Immune checkpoint inhibitors and radiosurgery for newly diagnosed melanoma brain metastases.

INTRODUCTION: Brain metastases are common in metastatic melanoma and radiosurgery is often utilized for local control. Immune checkpoint inhibitors (CPIs) play a central role in contemporary melanoma management; however, there is limited data exploring outcomes and potential toxicities for patients treated with CPIs and radiosurgery. METHODS: We retrospectively identified all consecutive cases of newly diagnosed melanoma brain metastases (MBM) treated with Gamma Knife radiosurgery at a single institution between 2012 and 2017, and included only patients that initiated CPIs within 8 weeks before or after radiosurgery. RESULTS: Thirty-eight patients were included with a median follow-up of 31.6 months. Two-year local control was 92%. Median time to out-of-field CNS and extra-CNS progression were 8.4 and 7.9 months, respectively. Median progression-free survival (PFS) was 3.4 months and median overall survival (OS) was not reached (NR). Twenty-five patients (66%) received anti-CTLA4 and 13 patients (34%) received anti-PD-1+/-anti-CTLA4. Compared with anti-CTLA4, patients that received anti-PD-1+/-anti-CTLA4 had significant improvements in time to out-of-field CNS progression (p = 0.049), extra-CNS progression (p = 0.015), and PFS (p = 0.043), with median time to out-of-field CNS progression of NR vs. 3.1 months, median time to extra-CNS progression of NR vs. 4.4 months, and median PFS of 20.3 vs. 2.4 months. Six patients (16%) developed grade ≥ 2 CNS toxicities (grade 2: 3, grade 3: 3, grade 4/5: 0). CONCLUSIONS: Excellent outcomes were observed in patients that initiated CPIs within 8 weeks of undergoing radiosurgery for newly diagnosed MBM. There appears to be an advantage to anti-PD-1 or combination therapy compared to anti-CTLA4.

Risk of Clinically Significant Prostate Cancer Associated With Prostate Imaging Reporting and Data System Category 3 (Equivocal) Lesions Identified on Multiparametric Prostate MRI.

OBJECTIVE: The objective of this study is to determine the frequency of clinically significant cancer (CSC) in Prostate Imaging Reporting and Data System (PI-RADS) category 3 (equivocal) lesions prospectively identified on multiparametric prostate MRI and to identify risk factors (RFs) for CSC that may aid in decision making. MATERIALS AND METHODS: Between January 2015 and July 2016, a total of 977 consecutively seen men underwent multiparametric prostate MRI, and 342 underwent MRI-ultrasound (US) fusion targeted biopsy. A total of 474 lesions were retrospectively reviewed, and 111 were scored as PI-RADS category 3 and were visualized using a 3-T MRI scanner. Multiparametric prostate MR images were prospectively interpreted by body subspecialty radiologists trained to use PI-RADS version 2. CSC was defined as a Gleason score of at least 7 on targeted biopsy. A multivariate logistic regression model was constructed to identify the RFs associated with CSC. RESULTS: Of the 111 PI-RADS category 3 lesions, 81 (73.0%) were benign, 11 (9.9%) were clinically insignificant (Gleason score, 6), and 19 (17.1%) were clinically significant. On multivariate analysis, three RFs were identified as significant predictors of CSC: older patient age (odds ratio [OR], 1.13; p = 0.002), smaller prostate volume (OR, 0.94; p = 0.008), and abnormal digital rectal examination (DRE) findings (OR, 3.92; p = 0.03). For PI-RADS category 3 lesions associated with zero, one, two, or three RFs, the risk of CSC was 4%, 16%, 62%, and 100%, respectively. PI-RADS category 3 lesions for which two or more RFs were noted (e.g., age ≥ 70 years, gland size ≤ 36 mL, or abnormal DRE findings) had a CSC detection rate of 67% with a sensitivity of 53%, a specificity of 95%, a positive predictive value of 67%, and a negative predictive value of 91%. CONCLUSION: Incorporating clinical parameters into risk stratification algorithms may improve the ability to detect clinically significant disease among PI-RADS category 3 lesions and may aid in the decision to perform biopsy.

MRI-Ultrasound Fusion Targeted Biopsy of Prostate Imaging Reporting and Data System Version 2 Category 5 Lesions Found False-Positive at Multiparametric Prostate MRI.

OBJECTIVE: The purpose of this study was to determine imaging and clinical features associated with Prostate Imaging Reporting and Data System (PI-RADS) category 5 lesions identified prospectively at multiparametric MRI (mpMRI) that were found benign at MRI-ultrasound fusion targeted biopsy. MATERIALS AND METHODS: Between January 2015 and July 2016, 325 men underwent prostate mpMRI followed by MRI-ultrasound fusion targeted biopsy of 420 lesions prospectively identified and assessed with PI-RADS version 2. The frequency of clinically significant prostate cancer (defined as Gleason score ≥ 7) among PI-RADS 5 lesions was determined. Lesions with benign pathologic results were retrospectively reassessed by three abdominal radiologists and categorized as concordant or discordant between mpMRI and biopsy results. Multivariate logistic regression was used to identify factors associated with benign disease. Bonferroni correction was used. RESULTS: Of the 98 PI-RADS 5 lesions identified in 89 patients, 18% (18/98) were benign, 10% (10/98) were Gleason 6 disease, and 71% (70/98) were clinically significant prostate cancer. Factors associated with benign disease at multivariate analysis were lower prostate-specific antigen density (odds ratio [OR], 0.88; p < 0.001) and apex (OR, 3.54; p = 0.001) or base (OR, 7.11; p = 0.012) location. On secondary review of the 18 lesions with benign pathologic results, 39% (7/18) were scored as benign prostatic hyperplasia nodules, 28% (5/18) as inflammatory changes, 5% (1/18) as normal anatomic structures, and 28% (5/18) as discordant with imaging findings. CONCLUSION: PI-RADS 5 lesions identified during routine clinical interpretation are associated with a high risk of clinically significant prostate cancer. A benign pathologic result was significantly correlated with lower prostate-specific antigen density and apex or base location and most commonly attributed to a benign prostatic hyperplasia nodule. Integration of these clinical features may improve the interpretation of high-risk lesions identified with mpMRI.

Role of MRI in the Use of an Absorbable Hydrogel Spacer in Men Undergoing Radiation Therapy for Prostate Cancer: What the Radiologist Needs to Know.

OBJECTIVE: Hydrogel spacers have a novel role in the treatment of low- and intermediate-risk prostate cancer with dose-escalated radiation therapy. Given the growing number of patients undergoing treatment with radiation therapy, the use of hydrogel spacers is expected to increase. The purpose of this article is to review what a radiologist needs to know about the imaging of hydrogel spacers, including MRI technique and appearance on CT and MRI. CONCLUSION: MRI has a critical role in the evaluation of hydrogel spacer placement and is used to facilitate contouring by the radiation oncologist. The radiologist should be familiar with the imaging appearance of hydrogel spacers on CT and MRI to avoid interpretation pitfalls and errors.

Significance of histology in determining management of lesions regrowing after radiosurgery.

Brain metastases treated with stereotactic radiosurgery may show delayed enlargement on post-treatment imaging that is of ambiguous etiology. Histopathologic interpretation of brain specimens is often challenging due to the presence of significant radiation effects admixed with irradiated residual tumor of indeterminate viability. The purpose of this study was to assess the impact of histologic findings on clinical outcomes following resection of these lesions. Between 2004 and 2010, 690 patients with brain metastases were enrolled in a prospective gamma knife data repository, and lesions requiring excision were identified. Tissue specimens were divided into four groups based on the ratio of treatment related inflammatory changes (TRIC) to tumor cells, and subsequently patient outcomes were assessed. Of 2,583 metastases treated, 36 were excised due to symptomatic enlargement. Only TRIC, without residual evidence of tumor, was seen in 36 % (13/36) of specimens. Resection of these lesions resulted in 100 % local control in follow-up. Of the remaining 23 lesions that contained any viable-appearing tumor within the resected specimen, 8 recurred after resection. Lesions that enlarged in the first 6 months were more likely to contain higher amounts of residual tumor cells. Patients with even <2 % tumors cells on excision had significantly worse local control (75 vs. 100 %, p = 0.024) and survival (HR 0.27, p = 0.029) compared with those patients with exclusively TRIC. In summary, our findings underscore the importance of surgically obtaining tissue in a method that facilitates complete lesional interpretive histology in order to accurately guide ongoing patient management.

Pilot Curriculum for Continued Professional Development of Radiation Oncology Nurses.

Purpose: Limited structured educational programs are available for the continued professional development of radiation oncology nurses. In this study, we evaluated a pilot curriculum focusing on clinical workflow and toxicity management for radiation oncology nurses at a single university-affiliated medical center network. Methods and Materials: Based on a previous multi-institutional needs assessment, a targeted curriculum on clinical workflow and toxicity management was developed, including didactic lectures, written disease-specific toxicity management guidelines, and standardized medication/laboratory order preference lists in the electronic health record. An anonymized survey was circulated to all participants pre- and postcurriculum. The survey was composed of Likert-type subjective questions and 11 objective knowledge-based questions (KBQs). Paired Likert-type data were analyzed using Wilcoxon signed ranks test. Objective question data were compared with the McNamar's mid P test. Results: Thirteen nurses participated in the pilot curriculum and 100% completed pre- and post curriculum surveys. After the didactics, nurses reported a significant increase in their understanding of the responsibilities of a nurse and overall process of care and their ability to explain computed tomography simulation, as well as their ability to assess, manage, and grade radiation-related toxicities (P < .01). There was significant improvement in the percent of correct answers on objective KBQs from a baseline of 52% to 80% after the curriculum (P < .01). Qualitatively, 70% (9/13) of nurses rated the curriculum as "extremely useful" and 30% (4/13) as "quite useful." Conclusions: Our pilot curriculum using a combination of in-person formal didactics, toxicity management guidelines, and electronic health record based order preference lists was well-received and showed promising results on KBQ assessment. This work may be used to guide the development of larger curricula for nurse onboarding and continuing education in a multicenter setting.

Outcomes for patients with cervical cancer treated with extended-field intensity-modulated radiation therapy and concurrent cisplatin.

OBJECTIVE: To evaluate disease outcomes and toxicity in patients with cervical cancer treated with extended-field intensity-modulated radiotherapy. MATERIALS AND METHODS: We included all patients treated with extended-field intensity-modulated radiotherapy and concurrent weekly cisplatin from 2003 to 2010 at 2 institutions. Overall survival and disease-free survival were estimated using Kaplan-Meier method. Locoregional failure (LRF), distant failure, and competing mortality were calculated using cumulative incidence functions. Acute and late toxicity were graded using Common Terminology Criteria for Adverse Events (CTCAE) and Radiation Therapy Oncology Group late radiation morbidity scoring criteria, respectively. RESULTS: The study included 21 patients, 14 and 20 of which had positive para-aortic and pelvic nodes, respectively. The median follow-up was 22 months. Eighteen-month overall survival and disease-free survival were 59.7% (95% confidence interval [CI], 41.2%-86.4%) and 42.9% (95% CI, 26.2%-70.2%). Eighteen-month cumulative incidences of LRF, distant failure, and competing mortality were 9.5% (95% CI, 1.5-26.8%), 42.9% (95% CI, 21.3-62.9%), and 4.8% (95% CI, 0.3-20.2%), respectively. Eighteen-month cumulative incidences of late grade 3 or higher-grade genitourinary and gastrointestinal toxicity were 4.8% (95% CI, 0.2%-20.3%) and 0%, respectively. CONCLUSIONS: Intensity-modulated extended-field radiotherapy was associated with low rates of late toxicity and LRF. High rates of distant failure indicate that this group of patients could benefit from intensified systemic therapy.

Practical Implementation of Emergent After-Hours Radiation Treatment Process Using Remote Treatment Planning on Optimized Diagnostic CT Scans.

The purpose of this report is to present the implementation of a process for after-hours radiation treatment (RT) utilizing remote treatment planning based on optimized diagnostic computed tomography (CT) scans for the urgent palliative treatment of inpatients. A standardized operating procedure was developed by an interprofessional panel to improve the quality of after-hours RT and minimize the risk of treatment errors. A new diagnostic CT protocol was created that could be performed after-hours on hospital scanners and would ensure a reproducible patient position and adequate field of view. An on-call structure for dosimetry staff was created utilizing remote treatment planning. The optimized CT protocol was developed in collaboration with the radiology department, and a novel order set was created in the electronic health system. The clinical workflow begins with the radiation oncologist notifying the on-call team (therapist, dosimetrist, and physicist) and obtaining an optimized diagnostic CT scan on a hospital-based scanner. The dosimetrist remotely creates a plan; the physicist checks the plan; and the patient is treated. Plans are intentionally simple (parallel opposed fields, symmetric jaws) to expedite care and reduce the risk of error. Education on the new process was provided for all relevant staff. Our process was successfully implemented with the use of an optimized CT protocol and remote treatment planning. This approach has the potential to improve the quality and safety of emergent after-hours RT by better approximating the normal process of care.

Observed magnetic resonance imaging changes in pediatric patients treated with stereotactic radiosurgery for intracranial tumors.

PURPOSE: This study seeks to characterize magnetic resonance imaging (MRI) changes following stereotactic radiosurgery (SRS) of pediatric brain malignancies. METHODS: Serial MRI evaluations were performed on 21 lesions treated with SRS for either medulloblastoma (n=12), juvenile pilocytic astrocytoma (n=4), ependymoma (n=2), atypical rhabdoid teratoid tumor (n=2), or pineocytoma (n=1). Prescription doses ranged from 14 to 30 Gy in one to five fractions. Tumor response was qualified as complete (CR), partial (PR), stable disease (SD), or progressive disease (PD) according to the RECIST v1.1. Median radiographic follow-up after SRS was 17 months. RESULTS: A total of 80 follow-up MRI scans were reviewed with a median of eight per patient. During serial MRI evaluation, eight lesions met criteria for PD at a median of 6 months. However, of these, three (37%) represented transient tumor edema with two lesions later developing a CR at a median of 15 months and one persisting as SD at 12 months. The remaining five lesions were true local failures. Of the 13 lesions that did not show evidence of PD, a CR was obtained in 11 lesions at a median of 3 months (range, 2-6), and SD was seen in the remaining two tumors at last follow-up. CONCLUSION: Lesion enlargement following SRS for pediatric intracranial tumors is common, and a proportion of patients meeting requirements for PD at early radiographic follow-up may later develop complete resolution of their lesions. Physicians should be aware of these radiographic changes to avoid unwarranted medical and surgical interventions.

Assessment of Radiation Oncology Nurse Education in the United States.

PURPOSE: Nurses in the radiation oncology (RO) clinic have a critical role in the management of patients receiving radiation therapy. However, limited data exist regarding the exposure of nurses to RO during training and the current educational needs of practicing RO nurses. This study assesses nurses' prior RO education, participation in national training efforts, and perceived educational needs. METHODS AND MATERIALS: A web-based survey using a 5-point Likert-type scale was distributed to RO nurses at 3 academic medical centers. Questions focused on prior education experiences, clinical areas of strength/weakness, and perceived value of future educational interventions. Likert-type scores are reported as median (interquartile range), and a Kruskal-Wallis test was conducted to assess for significant differences in responses. RESULTS: The survey response rate was 39 of 54 (72%). Respondents were 90% female and trained at 30 nursing schools in 17 states. Only 5% of nurses reported a curriculum in nursing school with RO content, and nearly all (97%) received their RO education on the job. Forty-one percent of nurses completed the Oncology Nursing Society radiation therapy certificate course, and only 5% completed the American Society for Radiation Oncology nursing module. Nurses felt most confident in the overall management of patients with breast (4 [3-4]), prostate (4 [3-5]), and central nervous system (4 [3-4]) cancers and least confident for lymphoma (3 [2-4]), gynecologic (3 [2-4]), and head and neck cancers (3 [2-4]; P < .01). Nurses rated didactic lectures from physicians (5 [3-5]), shadowing RO residents (4 [3-5]), and working with simulation therapists (4 [3-5]) as valuable components to include in a training curriculum (P = .08). CONCLUSIONS: Nursing school exposure to RO is limited, and only a minority of RO nurses complete RO-specific training or certification available from national organizations. This study identifies several areas of perceived clinical nursing strengths and weaknesses that can be used to inform the design of future RO nursing educational programs.

Intracranial application of IMRT based radiosurgery to treat multiple or large irregular lesions and verification of infra-red frameless localization system.

We have employed a frameless localization system for intracranial radiosurgery, utilizing a custom biteblock with fiducial markers and an infra-red camera for set-up and monitoring patient position. For multiple brain metastases or large irregular lesions, we use a single-isocenter intensity-modulated approach. We report our quality assurance measurements and our experience using Intensity Modulated Radiosurgery (IMRS) to treat such intracranial lesions. A phantom with integrated targets and fiducial markers was utilized to test the positional accuracy of the system. The frameless localization system was used for patient setup and target localization as well as for motion monitoring during treatment. Inverse optimization planning gave satisfactory dose coverage and critical organ sparing. Patient setup was guided by the infrared camera through fine adjustment in three translational and three rotational degrees for isocenter localization and verified by orthogonal kilovoltage (kV) images, taken before treatment to ensure the accuracy of treatment. The relative localization of the camera based system was verified to be highly accurate along three translational directions of couch motion and couch rotation. After verification, we began treating patients with this technique. About 8-12 properly selected fixed beams with a single isocenter were sufficient to achieve good dose coverage and organ sparing. Portal dosimetry with an Electronic Portal Imaging Device (EPID) and kV images provided excellent quality assurance for the IMRS plan and patient setup. The treatment time was less than 60 min to deliver doses of 16-20 Gy in a single fraction. The camera-based system was verified for positional accuracy and was deemed sufficiently accurate for stereotactic treatments. Single isocenter IMRS treatment of multiple brain metastases or large irregular lesions can be done within an acceptable treatment time and gives the benefits of dose-conformity and organ-sparing, easy plan QA, and patient setup verification.

Optically-guided frameless linac-based radiosurgery for brain metastases: clinical experience.

The purpose of this study was to describe our clinical experience using optically-guided linear accelerator (linac)-based frameless stereotactic radiosurgery (SRS) for the treatment of brain metastases. Sixty-five patients (204 lesions) were treated between 2005 and 2008 with frameless SRS using an optically-guided bite-block system. Patients had a median of 2 lesions (range, 1-13). Prescription dose ranged from 14 to 22 Gy (median, 18 Gy) and was given in a single fraction. Clinical and radiographic evaluation occurred every 2-4 months following treatment. At a median follow-up of 6.2 months, actuarial survival at 12 months was 40% [95% confidence interval (CI), 28-52). Of 135 lesions that were evaluable for local control (LC), 119 lesions (88%) did not show evidence of progression. Actuarial 12 month LC was 76% (95% CI, 66-86). Tumors 2 cm. Adverse events occurred in three patients (5%). Optically-guided linac-based frameless SRS can produce clinical outcomes that compare favorably to frame-based techniques. As this technique is convenient to use and allows for the uncomplicated delivery of hypofractionated radiotherapy, frameless SRS will likely have an increasingly important role in the management of brain metastases.

Impact of Radiation Dose to the Host Immune System on Tumor Control and Survival for Stage III Non-Small Cell Lung Cancer Treated with Definitive Radiation Therapy.

PURPOSE: The significance of radiation dose to the host immune system during the treatment of stage III non-small cell lung cancer (NSCLC) is unknown, but higher doses were associated with worse tumor control and overall survival (OS) in a secondary analysis of RTOG 0617. In this study, we sought to assess the impact of the estimated dose of radiation to immune cells (EDRIC) on cancer-specific outcomes in an independent cohort of patients treated at our institution. METHODS AND MATERIALS: We retrospectively identified 117 patients with stage III NSCLC treated with definitive fractionated radiation from 2004 to 2017 at a single academic center (median dose of 60 Gy; 60% underwent intensity modulated radiation therapy and 92% received concurrent platinum-based chemotherapy). EDRIC was calculated as a function of the number of radiation fractions and mean doses to the lung, heart, and remaining body based on a model developed by Jin et al. RESULTS: Median follow-up was 16 months with 77% of patients followed until death. In the entire population, 5-year OS was 11.2% with a median survival of 17.3 months. Median EDRIC for the entire cohort was 6.1 Gy (range, 2.5-10.0 Gy). A higher EDRIC was correlated with greater risk of grade ≥3 lymphopenia (P = .004). On multivariate analysis including total prescription radiation dose, planning target volume, and chemotherapy utilization, EDRIC was independently associated with OS (hazard ratio [HR] 1.17, P = .03), local progression-free survival (HR 1.17, P = .02), and disease-free survival (HR 1.15, P = .04). The median OS for patients with an EDRIC above 7.3 Gy (fourth quartile) and below 5.1 Gy (first quartile) was 14.3 and 28.2 months, respectively. CONCLUSIONS: Higher doses of radiation to the immune system were associated with tumor progression and death after the definitive treatment of stage III NSCLC. Tailoring radiation therapy to spare the immune system may be an important future direction to improve outcomes in this population.

High Single Doses of Radiation May Induce Elevated Levels of Hypoxia in Early-Stage Non-Small Cell Lung Cancer Tumors.

PURPOSE: Tumor hypoxia correlates with treatment failure in patients undergoing conventional radiation therapy. However, no published studies have investigated tumor hypoxia in patients undergoing stereotactic body radiation therapy (SBRT). We aimed to noninvasively quantify the tumor hypoxic volume (HV) in non-small cell lung cancer (NSCLC) tumors to elucidate the potential role of tumor vascular response and reoxygenation at high single doses. METHODS AND MATERIALS: Six SBRT-eligible patients with NSCLC tumors >1 cm were prospectively enrolled in an institutional review board-approved study. Dynamic positron emission tomography images were acquired at 0 to 120 minutes, 150 to 180 minutes, and 210 to 240 minutes after injection of 18F-fluoromisonidazole. Serial imaging was performed prior to delivery of 18 Gy and at approximately 48 hours and approximately 96 hours after SBRT. Tumor HVs were quantified using the tumor-to-blood ratio (>1.2) and rate of tracer influx (>0.0015 mL·min·cm-3). RESULTS: An elevated and in some cases persistent level of tumor hypoxia was observed in 3 of 6 patients. Two patients exhibited no detectable baseline tumor hypoxia, and 1 patient with high baseline hypoxia only completed 1 imaging session. On the basis of the tumor-to-blood ratio, in the remaining 3 patients, tumor HVs increased on day 2 after 18 Gy and then showed variable responses on day 4. In the 3 of 6 patients with detectable hypoxia at baseline, baseline tumor HVs ranged between 17% and 24% (mean, 21%), and HVs on days 2 and 4 ranged between 33% and 45% (mean, 40%) and between 18% and 42% (mean, 28%), respectively. CONCLUSIONS: High single doses of radiation delivered as part of SBRT may induce an elevated and in some cases persistent state of tumor hypoxia in NSCLC tumors. Hypoxia imaging with 18F-fluoromisonidazole positron emission tomography should be used in a larger cohort of NSCLC patients to determine whether elevated tumor hypoxia is predictive of treatment failure in SBRT.

Radiosurgery alone is associated with favorable outcomes for brain metastases from small-cell lung cancer.

INTRODUCTION: Whole-brain radiation therapy (WBRT) is the standard approach for brain metastases (BM) arising in patients with small-cell lung cancer (SCLC), but the neurocognitive toxicities of WBRT are well documented. For this reason, stereotactic radiosurgery (SRS) alone is the preferred modality for limited BM in most histologies, but in SCLC there are few data exploring this approach. METHODS: We queried the National Cancer Database (NCDB) for patients with SCLC with BM at diagnosis and stratified by upfront SRS compared with upfront WBRT ±â€¯SRS. We utilized multivariate Cox regression and propensity score matching (PSM) to determine the impact on overall survival (OS) of each approach. RESULTS: 5952 eligible patients (WBRT: 5752; SRS: 200) were identified from 2010 to 2014 with a median follow-up of 40.0 months. Upfront SRS was associated with superior OS (median 10.8 vs 7.1 months, HR 0.65, 95% CI 0.55-0.75, p < 0.001), which persisted on multivariate analysis controlling for comorbidities, extracranial metastases, age, race/ethnicity, and gender (HR 0.70, 95% CI 0.60-0.81, p < 0.001). These results were confirmed in PSM analysis. A subset analysis comparing outcomes after SRS vs SRS + WBRT showed no differences in OS (p = .601). CONCLUSIONS: To our knowledge, this is the largest dataset of patients treated with SRS alone for SCLC. The observation of favorable OS with SRS alone in this contemporary dataset suggests that SRS alone may be appropriate for some patients with SCLC. Prospective investigations of SRS in SCLC are warranted.

Excellent Outcomes with Radiosurgery for Multiple Brain Metastases in ALK and EGFR Driven Non-Small Cell Lung Cancer.

INTRODUCTION: Patients with brain metastases (BMs) arising from EGFR-mutated and anaplastic lymphoma kinase gene (ALK)-rearranged NSCLC have a favorable prognosis compared with patients with non-oncogene-addicted NSCLC, emphasizing the importance of minimizing toxicities such as the cognitive sequelae of whole brain radiation therapy (WBRT). Although radiosurgery without WBRT is the preferred strategy for one to three BMs, this paradigm remains controversial for patients with multiple BMs. METHODS: We reviewed the cases of patients with EGFR-mutated and ALK-rearranged NSCLC presenting to our cancer center between 2008 and 2017 and included only patients receiving treatment to four or more BMs in a single radiosurgery session. RESULTS: We identified 35 patients with a median follow-up of 4.1 years. The maximum number of BMs treated in a single radiosurgery session ranged from four to 26 (median number of BM treated per radiosurgery course: 6), and in total over all courses the number ranged from four to 47 (median: 10). The median survival was 3.0 years (4.2 for ALK-rearranged NSCLC; 2.4 for EGFR-mutated NSCLC) from the diagnosis of BM, and survival was comparable regardless of number of radiosurgery courses, number of BMs treated in total, or number of BMs treated in a single radiosurgery session. The mean hippocampal and whole-brain doses were exceedingly low even for patients receiving treatment to more than 10 BMs (1.2 and 0.8 Gy, respectively). Radiosurgery was well tolerated overall and the 5-year rate of freedom from neurologic death was 84%. The 5-year rate of freedom from WBRT was 97%. CONCLUSIONS: Radiosurgery for multiple BMs is controversial, yet patients with EGFR-mutated and ALK-rearranged NSCLC may be uniquely suited to benefit from this approach. These results support single and multiple courses of radiosurgery without WBRT for patients with oncogene-addicted NSCLC with four or more BMs.

Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA.

Purpose: Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging. However, immunotherapy responses are uniquely challenging to interpret because tumors often shrink slowly or can appear transiently enlarged due to inflammation. We hypothesized that monitoring tumor cell death in real time by quantifying changes in circulating tumor DNA (ctDNA) levels could enable early assessment of immunotherapy efficacy.Experimental Design: We compared longitudinal changes in ctDNA levels with changes in radiographic tumor size and with survival outcomes in 28 patients with metastatic non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitor therapy. CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using a multigene next-generation sequencing assay. We defined a ctDNA response as a >50% decrease in mutant allele fraction from baseline, with a second confirmatory measurement.Results: Strong agreement was observed between ctDNA response and radiographic response (Cohen's kappa, 0.753). Median time to initial response among patients who achieved responses in both categories was 24.5 days by ctDNA versus 72.5 days by imaging. Time on treatment was significantly longer for ctDNA responders versus nonresponders (median, 205.5 vs. 69 days; P < 0.001). A ctDNA response was associated with superior progression-free survival [hazard ratio (HR), 0.29; 95% CI, 0.09-0.89; P = 0.03], and superior overall survival (HR, 0.17; 95% CI, 0.05-0.62; P = 0.007).Conclusions: A drop in ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with immune checkpoint inhibitors for NSCLC. Clin Cancer Res; 24(8); 1872-80. ©2018 AACR.

Radiation Pneumonitis.

Radiation-induced lung injury is a well-known complication of thoracic radiation for patients with breast, lung, thymic, and esophageal malignancies, and mediastinal lymphomas. Improvements in radiation technique, as well as the understanding of the pathophysiology of radiation injury, have led to lower rates of pneumonitis and improved symptom control. Here, the authors provide an overview of the pathophysiology, diagnosis, and management of patients with radiation pneumonitis as a complication of treatment of chest malignancies.

Brachytherapy Boost Utilization and Survival in Unfavorable-risk Prostate Cancer.

BACKGROUND: There are limited comparative survival data for prostate cancer (PCa) patients managed with a low-dose rate brachytherapy (LDR-B) boost and dose-escalated external-beam radiotherapy (DE-EBRT) alone. OBJECTIVE: To compare overall survival (OS) for men with unfavorable PCa between LDR-B and DE-EBRT groups. DESIGN, SETTING, AND PARTICIPANTS: Using the National Cancer Data Base, we identified men with unfavorable PCa treated between 2004 and 2012 with androgen suppression (AS) and either EBRT followed by LDR-B or DE-EBRT (75.6-86.4Gy). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Treatment selection was evaluated using logistic regression and annual percentage proportions. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards, and propensity score matching. RESULTS AND LIMITATION: We identified 25038 men between 2004 and 2012, during which LDR-B boost utilization decreased from 29% to 14%. LDR-B was associated with better OS on univariate (7-yr OS: 82% vs 73%; p<0.001) and multivariate analyses (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.64-0.77). Propensity score matching verified an OS benefit associated with LDR-B boost (HR 0.74, 95% CI 0.66-0.89). The OS benefit of LDR-B boost persisted when limited to men aged <60 yr with no comorbidities. On subset analysis, there was no interaction between treatment and age, risk group, or radiation dose. Limitations include the retrospective design, nonrandomized selection bias, and the absence of treatment toxicity, hormone duration, and cancer-specific outcomes. CONCLUSIONS: Between 2004 and 2012, LDR-B boost utilization declined and was associated with better OS compared to DE-EBRT alone. LDR-B boost is probably the ideal treatment option for men with unfavorable PCa, pending long-term results of randomized trials. PATIENT SUMMARY: We compared radiotherapy utilization and survival for prostate cancer (PCa) patients using a national database. We found that low-dose rate brachytherapy (LDR-B) boost, a method being used less frequently, was associated with better overall survival when compared to dose-escalated external-beam radiotherapy alone for men with unfavorable PCa. Randomized trials are needed to confirm that LDR-B boost is the ideal treatment.

Trends in stereotactic body radiation therapy for stage I small cell lung cancer.

OBJECTIVES: We aimed to report trends in stereotactic body radiation therapy (SBRT) utilization, dose prescriptions, and chemotherapy administration for stage I small cell lung cancer (SCLC) in the United States. MATERIALS AND METHODS: The National Cancer Data Base (NCDB) was used to identify patients with cT1-2 N0 SCLC treated with SBRT between 2004 and 2013. Trends in SBRT use and dose prescription were analyzed over time. Multivariable logistic regression was used to determine factors associated with the administration of chemotherapy with SBRT. The Kaplan-Meier method was used to estimate overall survival. RESULTS: Of 9265 patients with clinical stage I SCLC who were examined for initial treatment allocation, 285 were treated with SBRT and represented the subject of the primary analysis. SBRT utilization increased from 2004 (0.4% of all stage I patients diagnosed that year) to 2013 (6.4%). During this same time period, definitive surgical management also increased from 14.9% of all patients in 2004 to 28.5% in 2013. The median SBRT biologically effective dose (BED10) was 112.5Gy (range, 72-290) and only 33 out of 285 (11.6%) received a BED10<100Gy. Nearly half of all patients (130/285, 45.6%) received chemotherapy, with 42.7% of those patients receiving their chemotherapy prior to SBRT. On multivariable logistic regression, only age<75 (the median) vs. ≥75years (OR 4.97, 95% CI 2.96-8.35, p<0.001) and year of diagnosis 2004-2008 vs. 2009-2013 (OR 2.58, 95% CI 1.27-5.26, p=0.009) were predictive of chemotherapy use with SBRT. After median follow up of 45 months, the median survival was 23.5 months. CONCLUSIONS: Our findings suggest that SBRT utilization for stage I SCLC has increased between 2004 and 2013, highlighting the need for additional research to validate the feasibility of this management approach for inoperable patients.