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OBJECTIVE Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment of patients with many tumor histologies. Simultaneously, stereotactic body radiotherapy (SBRT) provides excellent local control (LC) and plays an important role in the management of spine metastasis. Promising preclinical work suggests the potential therapeutic benefit of combining SBRT with ICI therapy, but the safety profile of combined therapy is unclear. This study aimed to evaluate the toxicity profile associated with ICI in patients receiving SBRT and, secondarily, whether ICI administration sequence with respect to SBRT affects LC or overall survival (OS) outcomes. METHODS The authors retrospectively reviewed patients with spine metastasis treated with SBRT at an academic center. Patients who received ICI at any point during their disease course were compared to those with the same primary tumor types who did not receive ICI by using Cox proportional hazards analyses. Primary outcomes were long-term sequelae, including radiation-induced spinal cord myelopathy, esophageal stricture, and bowel obstruction. Secondarily, models were created to evaluate OS and LC in the cohort. RESULTS Two hundred forty patients who received SBRT to 299 spine metastases were included in this study. The most common primary tumor types were non–small cell lung cancer (n = 59 [24.6%]) and renal cell carcinoma (n = 55 [22.9%]). One hundred eight patients received at least 1 dose of ICI, with the most common regimen being single-agent anti–PD-1 (n = 80 [74.1%]), followed by combination CTLA-4/PD-1 inhibitors (n = 19 [17.6%]). Three patients experienced long-term radiation-induced sequelae: 2 had esophageal stricture and 1 had bowel obstruction. No patients developed radiation-induced myelopathy. There was no association between receipt of ICI and development of any of these adverse events (p > 0.9). Similarly, ICI was not significantly associated with either LC (p = 0.3) or OS (p = 0.6). In the entire cohort, patients who received ICI prior to beginning SBRT had worse median survival, but ICI sequence with respect to SBRT was not significantly prognostic of either LC (p > 0.3) or OS (p > 0.07); instead, baseline performance status was most predictive of OS (HR 1.38, 95% CI 1.07–1.78, p = 0.012). CONCLUSIONS Treatment regimens that combine ICIs before, concurrent with, and after SBRT for spine metastases are safe, with minimal risk for increased rates of long-term toxicity.

In patients with known or suspected lung cancer, pathologic reports of cytologic "atypia" in the mediastinal nodal fine-needle aspirate samples pose a diagnostic and therapeutic dilemma. For the patents with non-operable disease, should the radiation oncologist empirically include lymph nodes with atypical findings in the radiation field, or should they exclude these mediastinal lymph nodes from the treatment field? Inclusion of an atypical finding in the management decision or radiation target would mean that the treating physicians are interpreting a pathologic report of "atypia" as probably "positive" rather than probably "negative" disease. Empirically treating lymph nodes without cancer involvement in thoracic radiotherapy for non-small cell lung cancer, also known as elective nodal irradiation, is generally avoided given increased treatment-related toxicities including esophagitis, pneumonitis, and cardiotoxicity without a demonstrated survival benefit. However, in the case of potentially curative chemoradiation, the discretion is left to the treating radiation oncologist to estimate the likelihood of oncologic involvement based on available and often clinically indeterminate radiologic findings and known routes of cancer spread. Alternatively, physicians may consider repeat or invasive diagnostic measures. The risks and benefits of additional procedures must be taken into careful consideration in our older patient population who present with co-morbid cardiopulmonary disease and pulmonary symptoms from their cancer. If atypia is reported, written and verbal communication to relay pathologist's concern for oncologic involvement is critical as it may affect oncologic treatment recommendations and cancer outcomes.

Background Patients with non‐small cell lung cancer may develop pneumonitis after thoracic radiotherapy (RT) and immune checkpoint inhibitors (ICIs). We hypothesized that distinct morphologic features are associated with different pneumonitis etiologies. Materials and Methods We systematically compared computed tomography (CT) features of RT‐ versus ICI‐pneumonitis. Clinical and imaging features were tested for association with pneumonitis severity. Lastly, we constructed an exploratory radiomics‐based machine learning (ML) model to discern pneumonitis etiology. Results Between 2009 and 2019, 82 patients developed pneumonitis: 29 after thoracic RT, 23 after ICI, and 30 after RT + ICI. Fifty patients had grade 2 pneumonitis, 22 grade 3, and 7 grade 4. ICI‐pneumonitis was more likely bilateral (65% vs. 28%; p = .01) and involved more lobes (66% vs. 45% involving at least three lobes) and was less likely to have sharp border (17% vs. 59%; p = .004) compared with RT‐pneumonitis. Pneumonitis morphology after RT + ICI was heterogeneous, with 47% bilateral, 37% involving at least three lobes, and 40% sharp borders. Among all patients, risk factors for severe pneumonitis included poor performance status, smoking history, worse lung function, and bilateral and multifocal involvement on CT. An ML model based on seven radiomic features alone could distinguish ICI‐ from RT‐pneumonitis with an area under the receiver‐operating curve of 0.76 and identified the predominant etiology after RT + ICI concordant with multidisciplinary consensus. Conclusion RT‐ and ICI‐pneumonitis exhibit distinct spatial features on CT. Bilateral and multifocal lung involvement is associated with severe pneumonitis. Integrating these morphologic features in the clinical management of patients who develop pneumonitis after RT and ICIs may improve treatment decision‐making. Implications for Practice Patients with non‐small cell lung cancer often receive thoracic radiation and immune checkpoint inhibitors (ICIs), both of which can cause pneumonitis. This study identified similarities and differences in pneumonitis morphology on computed tomography (CT) scans among pneumonitis due to radiotherapy (RT) alone, ICI alone, and the combination of both. Patients who have bilateral CT changes involving at least three lobes are more likely to have ICI‐pneumonitis, whereas those with unilateral CT changes with sharp borders are more likely to have radiation pneumonitis. After RT and/or ICI, severe pneumonitis is associated with bilateral and multifocal CT changes. These results can help guide clinicians in triaging patients who develop pneumonitis after radiation and during ICI treatment., Patients with non‐small cell lung cancer often receive thoracic radiotherapy and immune checkpoint inhibitors (ICIs), both of which can cause pneumonitis. The results of this study can help guide clinicians in triaging patients who develop pneumonitis after receipt of radiation and/or immune checkpoint inhibitor treatment.

Background We investigate the time to and clinical factors associated with patient-reported difficulty swallowing in lung cancer patients treated with radiation therapy (RT). Methods Between October 2016 and October 2019, lung cancer patients treated with conventionally fractionated RT at a tertiary cancer center were identified. Weekly, patients reported difficulty swallowing (patient-reported outcome version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE] v.1: 0-none, 1-mild, 2-moderate, 3-severe, 4-very severe). Physicians graded dysphagia (CTCAE v.4: 0-none, 1-symptoms without altered intake, 2-symptomatic; altered eating/swallowing, 3-severely altered eating/swallowing, 4-life-threatening consequences, 5-death). Tumor-related difficulty swallowing was not recorded at baseline; thus, patients reporting ≥moderate symptoms ≤7 days of RT start were excluded. We evaluated the time to new patient reports of ≥moderate difficulty swallowing and CTCAE grade 2+ dysphagia and development over time using the cumulative incidence method. Multivariable logistic regression evaluated associations between clinical factors, esophageal V60, and development of esophageal symptoms. Results Of the 200 patients identified: median age was 69 years, 52% were male, and 89% had stage III+ disease. Patients received a median of 63 Gy with chemotherapy (91.5%). At least moderate difficulty swallowing during RT was reported by 76 of 200 patients (38%); clinicians rated dysphagia as altering oral intake or worse for 26 of 200 (13%). Median time to first report of symptoms was 21 days (interquartile ratio [IQR], 18-34.5) for the 76 patients who reported ≥moderate symptoms and 33 days (IQR, 24-42) in the 26 patients whose provider reported grade 2+ dysphagia. The 30-day incidence of patient-reported ≥moderate swallowing difficulty and provider grade 2+ dysphagia was 26% (95% CI: 20%-32%) and 6% (95% CI: 3%-9%), respectively. Esophageal V60 >7 % was the clinical factor most associated with patient-reported ≥moderate esophageal symptoms (odds ratio 6.1, 95% CI: 3.0-12.3). Conclusions Patients report at least moderate difficulty swallowing more often and earlier than providers report grade 2+ dysphagia. Esophageal V60 ≥7% was most associated with development of moderate severity or worse patient-reported swallowing difficulty.

Background Here, we investigated radiological responses following chemotherapy alone as compared to both radiation/chemotherapy (chemoRT) in patients with thymic epithelial tumors (TETs) who did not receive upfront surgery. Methods TETs treated at a tertiary academic cancer center between January 2007 and July 2018 were identified. Patients received chemotherapy or chemoRT as initial therapy and pre‐ and post‐treatment scans were available. Student's t‐test, Wilcoxon rank‐sum tests, and Cox proportional hazards method were used to compare clinical details and survival between groups. The primary outcome was change in tumor size, which was compared between groups using linear mixed‐effects regression models, adjusting for baseline tumor size, age, and histology. Results A total of 24 of 114 patients with TETs identified met the inclusion criteria. The majority of patients had 67% thymoma (67%, n = 16) and AJCC8 III–IVA disease (58%, n = 14). Median age was 58.5 years (range: 33–76), median initial tumor volume was 187.1 cc (range: 28.7–653.6) and diameter was 8.5 cm (range: 4.5–14.3). Half of the patients received upfront chemotherapy (n = 12: 83% cisplatin/adriamycin/cyclophosphamide) or chemoRT (n = 12: 58% carboplatin/paclitaxel; median RT dose: 63 Gy [range: 60–70 Gy]). At a median imaging follow‐up of 15 months (range: 0–86): ChemoRT was associated with increased average radiological response compared to chemotherapy alone (volume: −47.0 cc more, P, ChemoRT was associated with a greater radiologic response than chemotherapy alone in patients with upfront unresectable TET

Patient-reported outcome measure (PROM) is an umbrella term that refers to any report on a health status measure that is reported directly from the patient, without the influence of clinicians (1). Heath status measures assessed by PROMs broadly include 3 categories: (I) overall measures of health-related quality of life (HR-QOL); (II) functional measures that may include but are not limited to physical, emotional, social, or cognitive well-being outcomes; (III) symptom-specific outcomes measures that may be disease-related or treatment-related (2). PROMS are of particular interest as physician-reported measures are known to under report important symptoms and toxicities from therapy and its associated level of burden on patients (3). Furthermore, PROMS have been shown to more closely associate with cancer patients’ overall well-being and function when compared to physician-reported treatment measures (4).

Advances in lung cancer therapy have resulted in improved clinical outcomes. Unfortunately, advances can come at a financial cost to patients and their families that poses a significant risk to overall quality of life (QoL). Financial distress has been shown to be associated with increased symptom burden and decreased treatment compliance but the magnitude of financial distress is not well characterized in lung cancer populations.Patients with stage II-IV newly diagnosed lung cancer and starting first-line therapy were recruited at a tertiary academic institution between July 2018 and April 2019. The comprehensive score for financial toxicity (COST) was used to assess financial toxicity and the Functional Assessment of Cancer Therapy-Lung (FACT-L) was used to assess QoL. Associations between financial toxicity and baseline variables were assessed using multivariable linear regression and correlations were assessed using the Pearson correlation.In this study, 143 consecutive patients were approached and 91.6% agreed to participate (N = 131). The median age was 65 years (35-90); 52.7% were male (n = 69), and 75.6% were white (n = 99). The inability to afford basic necessities and having1 month of savings was associated with increased financial toxicity (P0.001) after adjusting for other factors such as age, race, insurance, and income. There was also a trend toward increased financial toxicity among those who were employed but on sick leave (P = 0.06). Increased financial toxicity was correlated with a decrease in QoL (correlation coefficient 0.41, P0.001). Patients' anticipated out-of-pocket (OOP) expenses for the upcoming 6 months ranged from $0 to $50 000 (median $2150). However, there was no correlation between anticipated OOP expenses and either financial toxicity or QoL.These data identify key factors for identifying at-risk patients and builds a framework for exploring the benefit of financial counseling interventions, which may improve QoL and oncologic outcomes.

PurposeThis study aimed to quantitatively evaluate the range uncertainties that arise from daily cone-beam CT (CBCT) images for proton dose calculation compared to CT using a measurement-based technique.MethodsFor head and thorax phantoms, wedge-shaped intensity-modulated proton therapy (IMPT) treatment plans were created such that the gradient of the wedge intersected and was measured with a 2D ion chamber array. The measured 2D dose distributions were compared with 2D dose planes extracted from the dose distributions using the IMPT plan calculated on CT and CBCT. Treatment plans of a thymoma cancer patient treated with breath-hold (BH) IMPT were recalculated on 28 CBCTs and 9 CTs, and the resulting dose distributions were compared.ResultsThe range uncertainties for the head phantom were determined to be 1.2% with CBCT, compared to 0.5% for CT, whereas the range uncertainties for the thorax phantom were 2.1% with CBCT, compared to 0.8% for CT. The doses calculated on CBCT and CT were similar with similar anatomy changes. For the thymoma patient, the primary source of anatomy change was the BH uncertainty, which could be up to 8 mm in the superior–inferior (SI) direction.ConclusionWe developed a measurement-based range uncertainty evaluation method with high sensitivity and used it to validate the accuracy of CBCT-based range and dose calculation. Our study demonstrated that the CBCT-based dose calculation could be used for daily dose validation in selected proton patients.

Nonhomogeneous dose optimization (NHDO) is exploited in stereotactic body radiation therapy (SBRT) to increase dose delivery to the tumor and allow rapid dose falloff to surrounding normal tissues. We investigate changes in plan quality when NHDO is applied to inverse-planned conventionally fractionated radiation therapy (CF-RT) plans in patients with non-small cell lung cancer.Patients with near-central non-small cell lung cancer treated with CF-RT in 2018 at a single institution were identified. CF-RT plans were replanned using NHDO techniques, including normalizing to a lower isodose line, while maintaining clinically acceptable normal tissue constraints and target coverage. Tumor control probabilities were calculated. We compared delivered CF-RT plans using homogenous dose optimization (HDO) versus NHDO using Wilcoxon signed-rank tests. Median values are reported.Thirteen patients were replanned with NHDO techniques. Planning target volume coverage by the prescription dose was similar (NHDO = 96% vs HDO = 97%, P = .3). All normal-tissue dose constraints were met. NHDO plans were prescribed to a lower-prescription isodose line compared with HDO plans (85% vs 97%, P = .001). NHDO increased mean dose to the planning target volume (73 Gy vs 67 Gy), dose heterogeneity, and dose falloff gradient (P .03). NHDO decreased mean dose to surrounding lungs, esophagus, and heart (relative reduction of 6%, 14%, and 15%, respectively; P .05). Other normal tissue objectives improved with NHDO, including total lung V40 and V60, heart V30, and maximum esophageal dose (P .05). Tumor control probabilities doubled from 31.6% to 65.4% with NHDO (P = .001).In select patients, NHDO principles used in SBRT optimization can be applied to CF-RT. NHDO results in increased tumor dose, reduction in select organ-at-risk dose objectives, and better maintenance of target coverage and normal-tissue constraints compared with HDO. Our data demonstrate that principles of NHDO used in SBRT can also improve plan quality in CF-RT.

In patients with non–small-cell lung cancer treated with anti–PD-1/PD-L1 agents, no specific radiation parameter was significantly associated with immune-related (IR) pneumonitis. We identify on subset analysis of patients who developed IR pneumonitis and received chest radiation, patients were numerically more likely to have received chest radiation with curative intent than with palliative intent (89% vs. 11 that approached statistical significance. PURPOSE: To investigate the relationship between radiotherapy (RT), in particular chest RT, and development of immune-related (IR) pneumonitis in non–small-cell lung cancer (NSCLC) patients treated with anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-LI). PATIENTS AND METHODS: Between June 2011 and July 2017, NSCLC patients treated with anti–PD-1/PD-L1 at a tertiary-care academic cancer center were identified. Patient, treatment, prior RT (intent, technique, timing, courses), and IR pneumonitis details were collected. Treating investigators diagnosed IR pneumonitis clinically. Diagnostic IR pneumonitis scans were overlaid with available chest RT plans to describe IR pneumonitis in relation to prior chest RT. We evaluated associations between patient, treatment, RT details, and development of IR pneumonitis by Fisher exact and Wilcoxon rank-sum tests. RESULTS: Of the 188 NSCLC patients we identified, median follow-up was 6.78 (range, 0.30–79.3) months and median age 66 (range, 39–91) years; 54% (n = 102) were male; and 42% (n = 79) had stage I-III NSCLC at initial diagnosis. Patients received anti–PD-1/PD-L1 monotherapy (n = 127, 68%) or PD-I/PD-LI -based combinations (n = 61, 32%). In the entire cohort, 70% (132/188) received any RT, 53% (100/188) chest RT, and 37% (70/188) curative-intent chest RT. Any grade IR pneumonitis occurred in 19% (36/188; 95% confidence interval, 13.8–25.6). Of those who developed IR pneumonitis and received chest RT (n = 19), patients were more likely to have received curative-intent versus palliative-intent chest RT (17/19, 89%, vs. 2/19, 11%; P = .051). Predominant IR pneumonitis appearances were ground-glass opacities outside high-dose chest RT regions. CONCLUSION: No RT parameter was significantly associated with IR pneumonitis. On subset analysis of patients who developed IR pneumonitis and who had received prior chest RT, IR pneumonitis was more common in patients who received curative-intent chest RT. Attention should be paid to NSCLC patients receiving curative-intent RT followed by anti –PD-I/PD-LI agents.

Background National costs of lung cancer care exceed $12 billion. We investigate the resource-savings benefit of a single-day thoracic oncology multidisciplinary clinic (MDC) in the diagnostic period prior to non–small-cell lung cancer (NSCLC) treatment. Materials and Methods From July 2007 to January 2015, patients with NSCLC treated with multimodality therapy at a tertiary hospital-based cancer center in Maryland were identified. Patient and treatment details were collected. Health care resources utilized in the 90 days prior to receipt of first oncologic treatment were identified using billed activity codes. Associated total charges, including professional fees and hospital-based technical fees, were identified and inflated to 2014 dollars using the Consumer Price Index. Codes were categorized into provider visits, procedures, pathology/laboratory, radiology, and other tests. χ2, Student t, and Wilcoxon rank-sum tests compared charges of patients seen in and out of the MDC. Results Two-hundred ninety-seven (non-MDC = 161, 54%; MDC = 136, 46%) of 308 patients identified had total charges available. Patients seen through MDC had on average a 23% decrease in total charges per patient incurred ($5839 savings; range, $5213-$6464) compared with patients seen through non-MDC settings. Evaluation through MDC reduced the average number of provider visits per patient (non-MDC, 6.8 vs. MDC, 4.8; P Conclusions Evaluation of patients with NSCLC through a coordinated single-day MDC reduced hospital charges per patient by 23% during the diagnostic period prior to treatment when compared with evaluation through traditional referral-based thoracic oncology clinics.

With increasing use of immune checkpoint inhibitors (ICIs) for advanced NSCLC, there is increasing recognition of immune-related adverse events associated with ICI use. We recently reported increased incidence of checkpoint inhibitor pneumonitis (CIP) in ICI-treated NSCLC patients. Since development of immune-related adverse events in other organ systems has been associated with either no change or even improvement in tumor response/cancer outcomes, we sought to better understand the impact of CIP development on overall survival in ICI-treated NSCLC patients. Using baseline and follow-up data collected on a cohort of 205 ICI-treated NSCLC patients, we used a multi-state modeling approach to understand the effect of developing CIP on the risk of death. We observed time-dependent changes in risk of developing and recovery from CIP, with an increased risk of both developing and recovering from CIP in the first year after initiating ICI. We found that developing CIP independently increased the risk of transitioning to death in both adjusted and unadjusted models. In the multivariate model, we found that the increase in mortality associated with CIP was only seen in patients with adenocarcinoma tumor histology. Collectively, these findings suggest that in NSCLC, development of CIP worsens survival in patients receiving immunotherapy.

Purpose/Objective(s) Radiotherapy, especially high-dose radiation in the form of stereotactic body radiotherapy (SBRT), may stimulate the therapeutic effect of immune checkpoint inhibitors (ICIs). Both SBRT and ICIs play an increasingly important role in the management of spine metastasis. We hypothesize that SBRT and ICI may act synergistically to improve the outcomes of patients with spine metastasis. Materials/Methods We retrospectively reviewed patients with spine metastasis treated with SBRT at an academic center between 2009 and 2019. Patients who received ICI at any point during their disease course were compared to those with the same primary tumor types who did not receive ICI. Cox proportional hazard analyses were performed for overall survival (OS) and local control (LC), adjusting for primary tumor type, age, performance status, and prior spine surgery and/or radiation. Results 153 patients with 194 unique spine lesions were treated with SBRT. The most common primary tumor types were renal cell carcinoma (RCC), non-small cell lung cancer (N = 48, 31% each), colorectal cancer (N = 21, 14%), melanoma and liver cancer (N = 10, 6% each). 82 patients received at least one course of ICI. The most common type of ICI was single-agent anti-PD-1 (N = 71, 88%), followed by dual anti-CTLA-4/PD-1 inhibitors (N = 14, 17%). Of patients receiving ICI, 44 (53.6%) initiated ICI before SBRT, and 38 (46.4%) received ICI after SBRT. The median survival (MS) after SBRT was 14.8 months (95% confidence interval [CI] 11.4-19.6). On univariable analysis, MS was significantly longer for patients starting ICI after SBRT (27.3 months, 95% CI 16.0-33.9) than for those who did not receive any ICI (MS 11.3 months, 95% CI 8.9-15.8, P = 0.04). Patients with RCC (HR 0.67, 95% CI 0.45-1.00, P = 0.05) and higher body mass index (BMI, HR 0.97 as continuous variable, 95% CI 0.93-1.00, P = 0.05) trended toward longer OS. On multivariable analysis after adjusting for primary tumor type, performance status and BMI, only ICI treatment after SBRT was significantly associated with increased survival (HR 0.62, 95% CI 0.39-0.98, P = 0.04). LC after SBRT was numerically higher in patients receiving ICI (1-year LC 91.3%, 95% CI 82.4-95.8%; 2-year 79.7%, 95% CI 65.7-88.5%), than those who did not (1-year 81.5%, 95% CI 65.9-90.5%; 2-year LC 55.5%, 95% CI 35.6-71.4%), although this was not statistically significant (P = 0.18). ICI Initiation before SBRT trended toward superior LC compared to no ICI (multivariable HR 0.49, 95% CI 0.22-1.08, P = 0.08). Both epidural disease and paraspinal extension were associated with worse LC on univariable and multivariable analyses. Conclusion ICIs may enhance survival and tumor control after SBRT for patients with spine metastasis. Post-SBRT ICI may improve systemic disease control and survival, while pre-SBRT ICI may augment LC. Further research is needed to maximize the synergy between these two treatment modalities. Author Disclosure X. Chen: None. M.C. LeCompte: None. L.R. Kleinberg: Research Grant; Novartis, Novocure, Accuray, Arbor. Honoraria; Accuray. Advisory Board; Novocure. Travel Expenses; Accuray. R.K. Hales: Research Grant; Genentech. K. Voong: Research Grant; Radiation Oncology Institute, Lung Cancer Research Foundation, Canon, Inc. P. Forde: Research Grant; Bristol Myers-Squibb, AstraZeneca, Kyowa-Kirin, Novartis. Honoraria; Bristol Myers-Squibb, AstraZeneca, Novartis, Merck, AbbVie, EMD, Inivata. J.R. Brahmer: Research Grant; AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Merck, RAPT Therapeutics, Revolution Medicines. Consultant; Amgen, Bristol Myers Squibb, Genentech, Eli Lilly, GlaxoSmithKline, Merck, Sanofi. M. Markowski: Honoraria; Clovis Oncology, Exelixis. D.M. Ryan II: None. L. Lo: None. D.M. Sciubba: Consultant; Medtronic, DePuy-Synthes, Baxter. K.J. Redmond: Research Grant; Elekta AB, Accuray. Honoraria; AstraZeneca, Accuray. Travel Expenses; Elekta AB, Accuray.

Background Unplanned hospitalization during cancer treatment is costly, can disrupt treatment, and affect patient quality of life. However, incidence and risks factors for hospitalization during lung cancer radiotherapy are not well characterized. Methods Patients treated with definitive intent radiation (≥45 Gy) for lung cancer between 2008 and 2018 at a tertiary academic institution were identified. In addition to patient, tumor, and treatment related characteristics, specific baseline frailty markers (Charlson comorbidity index, ECOG, patient reported weight loss, BMI, hemoglobin, creatinine, albumin) were recorded. All cancer-related hospitalizations during or within 30 days of completing radiation were identified. Associations between baseline variables and any hospitalization, number of hospitalizations, and overall survival were identified using multivariable linear regression and multivariable Cox proportional-hazards models, respectively. Results Of 270 patients included: median age was 66.6 years (31–88), 50.4% of patients were male (n = 136), 62% were Caucasian (n = 168). Cancer-related hospitalization incidence was 17% (n = 47), of which 21% of patients hospitalized (n = 10/47) had > 1 hospitalization. On multivariable analysis, each 1 g/dL baseline drop in albumin was associated with a 2.4 times higher risk of any hospitalization (95% confidence interval (CI) 1.2–5.0, P = 0.01), and baseline hemoglobin ≤10 was associated with, on average, 2.7 more hospitalizations than having pre-treatment hemoglobin > 10 (95% CI 1.3–5.4, P = 0.01). After controlling for baseline variables, cancer-related hospitalization was associated with 1.8 times increased risk of all-cause death (95% CI: 1.02–3.1, P = 0.04). Conclusions Our data show baseline factors can predict those who may be at increased risk for hospitalization, which was independently associated with increased mortality. Taken together, these data support the need for developing further studies aimed at early and aggressive interventions to decrease hospitalizations during treatment.

Additional file 1: Table S1. Baseline variables and risk of multiple hospitalizations.

Hypofractionated prostate radiotherapy may increase biologically effective dose delivered while shortening treatment duration, but information on patient-reported urinary, bowel, and sexual function after dose-escalated hypofractionated radiotherapy is limited. We report patient-reported outcomes (PROs) from a randomized trial comparing hypofractionated and conventional prostate radiotherapy.Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity-modulated radiation therapy (CIMRT, 75.6 Gy in 1.8 Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4 Gy fractions). Questionnaires assessing urinary, bowel, and sexual function were completed pretreatment and at 2, 3, 4, and 5 years after treatment.Of 203 eligible patients, 185 were evaluable for PROs. A total of 173 completed the pretreatment questionnaire (82 CIMRT, 91 HIMRT) and 102 completed the 2-year questionnaire (46 CIMRT, 56 HIMRT). Patients who completed PROs were similar to those who did not complete PROs (all P0.05). Patient characteristics, clinical characteristics, and baseline symptoms were well balanced between the treatment arms (all P0.05). There was no difference in patient-reported bowel (urgency, control, frequency, or blood per rectum), urinary (dysuria, hematuria, nocturia, leakage), or sexual symptoms (erections firm enough for intercourse) between treatment arms at 2, 3, 4, and 5 years after treatment (all P0.01). Concordance between physician-assessed toxicity and PROs varied across urinary and bowel domains.We did not detect an increase in patient-reported urinary, bowel, and sexual symptom burden after dose-escalated intensity-modulated prostate radiation therapy using a moderate hypofractionation regimen (72 Gy in 2.4 Gy fractions) compared with conventionally fractionated radiation.

BackgroundDurvalumab consolidation after chemoradiation for unresectable stage III non-small cell lung cancer (NSCLC) improves overall survival. However, up to 25% of patients progress within 18 months following durvalumab consolidation. Little is known regarding the genomic determinants of response to therapy.1 2MethodsWe retrospectively reviewed medical records of 76 patients with stage III NSCLC who received definitive chemoradiation and durvalumab consolidation between 2015–2020 at a large tertiary academic center. Tumor characteristics, molecular profiling, and clinical outcomes including response, progression-free survival (PFS), and overall survival (OS) were documented in an IRB-approved database. Outcomes were assessed by molecular alterations identified from diagnostic biopsy samples using Kaplan-Meier analysis.ResultsOf 76 patients with stage III NSCLC treated with definitive chemoradiation and durvalumab consolidation, 74 were evaluable for PFS and OS. Median age at diagnosis was 66.5 years and 43% were women (n=32). Histology included adenocarcinoma (55%, n=41) and squamous cell carcinoma (32%, n=24). Median follow-up time was 23.0 months from start of durvalumab. The cohort’s median PFS was 15.9 months with 36 patients having documented radiographic progression. Overall survival for the cohort was 32.0 months with 28 deaths. Molecular profiling was performed at time of diagnosis in 35 patients (47%), of which 30 had adenocarcinoma histology. 18 patients had KRAS mutations including KRAS p.G12C (n=8), which were mutually exclusive with 8 patients who had other clinically targetable alterations (EGFR mutations n=1, ALK fusion n=1, RET fusion n=1, MET exon 14 skipping mutation n=1, or ERBB2 mutation n=4). Three patients had non-targetable mutations (BRAF non-p.V600E, STK11, KEAP1) and the remaining six patients lacked an identifiable alteration. There was no significant difference in PFS (p=0.92 by log-rank) or OS (p=0.36 by log-rank) between patients with KRAS mutations, other targetable alterations, non-targetable mutations, or those without molecular profiling. Within patients with KRAS mutations, there was no significant difference in PFS (p=0.33 by log-rank) or OS (p=0.69 by log-rank) when comparing KRAS p.G12C to non-p.G12C mutations.ConclusionsOur study of real-world cohort of patients with stage III NSCLC examined genomic determinants of response to treatment with definitive chemoradiation and durvalumab. Results from this retrospective study suggest that patients with KRAS-mutated tumors derive similar benefit from therapy than patients with other targetable, non-targetable or no identifiable genomic alterations. Future directions for this cohort include analysis of post-progression therapy, subgroup analysis comparing genomic alterations to patterns of progression, and examination of molecular signatures of patients with progression.ReferencesAntonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med 2017;377(20):1919–1929. doi:10.1056/NEJMoa1709937Faivre-Finn C, Vicente D, Kurata T, et al. Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC—an update from the PACIFIC trial. Journal of Thoracic Oncology 2021;16(5):860–867. doi:10.1016/j.jtho.2020.12.015Ethics ApprovalThis retrospective chart review study has obtained ethics approval from the Institutional Review Board at the Johns Hopkins School of Medicine (number: IRB00232313).

Introduction Checkpoint inhibitor pneumonitis (CIP) is a serious toxicity of anti–programmed death-(ligand) 1 immunotherapy. Whether pretreatment differences in pulmonary function exist in patients who develop CIP is unknown. We analyzed the pulmonary function tests (PFTs) of patients with NSCLC treated with immune checkpoint inhibitors (ICIs) to evaluate whether pretreatment lung function was associated with CIP development. Methods Patients were included if they completed greater than or equal to 1 PFT within 2 years preceding ICI initiation. CIP status (CIP+: developed CIP, CIP−: did not develop CIP) was determined clinically. Generalized estimating equation–based linear regression was used to evaluate the effects of time and CIP on lung function. Primary outcomes included the following: percent-predicted forced expiratory volume in 1 second (FEV1pp), percent-predicted forced vital capacity (FVCpp), and FEV1/FVC. Results A total of 43 patients (34 CIP−, 9 CIP+) with 79 PFTs (59 CIP−, 20 CIP+) were included. CIP+ patients had a 21.7% lower pretreatment FEV1pp compared with the CIP− group (95% confidence interval: −38.6 to −4.7). No statistically significant differences in FVCpp or FEV1/FVC were observed. The prevalence of obstructive lung disease was similar in both groups at 67% and 62% for the CIP+ and CIP− cohorts, as was the prevalence of current/former smoking at 100% and 93%, respectively. Conclusions Pretherapy differences in lung function were evident between patients who did and did not develop CIP, though the prevalence of obstructive lung disease was similar. Prospective studies are needed to validate these findings, inform potential risk factors for CIP, and investigate the effects of ICI treatment and CIP on pulmonary function in patients with NSCLC.

This study evaluated an association between whole brain volume loss and neurocognitive decline following prophylactic cranial irradiation (PCI) for limited-stage small-cell lung cancer (SCLC). This was a secondary analysis of a prospective clinical trial that accrued patients at a single institution from 2013 to 2016. Patients with limited-stage SCLC treated with standard chemo-radiation received PCI 25 Gy/10 fractions, with mean hippocampal dose limited to

Background Removal of a pin during Gamma Knife stereotactic radiosurgery (GK-SRS) may be necessary to prevent collision and allow treatment. Objective To investigate outcomes after GK-SRS for treatment of brain metastases using a head frame immobilized to the skull with only 3 pins. Methods Between 2009 and 2014, we retrospectively reviewed the records of 1971 patients and identified 20 patients with multiple brain metastases treated with GK-SRS in which 1 anterior pin was removed immediately before treatment of a single posterior lesion. GK-SRS was also delivered to 116 other lesions in these 20 patients using the standard 4 pins during the same session, serving as an internal control for comparison. Endpoints included local control, dosimetric parameters, toxicity, and overall survival. Results The median number of lesions treated per session was 6 (range, 2-14). The lesions treated using 3 pins were located in the occipital lobe (n = 14) or the cerebellum (n = 6). Median follow-up was 12.3 months. There was 1 local failure involving a control lesion. Lesions treated using 3 pins had a lower prescription isodose line. GK-SRS of a lesion using 3 pins did not cause any clinical toxicities or increase in radiographic edema or hemorrhage. Conclusion Treating posteriorly located brain metastases with GK-SRS using only 3 pins provided excellent local control and no difference in treatment toxicity, which may make it a safe and reasonable option for lesions that may otherwise be difficult to treat.

Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that can occur after initiation of anti-programmed death 1/programmed death ligand 1 immune checkpoint inhibitor (ICI) therapy for the treatment of multiple malignancies, including NSCLC. However, the incidence of CIP has not been previously examined in a population that included both trial-enrolled and non-trial-enrolled patients with advanced NSCLC. Furthermore, risk factors and other clinical characteristics associated with CIP severity are not known. In this study, we retrospectively examined clinical characteristics, incidence, and risk factors for CIP in a cohort of 205 patients with NSCLC, all of whom received anti-programmed death 1/programmed death ligand 1 ICIs. Our results demonstrate a higher incidence of CIP (19%) than previously reported in clinical trials (3%-5%). Our data also suggest that tumor histologic type may be a risk factor for CIP development. We observed a wide range of time to onset of CIP (median 82 days), with high morbidity and mortality associated with higher-grade CIP regardless of degree of immunosuppression. Our data provide new insight into the epidemiology and clinical characteristics of CIP. Further studies are needed to increase CIP pharmacovigilance, improve risk stratification, and refine diagnostic algorithms for the diagnosis and management of this potential life-threatening complication of ICI therapy.

Immune checkpoint blockade (ICB), which harnesses the body's immune system to recognize and kill cancer cells, has transformed the management landscape for patients with advanced non-small cell lung cancer (NSCLC). Building on the success of this approach, clinical and translational researchers are attempting to augment the benefit of anti-programmed death 1/programmed death ligand 1 monotherapy through the addition of other therapies, such as conventional cancer treatments. This article reviews the potential use of immunotherapeutic strategies combined with radiation therapy in patients with NSCLC, focusing on ICB. It describes the mechanism of action of immune checkpoint inhibitors, summarizes published studies that demonstrate the benefit of immune checkpoint inhibitors in advanced NSCLC, and provides the preclinical and clinical rationale supporting the potential immunologic synergy of radiation and ICB.

OBJECTIVE: Removal of a pin during Gamma Knife® stereotactic radiosurgery (GK_SRS) may be necessary to prevent collision and allow for treatment. We investigated outcomes following GK_SRS for treatment of brain metastases using a head frame immobilized to the skull with only 3 pins. MATERIALS/METHODS: Between 2009-2014, we retrospectively reviewed the records of 1,971 patients and identified 20 patients with multiple brain metastases treated with GK_SRS in which 1 anterior pin was removed immediately before treatment of a single posteriorly located lesion. GK_SRS was also delivered to 121 other lesions using the standard 4 pins during the same session, serving as an internal control for comparison. Endpoints included local control, dosimetric parameters, toxicity, and overall survival. Characteristics were compared using the Wilcoxon rank sum and Fisher's exact tests. Survival was analyzed using the Kaplan-Meier method. RESULTS: The median number of lesions treated per session was 6 (range 2-14). The lesions treated using 3 pins were located in the occipital lobe (n = 14) or cerebellum (n = 6). Median follow-up was 12.3 months. There was one local failure of a control lesion. Lesions treated using 3 pins had a lower prescription isodose line, and gradient index. GK_SRS of a lesion using 3 pins did not cause any clinical toxicities or increase in radiographic edema or hemorrhage. CONCLUSION: Treating posteriorly located brain metastases with GK_SRS using only 3 pins provides excellent local control and no difference in treatment toxicity, making it a safe and reasonable option for lesions that may otherwise not be possible to treat.

Background Brainstem metastases (BSMs) represent a significant treatment challenge. Stereotactic radiosurgery (SRS) is often used to treat BSM. We report our experience in the treatment of BSM with Gamma Knife SRS (GK_SRS). Methods The records of 1962 patients with brain metastases treated with GK_SRS between 2009 and 2013 were retrospectively reviewed. Seventy-four patients with 77 BSMs and follow-up brain imaging were identified. Local control (LC), overall survival (OS), progression-free survival (PFS), and toxicity were assessed. Results Median follow-up was 5.5 months (range, 0.2–48.5 months). Median tumor volume was 0.13 cm3 (range, 0.003–5.58 cm3). Median treatment dose was 16 Gy (range, 10–20 Gy) prescribed to 50% isodose line (range, 40%–86%). Crude LC was 94% (72/77). Kaplan-Meier estimate of median OS was 8.5 months (95% CI, 5.6–9.4 months). Symptomatic lesions and larger lesions, especially size ≥2 cm3, were associated with worse LC (HR = 8.70, P = .05; HR = 14.55, P = .02; HR = 62.81, P < .001) and worse OS (HR = 2.00, P = .02; HR = 2.14, P = .03; HR = 2.81, P = .008). Thirty-six percent of BSMs were symptomatic, of which 36% (10/28) resolved after SRS and 50% (14/28) had stable or improved symptoms. Actuarial median PFS was 3.9 months (95% CI, 2.7–4.9 months). Midbrain location was significant for worse PFS (HR = 2.29, P = .03). Toxicity was low (8%, 6/74), with size and midbrain location associated with increased toxicity (HR 1.57, P = .05; HR = 5.25, P = .045). Conclusions GK_SRS is associated with high LC (94%) and low toxicity (8%) for BSMs. Presence of symptoms or lesion size ≥ 2 cm3 was predictive of worse LC and OS.

Recently, a firmer understanding of tumor immunology and tumor escape mechanisms has led to the development of immune checkpoint inhibitors, antibodies against programmed death-1 (PD-1) and its ligand (PD-L1). Nivolumab, pembrolizumab, and atezolizumab have dramatically altered the treatment paradigm in non-small cell lung cancer (NSCLC) and have each demonstrated improvements in outcomes and quality of life when compared to chemotherapy. Enrichment strategies to better select those patients more likely to respond have identified PD-L1 staining by immunohistochemistry (IHC) to be a predictive biomarker in both treatment naïve and refractory patients. Unfortunately, many challenges exist with this strategy and underscore the need for further exploration for more reliable biomarkers. Multiple tissue and plasma-based enrichment strategies have been identified in the hope of identifying patients more likely to benefit from checkpoint inhibitors. These include tumor mutational load; the "inflamed phenotype" including tumor infiltrating lymphocytes (TILS) and immunoscore; T-cell receptor clonality; gene signatures, and several plasma biomarkers. Several studies have revealed many of these biomarkers to be reliable predictors of response to immune checkpoint inhibitors across multiple tumor types. Given the small nature of these studies, additional prospective studies are warranted to formalize and validate each of these enrichment strategies.

Purpose High cure rates for Hodgkin’s lymphoma must be balanced with long-term treatment-related toxicity. Here we report an intensity-modulated radiation therapy (IMRT) technique that achieves adequate target coverage for mediastinal disease while minimizing high- and low-dose exposure of critical organs. Methods and materials Treatment plans for IMRT and conventional anteroposterior-posteroanterior (AP-PA) techniques, with comparable coverage of the planning target volume (PTV), were generated for 9 female patients with mediastinal Hodgkin’s lymphoma assuming use of inclined positioning, daily breath-hold, and CT-on-rails verification. Our “butterfly” IMRT beam arrangement involved anterior beams of 300°−30° and posterior beams of 160°−210°. Percentages of normal structures receiving 30 Gy (V30), 20 Gy (V20), and 5 Gy (V5) were tabulated for the right and left breasts, total lung, heart, left and right ventricles, left anterior descending coronary artery (LAD), and spinal cord. Differences in each variable, conformity index, homogeneity index, and V107% between the two techniques were calculated (IMRT minus conventional). Results Use of IMRT generally reduced the V30 and V20 to critical structures: −1.4% and +0.1% to the right breast, −1.7% and −0.9% to the left breast, −14.6% and −7.7% to the total lung, −12.2% and −10.5% to the heart, −2.4% and −14.2% to the left ventricle, −16.4% and −8.4% to the right ventricle, −7.0% and −14.2% to the LAD, and −52.2% and −13.4% to the spinal cord. Differences in V5 were +6.2% for right breast, +2.8% for left breast, +12.9% for total lung, −3.5% for heart, −8.2% for left ventricle, −1.5% for right ventricle, +0.1% for LAD, and −0.1% for spinal cord. Use of IMRT significantly reduced the volume of tissue receiving 107% of the dose (mean 754 cm3 reduction). Conclusions This butterfly technique for IMRT avoids excess exposure of heart, breast, lung, and spinal cord to doses of 30 or 20 Gy; mildly increases V5 to the breasts; and decreases the V107%.