•In this multi-center study of patients with unresectable locally advanced non-small cell lung cancer undergoing concurrent chemoradiation followed by durvalumab, central nervous system (CNS) metastases developed in 16.6% of patients, higher than previously reported in the literature.•Higher baseline stage (IIIB/C vs. IIIA) and an interval of >3 months from staging brain MRI to initiation of durvalumab were associated with an increased risk of developing CNS metastases.•Overall survival was shorter for patients who developed CNS metastases. Patients with synchronous systemic and CNS metastases had a particularly short overall survival.

Background and purpose: A bolus is required when treating scalp lesions with photon radiation therapy. Traditional bolus materials face several issues, including air gaps and setup difficulty due to irregular, convex scalp geometry. A 3D-milled bolus is custom-formed to match individual patient anatomy, allowing improved dose coverage and homogeneity. Here, we describe the creation process of a 3D-milled bolus and report the outcomes for patients with scalp malignancies treated with Volumetric Modulated Arc Therapy (VMAT) utilizing a 3D-milled bolus. Materials and methods: Twenty-two patients treated from 2016 to 2022 using a 3D-milled bolus and VMAT were included. Histologies included squamous cell carcinoma (n = 14, 64%) and angiosarcoma (n = 8, 36%). A total of 7 (32%) patients were treated in the intact and 15 (68%) in the postoperative setting. The median prescription dose was 66.0 Gy (range: 60.0–69.96). Results: The target included the entire scalp for 8 (36%) patients; in the remaining 14 (64%), the median ratio of planning target volume to scalp volume was 35% (range: 25–90%). The median dose homogeneity index was 1.07 (range: 1.03–1.15). Six (27%) patients experienced acute grade 3 dermatitis and one (5%) patient experienced late grade 3 skin ulceration. With a median follow-up of 21.4 months (range: 4.0–75.4), the 18-month rates of locoregional control and overall survival were 75% and 79%, respectively. Conclusions: To our knowledge, this is the first study to report the clinical outcomes for patients with scalp malignancies treated with the combination of VMAT and a 3D-milled bolus. This technique resulted in favorable clinical outcomes and an acceptable toxicity profile in comparison with historic controls and warrants further investigation in a larger prospective study.

8076 Background: In the PACIFIC trial, 6.3% of patients with unresectable stage III NSCLC receiving durva after chemoRT developed CNSm. In a single center study, we previously reported real-world incidence of CNSm is higher at 19.8%. Risk factors for development of CNSm post-durva are incompletely understood. Methods: We conducted a multi-center retrospective study of patients with unresectable stage III NSCLC treated with durva after chemoRT from 2018 to 2022 with no CNSm on baseline brain MRI to assess for incidence of CNSm. Patient characteristics were compared between cohorts with and without CNSm to assess for risk factors for CNSm using Fisher’s exact test for categorical variables and two-sample t-test or Wilcoxon Mann-Whitney U-test for continuous variables. Overall survival was compared using log-rank test. Results: Of 193 patients in our study, 32 (16.6%) developed CNSm with median time to CNSm of 6.4 mo (IQR 4.5 - 13.7). Twenty-five (78%) had CNSm within one year. Patients with CNSm had a longer interval between baseline brain MRI and start of durva (median 3.7 mo vs 3.3 mo, p=0.02) and received fewer doses of durva compared to those without CNSm (median 7 vs 12, p=0.03). As some patients received Q2 week and others Q4 week durva, we also compared median durva treatment duration, which was consistent (3.7 mo vs 8.3 mo, p=0.02). There was no association between CNSm and age, sex, histology, T/N stage, PDL1 status, or chemoRT regimen (Table). Patients with CNSm had shorter median survival (19.6 mo vs 36.4 mo, p=0.008). Conclusions: Real-world incidence of CNSm is higher than that seen in PACIFIC. Patients with CNSm received less durva, likely due to early disease progression, and had longer intervals between baseline brain MRI and starting durva. Minimizing treatment delays may improve outcomes. Further research is needed to understand optimal surveillance strategies for CNSm in this patient population. [Table: see text]

PURPOSE:Primary tumor failure is common in patients treated with chemoradiation (CRT) for locally advanced NSCLC (LA-NSCLC). Stereotactic body radiation therapy (SBRT) yields high rates of primary tumor control (PTC) in early-stage NSCLC. This trial tested an SBRT boost to the primary tumor before the start of CRT to improve PTC. METHODS AND MATERIALS:Patients with LA-NSCLC received an SBRT boost in 2 fractions (central location 12 Gy, peripheral location 16 Gy) to the primary tumor, followed by standard CRT (60 Gy in 30 fractions). The primary objective was PTC rate at 1 year, and the hypothesis was that the 1-year PTC rate would be ≥90%. Secondary objectives included objective response rate, regional and distant control, disease-free survival (DFS), and overall survival (OS). Correlative studies included functional magnetic resonance imaging and blood-based miRNA analysis. RESULTS:The study enrolled 21 patients (10 men and 11 women); the median age was 62 years (range, 52-78). The median pretreatment primary tumor size was 5.0 cm (range, 1.0-8.3). The most common nonhematologic toxicities were pneumonitis, fatigue, esophagitis/dysphagia, dyspnea, and cough. Only 1 treatment-related grade 4 nonhematologic toxicity occurred (respiratory failure/radiation pneumonitis), and no grade 5 toxicities occurred. The objective response rate at 3 and 6 months was 72.7% and 80.0%, respectively, and PTC at 1 and 2 years was 100% and 92.3%, respectively. The 2-year regional and distant control rates were 81.6% and 70.3%, respectively. Disease-free survival and overall survival at 2 years were 46.1% and 50.3%, respectively, and median survival was 37.8 months. Functional magnetic resonance imaging detected a mean relative decrease in blood oxygenation level-dependent signal of -87.1% (P = .05), and miR.142.3p was correlated with increased risk of grade ≥3 pulmonary toxicity (P = .01). CONCLUSIONS:Dose escalation to the primary tumor using upfront SBRT appears feasible and safe. PTC was high and other oncologic endpoints compared favorably to standard treatment. Functional magnetic resonance imaging suggested changes in oxygenation with the first SBRT boost dose, and miR.142.3p was correlated with pulmonary toxicity.

e20605 Background: In the landmark PACIFIC trial, 6.3% of patients with unresectable stage III NSCLC receiving durva after chemoradiation developed mCNS. Data on incidence of mCNS in non-clinical trial patient populations are needed to evaluate CNS surveillance strategies. Methods: We conducted a retrospective study of patients with unresectable stage III NSCLC treated with durva following chemoradiation from 2018 to 2021 with baseline CNS imaging showing no mCNS. Patient characteristics and outcomes were assessed, including age, tumor histology, stage, mCNS incidence, and survival. OS was calculated from date of initiation of durva to death or censored at last follow-up. Results: Out of 86 patients included in our study, a total of 17 (19.8%) developed mCNS after starting durva. Development of mCNS was not associated with age, sex, histology, T or N staging or PD-L1 expression (Table 1). Three patients (3.5%) had CNS-only metastases whereas 14 (16.3%) had progression outside the CNS. The median time from baseline CNS imaging to first durva was 3.8 months (IQR 3.0 – 4.9) in the cohort. The median time from first durva to development of mCNS was 4.7 months (IQR 2.3 – 8.7). Median OS in patients with mCNS was 15.2 months (95% CI 8.6 – 25.9) compared to 36.9 months (95% CI 27.2 – NR) in patients without mCNS (p = 0.010). Conclusions: Incidence of mCNS among a cohort of patients with stage III NSCLC managed with durva after chemoradiation was 19.8% which is higher than that observed in landmark clinical trials. The OS for patients with mCNS was shorter than those without mCNS. Most mCNS occurred within 6 months of starting durva and were often accompanied by systemic progression. Further research is needed to understand optimal surveillance strategies for mCNS in this patient population. [Table: see text]

e23505 Background: Chondrosarcomas (CSC) constitute a diverse group of malignant bone tumors whose optimal management remains controversial, and patients with advanced disease have a dismal prognosis. Methods: Patients evaluated at The Ohio State University between January 1, 2010, to March 7, 2022, were included in the analysis. Data includes demographics, pathology, next-generation sequencing results, treatment combinations and responses, survival, time to progression, and recurrence. Results: 147 patients were eligible for this retrospective study. 29 patients were censored as they received no treatment or were lost to follow-up, leaving 118 evaluable patients. 83 patients had Conventional CSC, 16 had Dedifferentiated CSC, 4 Mesenchymal/Clear cell CSC, and 15 Myxoid/Extraskeletal myxoid CSC. 108 of 118 were white (91.5%), and 60 of 118 were male (50.8%). The median age at diagnosis was 57, ranging from 21-84 years old. 107 (92.2%) patients in the dataset had localized disease (Stage 1 or 2) and had curative treatment intent. The median tumor size was 6.3 cm for all patients. The most common site of the tumor was in the lower extremities (36.4%), followed by thoracoabdominal in 46 patients (38.9%), skull base/head and Neck in 17 patients (14.4%), and upper extremities in 12 of 118 (10.2%). The Median survival time differed significantly by subtype: Conventional CSC 104.6 months, dedifferentiated CSC 25.9 months, mesenchymal + clear cell CSC 57.2 months, myxoid or extraskeletal myxoid CSC 108.3 months, Overall survival in the entire cohort was 90.6 months. Overall comparison among subtypes Chi-square 57.41, ( p = 0.0). No association was seen between anatomic subsite and overall survival (upper extremities 202.80 months, lower extremities 85.30 months, and Pelvis & Retroperitoneal & lower back & Chest/Abdomen Wall/Upper Back 82.3 months, p = 0.216). The grade was associated with overall survival: grade 1 median 202.80 months, grade II 80.87 months, and grade III 21.067 months (p = 0.000). 18 patients received chemotherapy, 116 received surgery, and 12 received radiation. Among the 18 patients that received chemotherapy ( 4 patients had localized disease and 14 had the metastatic disease), the most used systemic therapy was Pazopanib 10/18 (55%), which had the longest time to progression of 22.42 months. The median time to progression of the 18 patients that received chemotherapy was 9.71 months. Conclusions: CSC remains a clinical challenge due to its rarity and limited treatment options. While surgical resection remains the mainstay of treatment for localized disease, systemic therapy and radiation can have important roles in selected subsets of patients. Further refinement of these care paradigms will require a multi-institutional/consortium effort to create a data repository and develop clinical trials to improve outcomes for these patients.

BACKGROUND:Immune checkpoint inhibitors (ICIs) are a first-line and perioperative treatment for lung cancer. Pneumonitis is a potentially life-threatening complication of ICI treatment in 2% to 5% of patients; however, risk factors for developing ICI pneumonitis (ICI-p) remain undefined. METHODS:We conducted a retrospective cohort study of consecutive patients with lung cancer who received at least one dose of ICI from 2015 through 2020 at The Ohio State University. Pneumonitis cases were documented by the treating oncologist and retrospectively evaluated for agreement between an oncologist and a pulmonologist. Patient demographic and clinical characteristics were recorded and summarized between those with and without pneumonitis for the overall cohort. Univariate and multivariable survival analyses using the Fine-Gray competing risk model were used to examine the associations. RESULTS:A total of 471 patients with lung cancer were included, of which 402 had non-small cell lung cancer and 69 had small cell lung cancer; 39 (8%) patients in the overall cohort developed ICI-p. Preexisting interstitial abnormalities and prior chest radiation were both significantly associated with ICI-p on univariate analysis (hazard ratio [HR], 8.91; 95% CI, 4.69-16.92; P<.001; and HR, 2.81; 95% CI, 1.50-5.28; P=.001). On multivariable analyses, interstitial abnormalities remained a strong independent risk factor for ICI-p when controlling for chest radiation and type of immunotherapy (HR, 9.77; 95% CI, 5.17-18.46; P<.001). Among patients with ICI-p (n=39), those with severe (grade 3-5) pneumonitis had worse overall survival compared with those with mild (grade 1 or 2) pneumonitis (P=.001). Abnormal pulmonary function test results at both 12 and 18 months prior to ICI initiation were not significantly associated with ICI-p. CONCLUSIONS:Preexisting interstitial abnormalities on chest CT and prior chest radiation are independent risk factors that are strongly associated with ICI-p in patients with lung cancer. These findings highlight a potential need for closer observation for ICI-p among patients with these risk factors.

IntroductionIncreasingly, early-stage non-small cell lung cancer (NSCLC) is treated with stereotactic body radiation therapy (SBRT). Although treatment is generally effective, a small subset of tumors will recur because of radioresistance. Preclinical studies suggested PI3K-AKT-mTOR activation mediates radioresistance. This study sought to validate this finding in tumor samples from patients who underwent SBRT for NSCLC. MethodsPatients with T1-3N0 NSCLC treated with SBRT at our institution were included. Total RNA of formalin-fixed paraffin-embedded tumor biopsy specimens (pretherapy) was isolated and analyzed using the Clariom D assay. Risk scores from a PI3K activity signature and four published NSCLC signatures were generated and dichotomized by the median. Kaplan-Meier curves and Cox regressions were used to analyze their association with recurrence and overall survival (OS). The PI3K signature was also tested in a data set of resected NSCLC for additional validation. ResultsA total of 92 patients were included, with a median follow-up of 18.3 months for living patients. There was no association of any of the four published gene expression signatures with recurrence or OS. However, high PI3K risk score was associated with higher local recurrence (hazard ratio [HR], 11.72; 95% CI, 1.40-98.0; p = .023) and worse disease-free survival (DFS) (HR, 3.98; 95% CI, 1.57-10.09; p = .0035), but not OS (p = .49), regional recurrence (p = .15), or distant recurrence (p = .85). In the resected NSCLC data set (n = 361), high PI3K risk score was associated with decreased OS (log-rank p = .013) but not DFS (p = 0.54). ConclusionsThis study validates that higher PI3K activity, measured by gene expression, is associated with local recurrence and worse DFS in early-stage NSCLC patients treated with SBRT. This may be useful in prognostication and/or tailoring treatment, and merits further validation.

Purpose/Objective(s) Malignant obstruction of the major airways is a complicated condition in the ICU, often requiring intubation and endobronchial interventions (EBIs), including stenting and tumor debulking. In cases where EBIs are unavailable or insufficient for respiratory stabilization, the role of radiotherapy (RT) is unknown. RT can reduce tumor burden, but treatment effects are not immediate. In addition, significant resources are required for RT, including costs of treatment and personnel. Our aim was to investigate treatment patterns and benefit of RT in the setting of patients with malignant obstruction requiring intubation. Materials/Methods We conducted a single-institution retrospective review at a tertiary care hospital of patients from 2016 – 2022 who underwent RT for a malignant obstruction in the thorax that required intubation and an ICU admission. Demographic information (age, sex, tobacco use, BMI) were collected, along with information regarding histology, staging and prior therapies. Interventions were noted, including EBIs, in-hospital systemic therapy and RT. Relevant dates were observed, including dates of RT, extubation and death. Successful extubation (SE) was defined as extubation for > 48 hours without death or reintubation. Results A total of 17 patients received RT for a malignant obstruction that required ICU admission. While only 41% of these patients (7/17) were intubated at the time of the radiation oncology consult, 100% were intubated at some point between the consultation and discharge/death. Dose and fractionation varied significantly, ranging from 5 Gy in 1 fraction to 60 Gy in 30 fractions. Courses with 5 or fewer prescribed fractions were completed in 80% (8/10) of cases, but only 14% of courses (1/7) with more than 5 fractions were completed. Patients did not complete RT due to electing for comfort care or worsening clinical condition that precluded RT. The median survival from RT initiation to death was 15 days for all patients with a maximum of 35 days. Two patients were able to be transferred home prior to death, the remainder died in the hospital. Only 17.6% of patients (3/17) achieved SE. One of these patients was extubated after 2/10 fractions and did not complete RT. The second patient received 17 Gy in 2 fractions and was extubated 3 days after RT completion. The third patient received 25 Gy in 5 fractions, then was extubated 4 days after RT following bronchoscopic debulking. These patients died 5, 5 and 16 days after extubation, respectively. Conclusion Intubation due to malignant obstruction carries an extremely poor prognosis when adequate bronchoscopic interventions are not possible. In a small minority of patients, RT may assist in facilitating extubation prior to death, but this outcome is rare. Courses of 5 or fewer fractions are more likely to be completed than courses with more than 5 fractions. Prospective data is merited to more accurately inform patients, physicians and caregivers about the true costs and benefits of RT in this scenario.

Purpose/Objective(s)Concurrent chemoradiotherapy (CCRT) followed by durvalumab consolidation up to 12 mo became the standard of care for patients (pts) with stage III NSCLC after the publication of the PACIFIC trial. Both radiation pneumonitis (RP) and immune checkpoint inhibitor pneumonitis (ICI-p) are serious toxicities that can occur in this population, and radiation and ICI modality individually is known to contribute to pneumonitis risk; when combined, they could work synergistically or additively to increase this risk. We set out to evaluate radiation treatment specific risk factors for symptomatic pneumonitis in pts receiving CCRT followed by durvalumab. We hypothesize that adjuvant ICI (durvalumab) will increase the pneumonitis risk from CCRT predicted by current consensus guidelines.Materials/MethodsWe conducted a retrospective study of pts with stage III NSCLC treated with CCRT followed by durvalumab from 2018 -21. Median follow up time was 18.8 mo from the last day of RT to last contact. RT dose parameters were extracted from each treatment plan. Normal lung volume (NLV) was defined as total lung volume minus clinical target volume (Lung -CTV). Percentage of NLV receiving more than 5, 10, or 20 Gy (V5, V10, V20), and mean lung dose (MLD) were calculated. The primary endpoint was development of symptomatic pneumonitis (≥gr 2), assessed via clinical presentation and available imaging. The association between the % NLV of radiation and the probability of developing pneumonitis was analyzed using logistic regression, and odds ratios (OR) were estimated.ResultsOf the 80 patients included in this study, 21 (26.3%) developed symptomatic pneumonitis following durvalumab initiation. 69 (86.3%) received carboplatin-paclitaxel and 11 (13.8%) received cisplatin-etoposide chemotherapy. 73 (91.2%) had received standard RT dose of 60 Gy, while 7 (8.8%) received an additional 12-16 Gy SBRT boost to the primary tumor on a separate study. We found no significant association between symptomatic pneumonitis and RT dose or type of chemotherapy. However, smaller treatment volumes receiving 5 or 10 Gy were associated with lower pneumonitis risk: V10 < 40%, vs ≥ 40% (OR = 0.347, 95% CI 0.11-1.07, P=0.067) and V5 <65% vs ≥65% (OR = 0.42, 95% CI: 0.15-1.17, P = 0.096). Mean MLD was 14.9 Gy (3.9-21.9 Gy), Mean V20 was 25.7% (4.5-40.1%), both well below current consensus guidelines. We did not identify a notable association between pneumonitis and other known clinical risk factors.ConclusionThis data is from our institution's first cohort of pts treated as in the PACIFIC study after durvalumab was approved by FDA for this indication. Our data suggest pts with a lower radiation treatment volume at 5 or 10 Gy (V5/V10) prior to durvalumab may have a lower risk of developing pneumonitis when other parameters (MLD, V20) are kept under the current recommended radiation tolerance without adjuvant ICI. Further research with larger study populations is needed to confirm this and inform guideline development. Concurrent chemoradiotherapy (CCRT) followed by durvalumab consolidation up to 12 mo became the standard of care for patients (pts) with stage III NSCLC after the publication of the PACIFIC trial. Both radiation pneumonitis (RP) and immune checkpoint inhibitor pneumonitis (ICI-p) are serious toxicities that can occur in this population, and radiation and ICI modality individually is known to contribute to pneumonitis risk; when combined, they could work synergistically or additively to increase this risk. We set out to evaluate radiation treatment specific risk factors for symptomatic pneumonitis in pts receiving CCRT followed by durvalumab. We hypothesize that adjuvant ICI (durvalumab) will increase the pneumonitis risk from CCRT predicted by current consensus guidelines. We conducted a retrospective study of pts with stage III NSCLC treated with CCRT followed by durvalumab from 2018 -21. Median follow up time was 18.8 mo from the last day of RT to last contact. RT dose parameters were extracted from each treatment plan. Normal lung volume (NLV) was defined as total lung volume minus clinical target volume (Lung -CTV). Percentage of NLV receiving more than 5, 10, or 20 Gy (V5, V10, V20), and mean lung dose (MLD) were calculated. The primary endpoint was development of symptomatic pneumonitis (≥gr 2), assessed via clinical presentation and available imaging. The association between the % NLV of radiation and the probability of developing pneumonitis was analyzed using logistic regression, and odds ratios (OR) were estimated. Of the 80 patients included in this study, 21 (26.3%) developed symptomatic pneumonitis following durvalumab initiation. 69 (86.3%) received carboplatin-paclitaxel and 11 (13.8%) received cisplatin-etoposide chemotherapy. 73 (91.2%) had received standard RT dose of 60 Gy, while 7 (8.8%) received an additional 12-16 Gy SBRT boost to the primary tumor on a separate study. We found no significant association between symptomatic pneumonitis and RT dose or type of chemotherapy. However, smaller treatment volumes receiving 5 or 10 Gy were associated with lower pneumonitis risk: V10 < 40%, vs ≥ 40% (OR = 0.347, 95% CI 0.11-1.07, P=0.067) and V5 <65% vs ≥65% (OR = 0.42, 95% CI: 0.15-1.17, P = 0.096). Mean MLD was 14.9 Gy (3.9-21.9 Gy), Mean V20 was 25.7% (4.5-40.1%), both well below current consensus guidelines. We did not identify a notable association between pneumonitis and other known clinical risk factors. This data is from our institution's first cohort of pts treated as in the PACIFIC study after durvalumab was approved by FDA for this indication. Our data suggest pts with a lower radiation treatment volume at 5 or 10 Gy (V5/V10) prior to durvalumab may have a lower risk of developing pneumonitis when other parameters (MLD, V20) are kept under the current recommended radiation tolerance without adjuvant ICI. Further research with larger study populations is needed to confirm this and inform guideline development.

Objectives Neutrophil-lymphocyte ratio (NLR) has been associated with mortality in non-small cell lung cancer (NSCLC), but its association with recurrence in locally advanced NSCLC (LA-NSCLC), specifically, is less established. We hypothesized pre- and posttreatment NLR would be associated with recurrence and mortality. Methods We studied the association of pretreatment NLR (pre-NLR) and posttreatment NLR at 1 (post-NLR1) and 3 months (post-NLR3) with outcomes in patients with LA-NSCLC treated with chemoradiation. Pre-NLR was dichotomized by 5, an a priori cutoff previously shown to be prognostic in LA-NSCLC. Post-NLR1 and post-NLR3 were dichotomized by their medians. Results We identified 135 patients treated with chemoradiation for LA-NSCLC between 2007 and 2016. Median follow-up for living patients was 61.1 months. On multivariable analysis, pre-NLR >= 5 was associated with worse overall survival (HR = 1.82; 95% CI 1.15 - 2.88; p = 0.011), but not with any recurrence, locoregional recurrence, or distant recurrence. Post-NLR1 >= 6.3 was not associated with recurrence or survival. Post-NLR3 >= 6.6 was associated with worse overall survival (HR = 3.27; 95% CI 2.01- 5.31; p < 0.001), any recurrence (HR = 2.50; 95% CI 1.53 - 4.08; p < 0.001), locoregional recurrence (HR = 2.50; 95% CI 1.40 - 4.46; p = 0.002), and distant recurrence (HR = 2.53; 95% CI 1.49 - 4.30; p < 0.001). Conclusion Pretreatment NLR is associated with worse overall survival and posttreatment NLR is associated with worse survival and recurrence. These findings should be validated independently and prospectively studied.

Data is conflicting with regard to the influence of consecutive (daily) treatment on toxicity and even local control in patients with non-small cell lung cancer (NSCLC) treated with lung stereotactic body radiation therapy (SBRT). Small retrospective studies suggest worse toxicity and local control with daily treatment while others have found no difference in outcomes. Large national databases may have sufficient statistical power to discern differences in survival outcomes between these two treatment regimens. We used the National Cancer Database (NCDB) to identify patients with stage I or II NSCLC treated with primary radiation therapy. We included only patients treated in 3-5 fractions with a biologically effective dose (BED) of ≥ 100 Gy. Daily treatment was considered to be treatment within 6 or 7 days for 4- and 5-fraction regimens, respectively, to account for a potential weekend treatment break. Daily treatment was considered to be treatment within 3 days for 3-fraction regimens. We used 1:1 nearest neighbor propensity score matching (caliper 0.1) to balance daily and non-daily cohorts on the basis of age, race, sex, treatment facility type, education, income, insurance status, county population, distance from treatment center, Charlson comorbidity index, tumor laterality, T-stage, histology, radiation dose, and year of diagnosis. Cox regression and Kaplan-Meier analysis were used to assess the association of daily treatment with overall survival. We identified 40,161 patients, 11,168 (27.8%) of which were treated with daily treatments. Daily treatment was associated with a higher proportion of Caucasians (90.6% vs 88.7%, p < 0.001), Charlson comorbidity index of 0-2 (95% vs 93.1%; p < 0.001), treatment at an academic medical center (41.9% vs 39.1%; p < 0.001), and increased distance to treatment facility (12.6 vs 10.8 miles; p < 0.001). There were no significant differences in age or sex. After propensity-score matching, there were 7176, 6402, and 4176 patients treated with 5, 4, and 3 fraction regimens, respectively. There were no significant differences in any of the variables. For 5-fraction regimens, there was no statistically significant difference in overall survival with non-daily vs daily treatment (HR = 1.06; 95% CI 1.00 – 1.13). Non-daily treatment was associated with improved overall survival for 4-fraction (HR = 0.93; 95% CI 0.88 – 0.995; p = 0.033) and 3-fraction (HR = 0.91; 95% CI 0.85 – 0.98; p = 0.018) regimens. We found improved overall survival in patients treated with non-daily fractions when treated with 3- or 4-fraction regimes. We found no significant difference in overall survival in patients treated with 5-fraction regimens. Altering fractionation scheme may be a simple means of improving outcomes in lung SBRT. More data is warranted on the effects of altering fractionation on tumor control outcomes, and these data should be considered to be validated in the context of a prospective randomized trial.

BACKGROUND:Although lobectomy remains the standard of care for early-stage non-small cell lung cancer, several studies suggest equipoise between lobectomy and stereotactic body radiation therapy (SBRT). However randomized evidence is lacking. We compared outcomes of early-stage non-small cell lung cancer patients treated with lobectomy or SBRT. METHODS:We included clinical T1-2N0 non-small cell lung cancer treated with lobectomy or SBRT to a biologically effective dose of ≥100 Gy10. We used Cox proportional hazards and nearest-neighbor propensity score (2:1) matching to adjust for confounders. Kaplan-Meier curves were used to assess survival and recurrence. RESULTS:We identified 554 patients treated with lobectomy (n = 389) or SBRT (n = 165) at our institution between 2008 and 2018. After propensity score matching, there were 132 SBRT patients and 85 lobectomy patients. SBRT was associated with increased local recurrence (hazard ratio [HR], 6.80; 95% confidence interval [CI], 1.92-24.10; P = .003) and regional nodal recurrence (HR, 2.58; 95% CI, 1.17-5.68; P = .018), and with worse overall survival (HR, 2.00; 95% CI, 1.21-3.32; P = .007) and progression-free survival (HR, 2.34; 95% CI, 1.50-3.67; P < .001). There was no difference in distant recurrence (HR, 1.19; 95% CI, 0.57-2.52; P = .64). CONCLUSIONS:We found superior outcomes in patients with early-stage non-small cell lung cancer treated with lobectomy compared with SBRT, including locoregional control. These findings should be interpreted with caution because of selection bias but underscore the importance of robust randomized prospective data to clarify the relative efficacy of these modalities.

Neutrophil-lymphocyte ratio (NLR) has been associated with mortality for non-small cell lung cancer (NSCLC), but its association with recurrence in locally advanced NSCLC, specifically, is less established. We hypothesized that pre- and post-treatment NLR would be associated with increased recurrence and mortality and further that increasing radiation dose to the thoracic vertebral bodies (TVB) during chemoradiation would be associated with increased post-treatment NLR. We used Cox proportional hazards and Kaplan-Meier analysis to study the association of pre- and post-treatment NLR with overall survival and recurrence in patients with locally advanced NSCLC treated with chemoradiation. Pre- and post-NLR were analyzed as continuous and dichotomized variables. Pre-treatment NLR was dichotomized by a value of 5, an a priori cutoff previously shown to be prognostic in locally advanced NLR. Post-treatment NLR was dichotomized by the median. We subsequently performed linear and logistic regression to correlate TVB dose with NLR at 3 months post treatment. We identified 144 patients with available survival data (88 with recurrence data) treated with chemoradiation for locally advanced NSCLC between 2007 and 2016. Median follow up for living patients was 14.9 months. On multivariable analysis, pre-treatment NLR ≥ 5 was associated with worse overall survival (HR = 2.56; 95% CI 1.53 – 4.30; p < 0.001), any recurrence (HR = 2.13; 95% CI 1.10 – 4.12; p = 0.026) and locoregional recurrence (HR = 2.64; 95% CI 1.12 – 6.23; p = 0.026), but not distant recurrence (HR = 1.85; 95% CI 0.76 – 4.51; p = 0.18). There was a statistically significant increase in NLR after treatment (p < 0.001). Three-month median post-treatment NLR ≥ 6.6 was associated with worse overall survival (HR = 3.16; 95% CI 1.70 – 5.86; p < 0.001), any recurrence (HR = 2.96; 95% CI 1.54 – 5.69; p = 0.001), and locoregional recurrence (HR = 6.53; 95% CI 2.44 – 17.44; p < 0.001). There was a trend toward significant association with distant recurrence (HR = 2.16; 95% CI 0.92 – 5.05; p = 0.077). On linear regression, there was a statistically significant correlation of post-treatment NLR at 3 months with thoracic vertebral body volume receiving 5, 10, 20, 30, 40, and 50 Gy. On logistic regression, there was a direct correlation of 3-month post-treatment NLR ≥ 6.6 with V5 (p = 0.13), V10 (p = 0.023), V50 (p = 0.045), and V60 (p = 0.042). We found that both pre-treatment NLR and post-treatment NLR are associated with worse overall survival and locoregional recurrence. Additionally, we found that post-treatment NLR is correlated with TVB. These findings suggest that limiting dose to the TVB is important for not only reducing acute hematologic toxicity but also for improving disease outcomes, and these results should be validated in an independent, ideally prospectively studied cohort.

Hypertrophic pulmonary osteoarthropathy (HPOA) is a well-known paraneoplastic syndrome associated with lung cancer, and some have hypothesized that its pathophysiology is immune-mediated. However, the clinical course of symptoms from this syndrome during treatment with immune checkpoint inhibitors (ICIs) has not previously been described, and effective treatments for pain secondary to HPOA have not been fully elucidated. We present the case of a patient who was diagnosed with HPOA involving the bilateral distal femurs causing severe pain and subsequently found to have adenocarcinoma of the lung. We describe changes in her symptoms during multiple lines of treatment, including ICIs, and we discuss effective strategies for pain management for this condition. The patient's pain improved with regression of her tumor burden after treatment with chemotherapy, combined modality chemotherapy-radiation, and immune checkpoint inhibition. Importantly, her pain did not flare even temporarily with administration of ICIs. Severe episodes of pain prior to initiating treatment and during periods of cancer progression were managed effectively with opioids, dexamethasone, and hydroxychloroquine, the use of which has not been previously described for this condition. This case provides evidence that ICIs do not worsen symptoms of HPOA, despite their stimulation of an anti-tumor immune response, supporting their use in patients with this condition. It also provides support for the possible efficacy of hydroxychloroquine for treatment of pain secondary to HPOA in conjunction with other therapies. (C) 2020 Elsevier Inc. All rights reserved.

BACKGROUND:Neutrophil-lymphocyte ratio (NLR) has been associated with mortality in several disease sites. We hypothesized that NLR is associated with inferior outcomes in localized non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). METHODS:We evaluated the association of pre-treatment NLR, obtained within 6 months of starting SBRT, with overall survival, as well as primary tumor, regional, and distant recurrence. Multivariate Cox regression was then used to assess pre-treatment NLR as a predictor of mortality. We validated our findings in an independent cohort of patients treated at two other institutions. In a secondary analysis, we also evaluated the association of post-treatment NLR with mortality in the training cohort. RESULTS:A total of 156 patients and 166 tumors were included in the training cohort with a median follow-up of 13.4 months. After dichotomization by median, NLR > 3.6 was associated with mortality on univariate (p = 0.010) and multivariate analysis (p = 0.023). In the validation cohort, NLR > 3.6 was similarly associated with mortality on univariate (p = 0.031) and multivariate (p = 0.007) analysis. In a secondary analysis in the training cohort, we found post-treatment NLR was significantly increased compared to pre-treatment NLR (p < 0.001) and associated with mortality on univariate analysis (p = 0.005) and multivariate analysis (p = 0.010). CONCLUSIONS:Pre-treatment NLR > 3.6 is associated with mortality in patients treated with SBRT. This finding was validated in an independent cohort of patients treated at two other institutions. Additionally, post-treatment NLR was significantly increased from pre-treatment and associated with overall survival.

BACKGROUND:Tumor aggressiveness and hypoxia are linked to acidosis in the tumor microenvironment (TME). We hypothesized that low pre-treatment serum bicarbonate, potentially correlating with an acidic and hypoxic TME, predicts for poor outcomes after stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC). METHODS:We included patients with localized NSCLC treated to a biologically effective dose (BED) ≥ 100 Gy, with available pre-treatment bicarbonate values within 3 months of treatment. We used receiver operating characteristic analysis to determine the bicarbonate concentration optimally predicting for primary tumor recurrence, and evaluated its association with recurrence and survival. We validated our findings in an independent cohort of patients from three collaborating institutions. RESULTS:A total of 110 patients and 114 tumors were included in the training cohort, with median follow-up of 15.0 months. Bicarbonate < 26 mEq/L was associated with primary tumor recurrence on univariate (HR = 5.92; 95% CI 1.69-24.88; p = 0.005) and multivariate analysis (HR = 5.48; 95% CI 1.37-25.19; p = 0.020). The validation cohort consisted of 195 patients and 208 tumors with median follow-up of 27.5 months. In the validation cohort, bicarbonate < 26 mEq/L was again associated with primary tumor recurrence on univariate (HR = 3.38; 95% CI 1.27-9.37; p = 0.015) and multivariate analysis (HR = 3.33; 1.18-10.07; p = 0.023). CONCLUSIONS:Pre-treatment bicarbonate predicts for primary tumor control in NSCLC treated with SBRT and may be useful for risk stratification. These findings should be confirmed prospectively.

Introduction: Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT. Methods and Materials: Patients with brain metastases (BM) received daily trametinib for 28 days, starting 7 days prior to and continuing through WBRT (37.5 Gy/15 fractions). Dose levels (DL)1-3 were 1.0, 1.5, and 2.0 mg. The MTD of trametinib plus WBRT, the max dose where <= 1 of 6 patients experienced a dose limiting toxicity (DLT), was the primary endpoint. Results: 10 patients were enrolled (median age-59 [47-64], BM-5 [1-10], 50% melanoma). Three and 7 patients were assigned to DL1 and 2. One DL2 patient withdrew. 89% of remaining patients completed therapy per protocol, but 1 DL2 patient with systemic progression discontinued therapy at 30 Gy. Thirteen grade (G)3-4 toxicities were observed, of which 12 occurred at DL2 (4/6 of patients). DLT was reached at DL2 (G4 thrombocytopenia and G3 diarrhea, 1 each). There were no G5 toxicities. Median overall survival was 2.2 months. During the study period, changing practice patterns favored utilization of stereotactic radiosurgery (SRS). Thus, the trial closed early prior to completion. Conclusions: In a patient population representative of modern candidates for WBRT, trametinib plus WBRT is highly toxic with a MTD <1.5 mg. The safety of trametinib with SRS remains an important question for future study. (c) 2022 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 170 (2022) 21-26

Larger tumors are associated with decreased local control in non-small cell lung cancer (NSCLC) treated with conventional radiotherapy. Although multiple studies characterize dose-response relationships in the setting of NSCLC treated with SBRT, fewer studies evaluate diameter-response. Furthermore, given the preponderance of bidimensional reporting of tumor volumes in CT chest radiology, as influenced by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, existing database studies may limit measurements, and thus prognostic sensitivity, to the axial plane. We hypothesized that higher 3-dimensional maximum tumor diameter (MTD) is associated with locoregional and distant recurrence. We retrospectively reviewed outcomes for patients with localized NSCLC treated at our institution between 2008 and 2017. MTD was measured using CT images for radiation planning and taken as the largest tumor diameter on axial, sagittal, and coronal planes. Endpoints included overall survival (OS), primary tumor failure (PTF), ; lobar failure (LF), defined as recurrence within the same lobe as but outside of the treatment volume of the treated tumor; regional nodal failure (RF; defined as recurrence in regional N1-N3 nodes), and distant metastasis (DM). Cox regression was used to test association between endpoints and MTD, which was dichotomized as high and low by the median. A total of 222 patients and 236 treated tumors were included. Median follow up was 14.3 months. Median age was 72 (range 49-92). Males comprised 57.7% (128) of the cohort and females comprised 42.3% (94). The majority of tumors were early-stage, with 172 (72.9%) T1 and 48 (20.3%) T2 tumors. A small minority of tumors (10 (4.2%) T3 and 6 (2.5%) T4) were included due to multiple nodules thought to be of the same primary. Adenocarcinomas, squamous cell carcinomas, and undifferentiated/unspecified NSCLC represented 52.7% (145), 36.7% (101), and 10.5% (30) of the cohort, respectively. Median SBRT total dose, dose per fraction, and number of fractions was 50 Gy, 10 Gy/fraction, and 5 fractions, respectively. Median MTD for patients was 2.5 cm (range 0.6 to 8.5). Cox regression analysis indicated higher MTD was significantly associated with PTF (HR 7.5; 95% CI 2.2-25.5, p=.001), LF (HR=3.3; 95% CI 1.5-7.5, p=.003) and DM (HR=7.2; 95% CI 2.818.6, p<.001). There was a trend toward significance with regard to OS (HR=1.4; 95% CI .95-2.05, p=.09) and RF (HR=1.74; 95% CI .89-3.23, p=.11). Three-dimensional MTD is associated with increased risk of local recurrence and distant metastasis after SBRT for localized NSCLC and may be useful in predicting treatment response. These findings require validation using a large, independent data set.