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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. [ABSTRACT FROM AUTHOR]

Background: Stereotactic body radiotherapy (SBRT) is the standard of care for patients with nonoperative, early-stage non-small cell lung cancer (NSCLC) measuring < 5 cm, but its use among patients with tumors measuring ≥5 cm is considerably less defined, with the existing literature limited to small, single-institution reports. The current multi-institutional study reported outcomes evaluating the largest such population reported to date.Methods: Clinical/treatment characteristics, outcomes, toxicities, and patterns of failure were assessed in patients with primary NSCLC measuring ≥5 cm without evidence of distant/lymph node metastasis who underwent SBRT using ≤5 fractions. Statistics included Kaplan-Meier survival analyses and univariate/multivariate Cox proportional hazards models.Results: A total of 92 patients treated from 2004 through 2016 were analyzed from 12 institutions. The median follow-up was 12 months (15 months in survivors). The median age and tumor size among the patients were 73 years (range, 50-95 years) and 5.4 cm (range, 5.0-7.5 cm), respectively. The median dose/fractionation was 50 Gray/5 fractions. The actuarial local control rates at 1 year and 2 years were 95.7% and 73.2%, respectively. The disease-free survival rate was 72.1% and 53.5%, respectively, at 1 year and 2 years. The 1-year and 2-year disease-specific survival rates were 95.5% and 78.6%, respectively. The median, 1-year, and 2-year overall survival rates were 21.4 months, 76.2%, and 46.4%, respectively. On multivariate analysis, lung cancer history and pre-SBRT positron emission tomography maximum standardized uptake value were found to be associated with overall survival. Posttreatment failures were most commonly distant (33% of all disease recurrences), followed by local (26%) and those occurring elsewhere in the lung (23%). Three patients had isolated local failures. Grade 3 to 4 toxicities included 1 case (1%) and 4 cases (4%) of grade 3 dermatitis and radiation pneumonitis, respectively (toxicities were graded according to the Common Terminology Criteria for Adverse Events [version 4.0]). Grades 2 to 5 radiation pneumonitis occurred in 11% of patients. One patient with a tumor measuring 7.5 cm and a smoking history of 150 pack-years died of radiation pneumonitis.Conclusions: The results of the current study, which is the largest study of patients with NSCLC measuring ≥5 cm reported to date, indicate that SBRT is a safe and efficacious option. Cancer 2017;123:688-696. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although surgery is the standard treatment for early-stage non-small cell lung cancer (NSCLC), stereotactic body radiotherapy (SBRT) has been disseminated as an alternative therapy. The comparative mortalities and toxicities of these treatments for patients of different life expectancies are unknown. METHODS: The Surveillance, Epidemiology, and End Results-Medicare linked database was used to identify patients who were 67 years old or older and underwent SBRT or surgery for stage I NSCLC from 2007 to 2009. Matched patients were stratified into short life expectancies (<5 years) and long life expectancies (5 years). Mortality and complication rates were compared with Poisson regression. RESULTS: Overall, 367 SBRT patients and 711 surgery patients were matched. Acute toxicity (0-1 month) was lower from SBRT versus surgery (7.9% vs 54.9%, P<.001). At 24 months after treatment, there was no difference (69.7% vs 73.9%, P5.31). The incidence rate ratio (IRR) for toxicity from SBRT versus surgery was 0.74 (95% confidence interval [CI], 0.64-0.87). Overall mortality was lower with SBRT versus surgery at 3 months (2.2% vs 6.1%, P5.005), but by 24 months, overall mortality was higher with SBRT (40.1% vs 22.3%, P<.001). For patients with short life expectancies, there was no difference in lung cancer mortality (IRR, 1.01; 95% CI, 0.40-2.56). However, for patients with long life expectancies, there was greater overall mortality (IRR, 1.49; 95% CI, 1.11-2.01) as well as a trend toward greater lung cancer mortality (IRR, 1.63; 95% CI, 0.95-2.79) with SBRT versus surgery. CONCLUSIONS: SBRT was associated with lower immediate mortality and toxicity in comparison with surgery. However, for patients with long life expectancies, there appears to be a relative benefit from surgery versus SBRT. [ABSTRACT FROM AUTHOR]

• IMRT use in PORT for NSCLC has increased significantly between 2006 and 2014. • IMRT does not reduce pulmonary, esophageal, or cardiac toxicity compared to 3D-CRT. • No difference between IMRT and 3D-CRT in unplanned hospitalizations or overall survival. • Patient comorbidities and receipt of trimodality therapy drive PORT toxicity. Post-operative radiation therapy (PORT) in locally advanced non-small cell lung cancer (LA-NSCLC) has historically been associated with toxicity. Conformal techniques like intensity modulated radiation therapy (IMRT) have the potential to reduce acute and long-term toxicity from radiation therapy. Among patients receiving PORT for LA-NSCLC, we identified factors associated with receipt of IMRT and evaluated the association between IMRT and toxicity. We queried the Surveillance, Epidemiology, and End Results (SEER)-Medicare database between January 1, 2006 to December 31, 2014 to identify patients diagnosed with Stage II or III NSCLC and who received upfront surgery and subsequent PORT. Baseline differences between patients receiving 3-dimentional conformal radiation therapy (3D-CRT) and IMRT were assessed using the chi-squared test for proportions and the t -test for means. Multivariable logistic regression was used to identify predictors of receipt of IMRT and pulmonary, esophageal, and cardiac toxicity. Propensity-score matching was employed to reduce the effect of known confounders. A total of 620 patients met the inclusion criteria, among whom 441 (71.2%) received 3D-CRT and 179 (28.8%) received IMRT. The mean age of the cohort was 73.9 years and 54.7% were male. The proportion of patients receiving IMRT increased from 6.2% in 2006 to 41.4% in 2014 (P < 0.001). IMRT was not associated with decreased pulmonary (OR 0.89; 95% CI, 0.62–1.29), esophageal (OR 1.09; 95% CI, 0.0.75–1.58), or cardiac toxicity (OR 1.02; 95% CI, 0.69–1.51). These findings held on propensity-score matching. Clinical risk factors including comorbidity and prior treatment history were associated with treatment toxicity. In a cohort of elderly patients, the use of IMRT in the setting of PORT for LA-NSCLC was not associated with a difference in toxicity compared to 3D-CRT. This finding suggests that outcomes from PORT may be independent of radiotherapy treatment technique. [ABSTRACT FROM AUTHOR]

• For NSCLC with biopsy suggestive of in situ disease, 49.3 % had invasion at resection. • Size and squamous histology were significantly associated with risk of invasion. • Even lesions with the most favorable characteristics, invasion was present in 38.2 %. • Nearly 30 % of biopsied lesions were observed, with 3 year OS in this cohort 51.5 %. • This supports definitive therapy for NSCLC with biopsy suggestive of in situ disease. Carcinoma in situ is a rare non-invasive histology of non-small cell lung cancer (NSCLC) with excellent survival outcomes with resection. However, management of lung biopsy suggestive of in situ disease remains unclear. To inform decision-making in this scenario, we determined the rate of invasive disease presence upon resection of lesions with an initial biopsy suggestive of purely in situ disease. The study included 960 patients diagnosed with NSCLC from 2003 to 2017 in the National Cancer Database whose workup included a lung biopsy suggestive of in situ disease. Among the cohort who proceeded to resection, we identified the rate of invasive disease discovered on surgical pathology along with significant demographic and clinical contributors to invasion risk. Survival outcomes were measured for the observed cohort that did not receive local therapy after biopsy. Invasive disease was identified at resection in 49.3 % of patients. Lesion size was associated with risk of invasive disease: 35.7 % for ≤1 cm, 45.2 % for 1−2 cm, 55.7 % for 2−3 cm, and 87.5 % for 3−5 cm (p < 0.001). Of patients with squamous histology, 61.5 % had invasive disease versus 46.5 % with adenocarcinoma histology (p = 0.026). On multivariable logistic regression, invasive disease remained associated with tumor size (OR 1.9 per cm, 95 % CI 1.5–2.4, p < 0.001), and squamous histology (OR 1.8, 95 % CI 1.1–3.2, p = 0.028). Overall survival at 3 years was 51.5 % in the observed cohort. Nearly half of patients with biopsy suggestive of in situ disease had invasive disease at resection. Tumor size and histology are strong predictors of invasive disease and may be used for risk stratification. However, the findings support the practice of definitive therapy whenever feasible. [ABSTRACT FROM AUTHOR]

Highlights • Systemic therapy is rarely used in early stage lung cancer treated with radiation. • Patients who receive adjuvant systemic therapy have fewer regional-distant failures. • In matched patients, systemic therapy associates with better disease-free survival. Abstract Purpose Although adjuvant systemic therapy (ST) is often recommended for the treatment of patients with high-risk, early-stage non-small cell lung carcinoma (NSCLC) after surgery, there is little evidence supporting the use of ST with stereotactic body radiotherapy (SBRT). Methods We conducted a retrospective cohort study using a multi-institutional database to identify consecutive patients with T1-3N0M0 NSCLC treated with definitive SBRT from 2006-2015. Treatment groups were defined as those who received SBRT + ST or SBRT alone. Regional-distant failure (RDF) was analyzed with Fine and Gray competing risks regression. Progression-free (PFS) and overall survival (OS) were analyzed with the Kaplan–Meier method and Cox regression. Additional comparisons were made after 2:1 nearest-neighbor propensity-score matching on clinical risk factors. Results We identified 54 patients who received SBRT + ST. The most common ST regimen was a platinum doublet (n = 38; 70.4%). Compared with patients receiving SBRT (n = 1269), SBRT + ST patients were younger (median age: 70 v 77 years, p < 0.001), had larger tumors (>3 cm: 38.9% v 21.6%, p = 0.02) and higher T-stage (T2-3: 42.6% v 22.5%, p = 0.002). Compared with SBRT patients, SBRT + ST patients had lower 2-year RDF (3.1% v 16.9%, p = 0.02). On multivariable analysis, SBRT + ST was associated with reduced RDF (HR: 0.15, 95%CI: 0.04–0.62), with a trend toward improved PFS (HR: 0.70, 95%CI: 0.48–1.03), but not OS (HR: 0.74, 95%CI: 0.49–1.11). After propensity-score matching, the SBRT + ST cohort demonstrated improved RDF (HR: 0.17, 95%CI: 0.04–0.76) and PFS (HR: 0.59, 95%CI: 0.38–0.93). Conclusion In this multi-institutional analysis, adjuvant ST was independently associated with reduced RDF in early-stage NSCLC patients treated with SBRT. [ABSTRACT FROM AUTHOR]

Purpose/Objective(s) Appropriate use of invasive mediastinal staging in patients with clinically node-negative NSCLC staged by PET-CT is critical in selecting patients for curative-intent therapy such as surgery or SBRT, but little data exists to guide this decision-making. We examined a large population of patients with clinical stage I NSCLC referred for mediastinoscopy or EBUS to find risk factors for occult N2 lymph nodes and determine which patients benefit from invasive staging. Materials/Methods We identified consecutive clinical T1-2N0 NSCLC patients being evaluated for curative-intent therapy between 2011 and 2015. None had evidence of nodal disease by PET-CT; the endpoint was pathologic confirmation of occult N2 disease by EBUS or mediastinoscopy. Tumor size, location, histology, SUV max , and radiographic appearance were evaluated as determinants of occult N2 disease. Two group comparisons of continuous variables were done with independent t-tests and categorical variables were compared with χ 2 or Fisher’s exact test. Results In 284 patients with PET-CT-staged clinical T1-2N0 disease, the prevalence of occult N2 metastases was 7.0%. The negative predictive value of PET-CT was 92.9% and the negative predictive value of mediastinoscopy/EBUS was 96.3%. T2 tumors were more likely to have occult N2 disease than T1 tumors (11.8% v 3.6% p = 0.009). Pure solid tumors had greater involvement of N2 nodes than tumors with any ground glass component (12.6% v 3.1%, p < 0.001). 17.5% of central tumor cases were found to have occult N2 metastases while 4.4% of patients with peripheral tumors (P < 0.001). 33.3% of patients with solid central T2 tumors had occult N2 metastases whereas 2.0% of patients with peripheral T2 tumors with a ground glass component, 1.2% of patients with peripheral T1 tumors with a ground glass component and 3.6% of patients with peripheral T1 solid tumors had N2 metastases. Conclusions Invasive mediastinal staging should be strongly encouraged in central tumors and solid T2 tumors because the risk of occult nodal involvement is greater than 10% in these cohorts. However, for patients with peripheral T1 tumors or peripheral T2 tumors with a significant ground glass component, the yield of invasive staging after a negative PET-CT is very low and invasive staging may not be warranted. [ABSTRACT FROM AUTHOR]

Purpose: To describe the impact of fractionation scheme and tumor location on toxicities in stereotactic body radiation therapy (SBRT) for ≥5-cm non-small cell lung cancer (NSCLC), as part of a multi-institutional analysis.Methods: Patients with primary ≥5-cm N0 M0 NSCLC who underwent ≤5-fraction SBRT were examined across multiple high-volume SBRT centers. Collected data included clinical/treatment parameters; toxicities were prospectively assessed at each institution according to the Common Terminology Criteria for Adverse Events. Patients treated daily were compared with those treated every other day (QOD)/other nondaily regimens. Stratification between central and peripheral tumors was also performed.Results: Ninety-two patients from 12 institutions were evaluated (2004-2016), with median follow-up of 12 months. In total there were 23 (25%) and 6 (7%) grade ≥2 and grade ≥3 toxicities, respectively. Grades 2 and 3 pulmonary toxicities occurred in 9% and 4%, respectively; 1 patient treated daily experienced grade 5 radiation pneumonitis. Of the entire cohort, 46 patients underwent daily SBRT, and 46 received QOD (n=40)/other nondaily (n=6) regimens. Clinical/treatment parameters were similar between groups; the QOD/other group was more likely to receive 3-/4-fraction schemas. Patients treated QOD/other experienced significantly fewer grade ≥2 toxicities as compared with daily treatment (7% vs 43%, P<.001). Patients treated daily also had higher rates of grade ≥2 pulmonary toxicities (P=.014). Patients with peripheral tumors (n=66) were more likely to receive 3-/4-fraction regimens than those with central tumors (n=26). No significant differences in grade ≥2 toxicities were identified according to tumor location (P>.05).Conclusions: From this multi-institutional study, toxicity of SBRT for ≥5-cm lesions is acceptable, and daily treatment was associated with a higher rate of toxicities. [ABSTRACT FROM AUTHOR]

Purpose: To determine the effect of biologically effective dose (BED10) and radiation treatment schedule on overall survival (OS) in patients with early-stage non-small cell lung cancer (NSCLC) undergoing stereotactic body radiation therapy (SBRT).Methods and Materials: Using data from 65 treatment centers in the United States, we retrospectively reviewed the records of T1-2 N0 NSCLC patients undergoing SBRT alone from 2006 to 2014. Biologically relevant covariates, including dose per fraction, number of fractions, and time between fractions, were used to quantify BED10 and radiation treatment schedule. The linear-quadratic equation was used to calculate BED10 and to generate a dichotomous dose variable of <105 Gy versus ≥105 Gy BED10. The primary outcome was OS. We used the Kaplan-Meier method, the log-rank test, and Cox proportional hazards regression with propensity score matching to determine whether prescription BED10 was associated with OS.Results: We identified 747 patients who met inclusion criteria. The median BED10 was 132 Gy, and 59 (7.7%) had consecutive-day fractions. Median follow-up was 41 months, and 452 patients (60.5%) had died by the conclusion of the study. The 581 patients receiving ≥105 Gy BED10 had a median survival of 28 months, whereas the 166 patients receiving <105 Gy BED10 had a median survival of 22 months (log-rank, P=.01). Radiation treatment schedule was not a significant predictor of OS on univariable analysis. After adjusting for T stage, sex, tumor histology, and Eastern Cooperative Oncology Group performance status, BED10 ≥105 Gy versus <105 Gy remained significantly associated with improved OS (hazard ratio 0.78, 95% confidence interval 0.62-0.98, P=.03). Propensity score matching on imbalanced variables within high- and low-dose cohorts confirmed a survival benefit with higher prescription dose.Conclusions: We found that dose escalation to 105 Gy BED10 and beyond may improve survival in NSCLC patients treated with SBRT. [ABSTRACT FROM AUTHOR]

Objectives It is unclear whether elderly patients face an increased risk of complications following stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC), as has been reported following surgical resection. This study evaluates toxicity and outcomes achieved with SBRT in elderly versus non-elderly patients. Materials and methods We retrospectively identified patients treated with SBRT for cT1-3N0M0 NSCLC between 2007 and 2013. We defined elderly and non-elderly cohorts by age ≥75 and <75. We used chi-square and logistic regression analyses to compare toxicity, and employed Kaplan-Meier, log-rank, and multivariable Cox proportional hazard analyses to assess overall survival (OS), local control (LC), and distant control (DC). Results We identified 251 patients (126 elderly, 125 non-elderly) with a median follow-up of 3.0 years. No differences in acute or late grade ≥3 toxicity were observed. Acute grade ≥3 toxicity was 11.1% in elderly vs. 8.0% in non-elderly ( p = 0.66). Late grade ≥3 toxicity was 10.3% in elderly vs. 7.2% in non-elderly ( p = 0.50). There was one grade 5 toxicity (hemoptysis). There were no 3-year OS or LC differences between elderly and non-elderly patients (OS 47.5% vs. 41.0%, p = 0.75; LC 84.2% vs. 86.4%, p = 0.89). However, 3-year DC was superior in elderly patients (89.1% vs. 76.0%, p = 0.01). Improved DC remained associated with elderly age in Cox regression (HR 0.42, p = 0.01). Conclusion Elderly patients undergoing SBRT for early stage NSCLC appear to have similar risk of toxicity and rate of efficacy as in younger patients. These findings support the use of SBRT in appropriately selected elderly patients. [ABSTRACT FROM AUTHOR]