulation through treatment planning and delivery. The dosimetric outcomes from the 60 patients who completed therapy on study are reported both for target coverage and normal structure doses. We also report correlation between radiation-related toxicities and dosimetric parameters. RESULTS:Sixty patients were enrolled between 2017 and 2022. Planning techniques used were primarily volumetric modulated arc therapy for SBRT to the primary tumor and conventionally fractionated radiation to the involved nodes, with a minority of cases using dynamic conformal arc technique or static dynamic multileaf collimator intensity modulated radiation therapy. Grade 2 or higher pneumonitis was associated with lung dose V5 Gy > 70% and grade 2 or higher pulmonary toxicity was associated with lung dose V10 Gy > 50%. Only 3 patients (5%) experienced grade 3 or higher pneumonitis. Grade 2 or higher esophagitis was associated with esophageal doses, including mean dose > 20 Gy, V60 Gy > 7%, and D1cc > 55 Gy. Only 1 patient (1.7%) experienced grade 3 esophagitis. CONCLUSIONS:SBRT to the primary tumor followed by conventionally fractionated chemoradiation to the involved lymph nodes is feasible with planning techniques as described. Radiation-related toxicity on this phase 2 study was low. This manuscript serves as a guideline for the recently activated NRG Oncology LU-008 phase 3 trial evaluating this experimental regimen.

Purpose/Objectives: Accelerated partial breast irradiation (APBI) has been shown to have both acceptable oncologic and cosmetic outcomes for early stage breast cancer following breast-conserving surgery (BCS). Given the demonstrated financial toxicity (FT) of conventional radiation treatments on breast cancer patients, we wanted to quantitatively assess the FT on patients treated with APBI in our phase I five fraction stereotactic APBI (S-PBI) trial, which could be generalized across APBI treatment regimens. Methods: A phase I dose escalation trial of S-PBI for early stage breast cancer following BCS was conducted. Women age > 18 years with in-situ or stage I-II (AJCC 7) invasive breast cancer < 3 cm following BCS with > 2 mm margins were treated with S-PBI in 5 fractions to a total dose of 30 to 40 Gy over 2.5 Gy increments (Clinical trials.gov ID NCT01162200). One month following completion of treatment, patients were asked to complete our novel “Patient Perspective Cost and Convenience of Care Questionnaire” developed at our institution. Results: Of 75 patients enrolled and treated, questionnaire data was available for 66 patients. Our trial encompassed a wide spectrum of annual household incomes, with 25.5% of patients (n=14/55) reporting income of less than $30k and 45.5% (n=25/55) reporting incomes of more than $80k. Educational status was also well represented with 53.1% completing at least some college (n= 34/64), 25% holding post graduate or professional degrees (n=16/64), and 21.9% patients reporting a high school equivalent or less (n=14/64). Overall 48.4% of patients (n=30/62) said that oncologic treatment did not present a financial burden; however, 29.0% (n=20/62) patients reported a somewhat to significant financial burden. Neither household income nor patient education status predicted perceived FT. Of the 6 patients (9.7%) who reported significant FT, 5 reported travelling at least 25 miles one way for treatment with 2 of these patient travelling over 175 miles. Half of the patients reported having private insurance for medication (49.2%, n=32/65), 33.8% had governmental coverage (n=22/65), 6.1% had both private and government coverage, 7.7% had no coverage (n=5/65), and 3.0% were unsure of their coverage (n=2/65). Only 1 of the 6 patients with significant FT had no coverage. Over half of the patients (54.2%, n=34/62) reported a co-pay during their treatment with a median out of pocket cost of $300 for treatment (range $10-10000, n=16). Over half of the patients were working full or part time during treatment (54.2%, n=32/59). All 26 patients that were working full time had to take time off work for treatment (median of 5 days, range 0.25 days – 10 days). Over a third of these patients (34.6%, n=9) had to use vacation time or unpaid time off. There was an additional patient who reported months off without pay. Additionally, 24.2% of patients (n=15/62) reported they had family or friends take time off work due to the patient’s treatment. Finally, patients were surveyed on the treatment related disruption to their daily activities and enjoyment of life rated on a scale 0-10, with 0 being no disruption, median values were 3 and 1, respectively. Patients also reported a median score of 10 (scale 0-10, 10 being most satisfied) on satisfaction with treatment time. Conclusions: In this cohort of patients, interestingly FT was significant primarily in the 10% of patients who traveled a significant distance for these treatments. However, despite this, and the fact that patients were undergoing cytotoxic cancer therapy, impressively, all patients were uniformly satisfied with treatment time (median score of 10), and most did not express significant disruption to their life. We plan to explore the impact of further reducing treatment fractions (with our single fraction S-PBI studies) on FT and quality of life in future studies. Citation Format: Ambrosia Simmons, David Sher, Dong W. Nathan Kim, Marilyn Leitch, Rachel Wooldridge, Sally Goudreau, Stephen Seiler, Sarah Neufeld, Maggie Stein, Kevin Albuquerque, Ann Spangler, John Heinzerling, Dan Gardwoood, Stella Stevenson, Chul Ahn, Chuxiong Ding, Robert Timmerman, Asal Rahimi. Financial Toxicity Outcomes on a Phase I 5-fraction Partial Breast Irradiation Protocol for Early Stage Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-55.

PURPOSE:Volumetric modulated arc therapy (VMAT) craniospinal irradiation (CSI) has been shown to have significant dosimetric advantages compared to 3-dimensional conformal therapy but is a technically complex process. We sought to develop a guide for all aspects of the VMAT CSI process and report patient dosimetry results. METHODS AND MATERIALS:We initiated VMAT CSI in 2017 and have regularly revised our standard operating procedure for this process since then. Herein, we report a detailed template for the entire VMAT CSI process from initial patient setup and immobilization at time of computed tomography (CT) simulation to contouring and treatment planning, quality assurance, and therapy delivery. The records of 12 patients who were treated with VMAT CSI were also retrospectively reviewed. RESULTS:Patient age ranged from 2 to 59 years with 5 pediatric patients (age <18 years), 5 young adults (age 18-35 years), and 2 older adults (age >35 years). The majority of patients (67%) had medulloblastoma. CSI dose ranged from 21.6 to 36 Gy, with a median of 36 Gy. The median CSI planning target volume was 2383 cc with a median V95% of 99.8% and median 0.03 cc hotspot of 112.5%. The average V107% was 7.4% and the average conformality index was 1.01. CONCLUSIONS:VMAT CSI has potentially significant dosimetric and acute toxicity advantages compared to 3-dimensional conformal. However, proper procedures need to be in place throughout the process in order to be able to realize these potential advantages. We herein describe our detailed standard operating procedure for VMAT CSI. Recognizing the scarcity of proton beam centers in many areas, VMAT CSI represents a feasible treatment with more widespread availability.

SGRT provides a reliable technique for BH SBRT treatments of the lung. Minimal target displacements on mid treatment BH CBCT were observed. Higher 4D ROM on free breathing scans correlated with larger displacements in tumor position utilizing this technique.

Despite decreasing smoking rates, lung cancer remains the leading cause of death from cancer in the United States. Radiation therapy has been established as an effective locoregional therapy for both early stage and locally advanced disease and is known to stimulate local immune response. Past treatment paradigms have established the role of combining cytotoxic chemotherapy regimens and radiation therapy to help address the local and systemic nature of lung cancer. However, these regimens have limitations in their tolerability due to toxicity. Additionally, cytotoxic chemotherapy has limited efficacy in preventing systemic spread of lung cancer. Newer systemic agents such as immune checkpoint inhibitors have shown improved survival in metastatic and locally advanced lung cancer and have the advantage of more limited toxicity profiles compared to cytotoxic chemotherapy. Furthermore, improved overall response rates and systemic tumor responses have been observed with the combination of radiation therapy and immunotherapy, leading to numerous active clinical trials evaluating the combination of immune checkpoint inhibition with radiotherapy. This comprehensive review discusses the current clinical data and ongoing studies evaluating the combination of radiation therapy and immunotherapy in both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

Metastatic epidural spinal cord compression (MESCC) is a common complication of malignancy. Surgical decompression and stabilization are commonly undertaken to prevent mechanical instability and deformity, relieve neurologic compression, and facilitate stereotactic body radiation therapy (SBRT). We report a case of an esophageal-meningeal fistula following anterior cervical corpectomy, SBRT, and bevacizumab-containing systemic therapy for MESCC. Esophageal-meningeal fistulae have been rarely reported following injury to the esophagus and dura at the time of surgery or in a delayed manner secondary to hardware failure. Our report is the first to highlight that, in the absence of such injury, anterior decompression can still create the possibility of esophageal-meningeal fistula in the treatment field.

Importance A significant subset of patients with stage II/III non-small cell lung cancer (NSCLC) cannot receive standard concurrent chemoradiotherapy owing to the risk of toxic effects outweighing potential benefits. Without concurrent chemotherapy, however, the efficacy of conventional radiotherapy is reduced. Objective To determine whether hypofractionated image-guided radiotherapy (IGRT) would improve overall survival in patients with stage II/III NSCLC who could not receive concurrent chemoradiotherapy and therefore were traditionally relegated to receiving only conventionally fractionated radiotherapy (CFRT). Design, Setting, and Participants This nonblinded, phase 3 randomized clinical study enrolled 103 patients and analyzed 96 patients with stage II/III NSCLC and Zubrod performance status of at least 2, with greater than 10% weight loss in the previous 6 months, and/or who were ineligible for concurrent chemoradiotherapy after oncology consultation. Enrollment occurred at multiple US institutions. Patients were enrolled from November 13, 2012, to August 28, 2018, with a median follow-up of 8.7 (3.6-19.9) months. Data were analyzed from September 14, 2018, to April 11, 2021. Interventions Eligible patients were randomized to hypofractionated IGRT (60 Gy in 15 fractions) vs CFRT (60 Gy in 30 fractions). Main Outcomes and Measures The primary end point was 1-year overall survival. Results A total of 103 patients (96 of whom were analyzed [63 men (65.6%); mean (SD) age, 71.0 (10.2) years (range, 50-90 years)]) were randomized to hypofractionated IGRT (n = 50) or CFRT (n = 46) when a planned interim analysis suggested futility in reaching the primary end point, and the study was closed to further accrual. There was no statistically significant difference between the treatment groups for 1-year overall survival (37.7% [95% CI, 24.2%-51.0%] for hypofractionated IGRT vs 44.6% [95% CI, 29.9%-58.3%] for CFRT; P = .29). There were also no significant differences in median overall survival, progression-free survival, time to local failure, time to distant metastasis, and toxic effects of grade 3 or greater between the 2 treatment groups. Conclusions and Relevance This phase 3 randomized clinical trial found that hypofractionated IGRT (60 Gy in 15 fractions) was not superior to CFRT (60 Gy in 30 fractions) for patients with stage II/III NSCLC ineligible for concurrent chemoradiotherapy. Further studies are needed to verify equivalence between these radiotherapy regimens. Regardless, for well-selected patients with NSCLC (ie, peripheral primary tumors and limited mediastinal/hilar adenopathy), the convenience of hypofractionated radiotherapy regimens may offer an appropriate treatment option. Trial Registration ClinicalTrials.gov Identifier: NCT01459497.

Purpose: Previous trials have shown no benefit for radiation therapy (RT) dose escalation when RT is given as adjuvant monotherapy for infiltrative low-grade glioma (LGG). However, the current standard of care for high-risk LGG is RT with concurrent and/or adjuvant chemotherapy. The effect of RT dose escalation on overall survival (OS) in the setting of concurrent and/or adjuvant chemotherapy is not well established. Methods and Materials: We used the National Cancer Database to select records for adult patients with intracranial grade 2 LGG diagnosed between 2004 and 2015. Patients must have received adjuvant external beam RT with concurrent and/or adjuvant chemotherapy. RT dose level was categorized as standard (45-54 Gy) or high (>54-65 Gy). Multivariable and propensity score matched analyses were used. Results: The study cohort consisted of 1043 patients, of whom 644 (62%) received standard dose (median, 54 Gy) and 399 (38%) received high-dose RT (median, 60 Gy). RT dose level was not associated with OS (hazard ratio, 1.2; P = .1) in multivariable analysis. Propensity score matching yielded 380 matched pairs (n = 760). There was no difference in OS for high-dose versus standard-dose RT in the matched cohort (5-year OS 64% vs 69%; P = .14) or in the 2 prespecified subgroups of astrocytoma histology and 1p/19q noncodeleted. Conclusions: Adjuvant RT dose escalation above 54 Gy in the setting of concurrent and/or adjuvant chemotherapy was not associated with improved OS for patients with infiltrative LGG in this National Cancer Database retrospective study. This was also true for the subgroups with less chemotherapy-sensitive disease, including astrocytoma histology and 1p/19q noncodeleted, although these analyses were limited by small size. Methods to improve OS other than RT dose escalation in the setting of concurrent and/or adjuvant chemotherapy should be considered for patients with poor-prognosis LGG.