Multi-institutional analysis of stereotactic body radiotherapy for sarcoma pulmonary metastases: High rates of local control with favorable toxicity.

BACKGROUND/OBJECTIVES: Oligometastatic sarcoma pulmonary metastases (PM's) are traditionally treated with resection and/or chemotherapy. We hypothesize that stereotactic body radiotherapy (SBRT) is an effective, safe alternative to surgery that can achieve excellent local control (LC) with a favorable toxicity profile. METHODS: Patients treated with SBRT for sarcoma PM's from 2011 to 2016 at Massachusetts General Hospital and the University of Pennsylvania were included. Median dose was 50 Gy. Patients underwent computed tomography (CT) or positron emission tomography/CT Q3 months post-SBRT. RESULTS: 44 patients with 56 separate PM's were treated with SBRT. Median age was 59 (range 19-82). 82% received prior chemotherapy, 66% had prior pulmonary resections (range, 1-5 resections), and 32% received prior thoracic radiotherapy. Median lesion size was 2.0 cm (range, 0.5-8.1 cm). Median follow-up was 16 months and 25 months for patients alive at last follow-up. Overall survival at 12 and 24 months was 74% (95% confidence interval [CI], 67%-81%) and 46% (95% CI, 38%-55%). LC at 12 and 24 months was 96% (95% CI, 93%-98%) and 90% (95% CI, 84%-96%). LC and overall survival did not differ based on age, gender, histology, fractionation, lesion location, or size (P > .05). Three developed Common Terminology Criteria for Adverse Events version 4 grade-2 chest-wall toxicities; one had grade-2 pneumonitis. CONCLUSIONS: In the first multi-institutional series on SBRT for sarcoma PM's, SBRT has excellent LC and is well-tolerated. SBRT should be considered as an alternative/complement to resection.

Preclinical Evaluation of Cetuximab and Benzoporphyrin Derivative-Mediated Intraperitoneal Photodynamic Therapy in a Canine Model.

Peritoneal carcinomatosis (PC) can occur as an advanced consequence of multiple primary malignancies. Surgical resection, radiation or systemic interventions alone have proven inadequate for this aggressive cancer presentation, since PC still has a poor survival profile. Photodynamic therapy (PDT), in which photosensitive drugs are exposed to light to generate cytotoxic reactive oxygen species, may be an ideal treatment for PC because of its ability to deliver treatment to a depth appropriate for peritoneal surface tumors. Additionally, epidermal growth factor receptor (EGFR) signaling plays a variety of roles in cancer progression and survival as well as PDT-mediated cytotoxicity, so EGFR inhibitors may be valuable in enhancing the therapeutic index of intraperitoneal PDT. This study examines escalating doses of benzoporphyrin derivative (BPD)-mediated intraperitoneal PDT combined with the EGFR-inhibitor cetuximab in a canine model. In the presence or absence of small bowel resection (SBR) and cetuximab, we observed a tolerable safety and toxicity profile related to the light dose received. Additionally, our findings that BPD levels are higher in the small bowel compared with other anatomical regions, and that the risk of anastomotic failure decreases at lower light doses will help to inform the design of similar PC treatments in humans.

Circulating Tumor Cells Are Associated with Recurrent Disease in Patients with Early-Stage Non-Small Cell Lung Cancer Treated with Stereotactic Body Radiotherapy.

PURPOSE: Although stereotactic body radiotherapy (SBRT) is effective in early-stage non-small cell lung cancer (NSCLC), approximately 10%-15% of patients will fail regionally and 20%-25% distantly. We evaluate a novel circulating tumor cell (CTC) assay as a prognostic marker for increased risk of recurrence following SBRT. EXPERIMENTAL DESIGN: Ninety-two subjects (median age, 71 years) with T1a (64%), T1b (23%), or T2a (13%) stage I NSCLC treated with SBRT were prospectively enrolled. CTCs were enumerated by utilizing a GFP-expressing adenoviral probe that detects elevated telomerase activity in cancer cells. Samples were obtained before, during, and serially up to 24 months after treatment. SBRT was delivered to a median dose of 50 Gy (range, 40-60 Gy), mostly commonly in four to five fractions (92%). RESULTS: Thirty-eight of 92 subjects (41%) had a positive CTC test prior to SBRT. A cutoff of ≥5 CTCs/mL before treatment defined favorable (n = 78) and unfavorable (n = 14) prognostic groups. Increased risk of nodal (P = 0.04) and distant (P = 0.03) failure was observed in the unfavorable group. Within 3 months following SBRT, CTCs continued to be detected in 10 of 35 (29%) subjects. Persistent detection of CTCs was associated with increased risk of distant failure (P = 0.04) and trended toward increased regional (P = 0.08) and local failure (P = 0.16). CONCLUSIONS: Higher pretreatment CTCs and persistence of CTCs posttreatment is significantly associated with increased risk of recurrence outside the targeted treatment site. This suggests that CTC analysis may potentially identify patients at higher risk for regional or distant recurrences and who may benefit from either systemic therapy and/or timely locoregional salvage treatment.

Biologically Effective Dose in Stereotactic Body Radiotherapy and Survival for Patients With Early-Stage NSCLC.

INTRODUCTION: Stereotactic body radiotherapy (SBRT) results in excellent local control of stage I NSCLC. Radiobiology models predict greater tumor response when higher biologically effective doses (BED10) are given. Prior studies support a BED10 greater than or equal to 100 Gy with SBRT; however, data are limited comparing outcomes after various SBRT regimens. We therefore sought to evaluate national trends and the effect of using "low" versus "high" BED10 SBRT courses on overall survival (OS). METHODS: This retrospective study used the National Cancer Data Base to identify patients diagnosed with clinical stage I (cT1-2aN0M0) NSCLC from 2004 to 2014 treated with SBRT. Patients were categorized into LowBED (100-129 Gy) or HighBED (≥130 Gy) groups. A 1:1 matched analysis based on patient and tumor characteristics was used to compare OS by BED10 group. Tumor centrality was not assessed. RESULTS: O 25,039 patients treated with LowBED (n = 14,756; 59%) or HighBED (n = 10,283; 41%) SBRT, 20,542 were matched. Shifts in HighBED to LowBED SBRT regimen use correlated with key publications in the literature. In the matched cohort, 5-year OS rates were 26% for LowBED and 34% for HighBED groups (p = 0.039). On multivariate analysis, receipt of LowBED was associated with significantly worse survival (hazard ratio = 1.046, 95% confidence interval: 1.004-1.090, p = 0.032). CONCLUSIONS: LowBED SBRT for treating stage I NSCLC is becoming more common. However, our findings suggest SBRT regimens with BED10 greater than or equal to 130 Gy may confer an additional survival benefit. Additional studies are required to evaluate the dose-response relationship and toxicities associated with modern HighBED SBRT.

Clinical Outcomes of the HIV Protease Inhibitor Nelfinavir With Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-Small Cell Lung Cancer: A Phase 1/2 Trial.

IMPORTANCE: Local failure after chemoradiotherapy (CT-RT) significantly contributes to mortality in patients with locally advanced non-small cell lung cancer (LA-NSCLC). One approach to improve local control is through targeted radiosensitization of the tumor. OBJECTIVE: To evaluate the dose-limiting toxic effects, maximally tolerated dose, and recommended phase 2 dose of the protease inhibitor nelfinavir mesylate, administered concurrently with CT-RT in patients with LA-NSCLC, and, in the phase 2 portion of the study, to estimate the objective response rate, local and distant failure rates, and overall survival. DESIGN, SETTING, AND PARTICIPANTS: This prospective, open-label, single-group, single-institution phase 1/2 trial tested the oral protease inhibitor nelfinavir in combination with concurrent CT-RT in 35 patients aged 18 to 89 years with biopsy-confirmed unresectable stage IIIA/IIIB LA-NSCLC and a minimum Karnofsky performance status from June 29, 2007, to February 22, 2012, with an analysis date of May 9, 2017. Median follow-up for all patients was 6.8 years, with a minimum 5 years of follow-up for all survivors. INTERVENTIONS: Oral nelfinavir mesylate, 625 mg, twice daily or 1250 mg, twice daily was administered for 7 to 14 days before and during concurrent CT-RT. MAIN OUTCOMES AND MEASURES: Graded toxic effects, overall survival, local failure, distant failure, objective response rate, and progression-free survival as measured by Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Thirty-five patients (16 women and 19 men; median age, 60 years [range, 39-79 years]) enrolled and met protocol-specified criteria for adherence, with 5 at a dose of 625 mg twice daily and 30 at a dose of 1250 mg twice daily. No dose-limiting toxic effects were observed. No grade 4 or higher nonhematologic toxic effects were observed. Thirty-three of the 35 patients had evaluable posttreatment computed tomographic scans, with an objective response rate of 94% (31 of 33; 95% CI, 86%-100%). The cumulative incidence of local failure was 39% (95% CI, 30.5%-47.5%). Median progression-free survival was 11.7 months (95% CI, 6.2-17.1 months). Median overall survival for all patients was 41.1 months (95% CI, 19.0-63.1 months); the 5-year mean (SE) overall survival rate was 37.1% (8.2%). CONCLUSIONS AND RELEVANCE: This study suggests that nelfinavir administered with concurrent CT-RT is associated with acceptable toxic effects and a promising objective response rate, local failure, progression-free survival, and overall survival in unresectable LA-NSCLC. These data suggest that nelfinavir may enhance the efficacy of standard CT-RT in this disease. Additional testing in the randomized phase 3 setting should be conducted to establish the improvement associated with nelfinavir with concurrent CT-RT. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00589056.

Single-Fraction Stereotactic vs Conventional Multifraction Radiotherapy for Pain Relief in Patients With Predominantly Nonspine Bone Metastases: A Randomized Phase 2 Trial.

Importance: Consensus is lacking as to the optimal radiotherapy dose and fractionation schedule for treating bone metastases. Objective: To assess the relative efficacy of high-dose, single-fraction stereotactic body radiotherapy (SBRT) vs standard multifraction radiotherapy (MFRT) for alleviation of pain in patients with mostly nonspine bone metastases. Design, Setting, and Participants: This prospective, randomized, single-institution phase 2 noninferiority trial conducted at a tertiary cancer care center enrolled 160 patients with radiologically confirmed painful bone metastases from September 19, 2014, through June 19, 2018. Patients were randomly assigned in a 1:1 ratio to receive either single-fraction SBRT (12 Gy for ≥4-cm lesions or 16 Gy for <4-cm lesions) or MFRT to 30 Gy in 10 fractions. Main Outcomes and Measures: The primary end point was pain response, defined by international consensus criteria as a combination of pain score and analgesic use (daily morphine-equivalent dose). Pain failure (ie, lack of response) was defined as worsening pain score (≥2 points on a 0-to-10 scale), an increase in morphine-equivalent opioid dose of 50% or more, reirradiation, or pathologic fracture. We hypothesized that SBRT was noninferior to MFRT. Results: In this phase 2 noninferiority trial of 96 men and 64 women (mean [SD] age, 62.4 [10.4] years), 81 patients received SBRT and 79 received MFRT. Among evaluable patients who received treatment per protocol, the single-fraction group had more pain responders than the MFRT group (complete response + partial response) at 2 weeks (34 of 55 [62%] vs 19 of 52 [36%]) (P = .01), 3 months (31 of 43 [72%] vs 17 of 35 [49%]) (P = .03), and 9 months (17 of 22 [77%] vs 12 of 26 [46%]) (P = .03). No differences were found in treatment-related toxic effects or quality-of-life scores after SBRT vs MFRT; local control rates at 1 and 2 years were higher in patients receiving single-fraction SBRT. Conclusions and Relevance: Delivering high-dose, single-fraction SBRT seems to be an effective treatment option for patients with painful bone metastases. Among evaluable patients, SBRT had higher rates of pain response (complete response + partial response) than did MFRT and thus should be considered for patients expected to have relatively long survival. Trial Registration: ClinicalTrials.gov identifier: NCT02163226.

Role of Radiation Therapy in Modulation of the Tumor Stroma and Microenvironment.

In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has been the cross-talk between tumor cells and the surrounding environment or stroma. This tumor stroma, comprised of various cells, and extracellular matrix (ECM), has been shown to aid in suppressing host immune responses against tumor cells. Through immunosuppressive cytokine secretion, metabolic alterations, and other mechanisms, the tumor stroma provides a complex network of safeguards for tumor proliferation. With recent advances in more effective, localized treatment, radiation therapy (XRT) has allowed for strategies that can effectively alter and ablate tumor stromal tissue. This includes promoting immunogenic cell death through tumor antigen release to increasing immune cell trafficking, XRT has a unique advantage against the tumoral immune evasion mechanisms that are orchestrated by stromal cells. Current studies are underway to elucidate pathways within the tumor stroma as potential targets for immunotherapy and chemoradiation. This review summarizes the effects of tumor stroma in tumor immune evasion, explains how XRT may help overcome these effects, with potential combinatorial approaches for future treatment modalities.

Spatial Dose Patterns Associated With Radiation Pneumonitis in a Randomized Trial Comparing Intensity-Modulated Photon Therapy With Passive Scattering Proton Therapy for Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE: Radiation pneumonitis (RP) is commonly associated with thoracic radiation therapy, and its incidence is related to dose and volume of the normal lung in the path of radiation. Our aim was to investigate dose patterns associated with RP in patients enrolled in a randomized trial of intensity modulated radiation therapy (IMRT) versus passive scattering proton therapy (PSPT) for locally advanced non-small cell lung cancer. METHODS: We analyzed 178 patients prospectively treated with PSPT or IMRT for non-small cell lung cancer to a prescribed dose of 66 or 74 Gy in conventional daily fractionation with concurrent chemotherapy. Forty patients (22%) developed clinically symptomatic RP. Voxel-based analysis of local dose differences was done with a nonparametric permutation test accounting for multiple comparisons. From the obtained 3-dimensional significance maps, we derived clusters of voxels that exhibited dose differences between groups at a statistical significance level of 0.05. RESULTS: The voxel-based analysis highlighted that (1) significant dose differences between patients with and without RP were found in the lower part of the lungs and in the heart and (2) the anatomic regions significantly spared by PSPT and the clusters in which doses were significantly correlated with RP development were disjoint. CONCLUSIONS: The analyzed trial data provide an unprecedented opportunity to substantiate previous hypotheses regarding the role of the heart and the lower lungs in the development of RP. Knowledge of this relationship between RP and thoracic regional radiosensitivity should be considered in clinical practice and in the design of future trials.

Phase I trial of concurrent stereotactic body radiotherapy and nelfinavir for locally advanced borderline or unresectable pancreatic adenocarcinoma.

INTRODUCTION: The HIV protease inhibitor nelfinavir (NFV) displays notable radiosensitizing effects. There have been no studies evaluating combined stereotactic body radiotherapy (SBRT) and NFV for borderline/unresectable pancreatic cancer. The primary objective of this phase I trial (NCT01068327) was to determine the maximum tolerated SBRT/NFV dose, and secondarily evaluate outcomes. METHODS: Following initial imaging, pathologic confirmation, and staging laparoscopy, subjects initially received three 3-week cycles of gemcitabine/leucovorin/fluorouracil; patients without radiologic progression received 5-fraction SBRT/NFV. Dose escalation was as follows: (1) 25 Gy/625 mg BID ×3wks; (2) 25 Gy/1250 mg BID ×3wks; (3) 30 Gy/1250 mg BID ×3wks; (4) 35 Gy/1250 mg BID ×3wks; (5) 35 Gy/1250 mg BID ×5wks; and (6) 40 Gy/1250 mg BID ×5wks. Pancreaticoduodenectomy was performed thereafter if resectable; if not, gemcitabine/leucovorin/fluorouracil was administered. RESULTS: Forty-six patients enrolled (10/2008-5/2013); 39 received protocol-directed therapy. Sixteen (41%) experienced any grade ≥2 event during and 1 month after SBRT. Four grade 3 and both grade 4 events occurred in a single patient at the initial dose level. 40 Gy/1250 mg BID ×5wks was the maximum tolerated dose. Five patients had late gastrointestinal bleeding (n = 2 superior mesenteric artery pseudo-aneurysm, n = 1 disease progression, n = 1 lower GI tract, n = 1 unknown location). The median overall survival was 14.4 months. Six (15%) patients recurred locally; median local failure-free survival was not reached. The median distant failure-free survival was 11 months, and median all failure-free survival was 10 months. CONCLUSIONS: Concurrent SBRT (40 Gy)/NFV (1250 mg BID) for locally advanced pancreatic cancer is feasible and safe, although careful attention to treatment planning parameters is recommended to reduce the incidence of late gastrointestinal bleeding.

Gender, Professional Experiences, and Personal Characteristics of Academic Radiation Oncology Chairs: Data to Inform the Pipeline for the 21st Century.

PURPOSE: Understanding the pathways and gateways to leadership and challenges faced by individuals in such roles can inform efforts to promote diversity and equity. We sought to describe the professional experiences and personal characteristics of academic radiation oncology (RO) chairs and to evaluate whether differences exist by gender. METHODS AND MATERIALS: Anonymous surveys were distributed to 95 chairs of RO departments during the 2016 annual meeting of the Society of Chairs of Academic Radiation Oncology Programs. The surveys included 28 closed-ended questions and the Leadership Practices Inventory. Results were analyzed by gender using χ2 tests, rank-sum, and t tests (significance P < .05). RESULTS: A total of 72 chairs responded (61 male, 10 female, 1 declined to identify gender) for a response rate of 76%. There were no significant gender differences in age, academic rank, publications, or prior leadership positions held at the time of the first chair appointment, but female respondents held significantly greater total direct funding from extramural grants than their male counterparts (median, $1.89 million [interquartile range, $0.5-$5 million] vs $0.25 million [interquartile range, $0-$1.0 million]; P = .006). Women were more likely to have spouses employed outside the home at time of their first chair appointment than men were, with a trend toward women experiencing greater difficulty relocating. Men and women identified budgeting and resource allocation as their greatest professional challenges. There were no gender differences in the Leadership Practices Inventory-identified leadership domains or professional goals. CONCLUSIONS: Female RO chairs are as equally qualified as men in terms of productivity or leadership skills, but they face distinct challenges in the context of a gender-structured society. The observation of higher grant funding among women at the time of chair appointment suggests a possible need for interventions such as unconscious bias training to ensure that selection processes do not unnecessarily hold women to a higher standard.

Five-year Long-term Outcomes of Stereotactic Body Radiation Therapy for Operable Versus Medically Inoperable Stage I Non-small-cell Lung Cancer: Analysis by Operability, Fractionation Regimen, Tumor Size, and Tumor Location.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is standard for medically inoperable stage I non-small-cell lung cancer (NSCLC) and is emerging as a surgical alternative in operable patients. However, limited long-term outcomes data exist, particularly according to operability. We hypothesized long-term local control (LC) and cancer-specific survival (CSS) would not differ by fractionation schedule, tumor size or location, or operability status, but overall survival (OS) would be higher for operable patients. PATIENTS AND METHODS: All consecutive patients with stage I (cT1-2aN0M0) NSCLC treated with SBRT from June 2009 to July 2013 were assessed. Thoracic surgeon evaluation determined operability. Local failure was defined as growth following initial tumor shrinkage or progression on consecutive scans. LC, CSS, and OS were calculated using Cox proportional hazards regression. RESULTS: A total of 186 patients (204 lesions) were analyzed. Most patients were inoperable (82%) with Eastern Cooperative Oncology Group performance status of 1 (59%) or 2 (26%). All lesions received biological effective doses ≥ 100 Gy most commonly (94%) in 3 to 5 fractions. The median follow-up was 4.0 years. LC at 2 and 5 years were 95.6% (95% confidence interval, 92%-99%) and 93.7% (95% confidence interval, 90%-98%), respectively. Compared with operable patients, inoperable patients did not have significant differences in 5-year LC (93.1% vs. 96.7%; P = .49), nodal failure (31.4% vs. 11.0%; P = .12), distant failure (12.2% vs. 10.4%; P = .98), or CSS (80.6% vs. 91.0%; P = .45) but trended towards worse OS (34.2% vs. 45.3%; P = .068). Tumor size, location, and fractionation did not significantly influence outcomes. CONCLUSIONS: SBRT has excellent, durable LC and CSS rates for early-stage NSCLC, although inoperable patients had somewhat lower OS than operable patients, likely owing to greater comorbidities.

Clinical Development of Novel Drug-Radiotherapy Combinations.

Radiotherapy is a fundamental component of treatment for the majority of patients with cancer. In recent decades, technological advances have enabled patients to receive more targeted doses of radiation to the tumor, with sparing of adjacent normal tissues. There had been hope that the era of precision medicine would enhance the combination of radiotherapy with targeted anticancer drugs; however, this ambition remains to be realized. In view of this lack of progress, the FDA-AACR-ASTRO Clinical Development of Drug-Radiotherapy Combinations Workshop was held in February 2018 to bring together stakeholders and opinion leaders from academia, clinical radiation oncology, industry, patient advocacy groups, and the FDA to discuss challenges to introducing new drug-radiotherapy combinations to the clinic. This Perspectives in Regulatory Science and Policy article summarizes the themes and action points that were discussed. Intelligent trial design is required to increase the number of studies that efficiently meet their primary outcomes; endpoints to be considered include local control, organ preservation, and patient-reported outcomes. Novel approaches including immune-oncology or DNA-repair inhibitor agents combined with radiotherapy should be prioritized. In this article, we focus on how the regulatory challenges associated with defining a new drug-radiotherapy combination can be overcome to improve clinical outcomes for patients with cancer.

Snapshot of a Specialty: Results of the ABR 2016 Radiation Oncology Clinical Practice Analysis.

PURPOSE: Beginning in 2010, the ABR has administered triennial clinical practice analysis surveys to inform examination development volunteers and staff about the actual state of radiation oncology practice. METHODS AND MATERIALS: As reported here, the 2016 survey was designed to provide objective data regarding actual patient volumes of specific disease sites and subjective insight as to the importance and relevance of site-specific therapy to individual practices. RESULTS: The survey instrument was circulated to 4,075 radiation oncologists listed in the membership database of the American Society for Radiation Oncology, and responses were received from 690 (16.9%); a total of 287 (41.5%) self-identified as being in academic practice. Even in the academic setting, a majority (216 of 287, or 75.3%) indicated that they spend most of their time in clinical practice. CONCLUSIONS: Data from the survey are informative regarding changes in the practice of radiation oncology over the past 6 years.

A phase I trial of pembrolizumab with hypofractionated radiotherapy in patients with metastatic solid tumours.

BACKGROUND: We conducted a phase I trial evaluating pembrolizumab+hypofractionated radiotherapy (HFRT) for patients with metastatic cancers. METHODS: There were two strata (12 patients each): (i) NSCLC/melanoma progressing on prior anti-PD-1 therapy, (ii) other cancer types; anti-PD-1-naive. Patients received 6 cycles of pembrolizumab, starting 1 week before HFRT. Patients had ≥2 lesions; only one was irradiated (8 Gy × 3 for first half; 17 Gy × 1 for second half in each stratum) and the other(s) followed for response. RESULTS: Of the 24 patients, 20 (83%) had treatment-related adverse events (AEs) (all grade 1 or 2). There were eight grade 3 AEs, none treatment related. There were no dose-limiting toxicities or grade 4/5 AEs. Stratum 1: two patients (of 12) with progression on prior PD-1 blockade experienced prolonged responses (9.2 and 28.1 months). Stratum 2: one patient experienced a complete response and two had prolonged stable disease (7.4 and 7.0 months). Immune profiling demonstrated that anti-PD-1 therapy and radiation induced a consistent increase in the proliferation marker Ki67 in PD-1-expressing CD8 T cells. CONCLUSIONS: HFRT was well tolerated with pembrolizumab, and in some patients with metastatic NSCLC or melanoma, it reinvigorated a systemic response despite previous progression on anti-PD-1 therapy. CLINICAL TRIAL REGISTRATION: NCT02303990 ( www.clinicaltrials.gov ).

Circulating Tumor Cell Assessment in Presumed Early Stage Non-Small Cell Lung Cancer Patients Treated with Stereotactic Body Radiation Therapy: A Prospective Pilot Study.

PURPOSE: In patients treated with stereotactic body radiation therapy (SBRT) for presumed early stage non-small cell lung cancer (NSCLC), detection and monitoring of circulating tumor cells (CTCs) may be useful for assessing treatment response safely and noninvasively. No published reports of CTC trends in this patient population exist to date. METHODS AND MATERIALS: Patients with clinically diagnosed stage I NSCLC treated with SBRT were eligible for this institutional review board-approved prospective clinical trial. Peripheral blood samples were assayed for CTCs via a green fluorescent protein-expressing adenoviral probe. CTC positivity was defined as 1.3 green fluorescent protein-positive cells/mL of collected blood. Samples were obtained before (pre-radiation therapy [RT]), during, and after SBRT (post-RT; months 1, 3, 6, 12, 18, and 24). SBRT was delivered in ≤5 fractions (median dose of 50 Gy in 12.5 Gy fractions) to a biological equivalent dose of ≥100 Gy in all cases. RESULTS: Forty-eight consecutive patients (T1a [73%], T1b [21%], and T2a [6%]) were enrolled. Median follow-up was 14.2 months. Twenty patients (42%) had a positive CTC level pre-RT, with a median CTC count of 4.2 CTCs per mL (interquartile range [IQR], 2.2-18.7). Of these 20 patients, 17 had evaluable post-RT CTC evaluations showing reduced CTC counts at 1 month (median, 0.2; IQR, 0.1-0.8) and 3 months (median, 0.6; IQR, 0-1.1). Three of these 17 patients experienced disease progression at a median of 19.9 months; all 3 experienced ≥1 positive post-RT CTC test predating clinical progression by a median of 16 months (range, 2-17 months). In contrast, among patients presenting with CTC-detectable disease and for whom all post-RT CTC tests were negative, none experienced recurrence or progression. CONCLUSIONS: CTC monitoring after SBRT for presumed early stage NSCLC may give lead-time notice of disease recurrence or progression. Conversely, negative CTC counts after treatment may provide reassurance of disease control. CTC analysis is thus potentially useful in enhancing clinical diagnosis and follow-up in this population.