Development of Radiographic Radiation Pneumonitis (RP) in Non-small Cell Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy (SBRT) May Be Protective Against Further Disease Progression.

OBJECTIVES: Radiation pneumonitis (RP) is a local inflammatory response, and we hypothesize that RP serves as an immune stimulator and is a protective factor against disease progression.  Methods: We analyzed patients with early-stage non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT) at two institutions. Radiographic RP (RRP) was evaluated and maximal axial dimensions were measured at three-, six-, and twelve-month timepoints with surveillance CT. RRP was measured using radiographic markers such as ground-glass opacities and airspace consolidation. Disease recurrence was evaluated and categorized as local, regional, and distant.  Results: Seventy-seven unique patient records were randomly selected from the database, 72 patients (93.5%) had RRP and five patients (6.5%) did not. The median follow-up was 24.3 months (IQR: 12.0 - 41.9). Disease failure occurred in 28.6% of patients with 6.5% local only, 2.6% regional only, 7.8% distant only, and 11.7% with multiple recurrences. Patients with RRP demonstrated a lower rate of disease failure with 25.0% of those with RRP experiencing disease failure and 80% of those without RRP experiencing disease failure (p=0.02). Patients with RRP had a 71% reduced risk of disease recurrence, compared to patients with no RRP, after adjusting for maximum tumor dimension (HR 0.29, p = 0.05). Among patients with RRP, there was no significant difference in recurrence based on extent of RRP (maximal area of RRP on CT). RRP did not correlate with overall survival.  Discussion: Most patients who received SBRT had RRP, and this study suggests that it may be protective of cancer recurrence. These results are hypothesis-generating and will need to be validated in larger and independent datasets.

Impact of Concurrent Coincident Use of Metformin During Lung Stereotactic Body Radiation Therapy.

Introduction Recent data suggest synergy of chemoradiotherapy and metformin in locally-advanced non-small cell lung cancer (NSCLC). It remains unclear if similar synergy exists with stereotactic lung body radiation therapy (SBRT) and metformin. We analyzed the role of metformin on progression-free survival (PFS) and toxicity in the setting of lung SBRT. Methods We identified 31 patients on metformin-treated with SBRT for early-stage NSCLC. Eighty-nine similarly treated patients were chosen as controls. Kaplan-Meier method was used to estimate cumulative PFS probabilities. Results Median follow-up was 30.7 months. Forty-two patients had diabetes, 31 (74%) of which were taking metformin concurrent with SBRT. Median PFS for metformin-users vs. metformin non-users was 36.4 months vs 48.9 months, respectively (p = 0.29). Among diabetic patients, median PFS for metformin users was 36.4 months and was unobserved for non-users (p= 0.40). On univariable analysis, male sex (p = 0.03) and tumor size (p = 0.01) were associated with the risk of progression or death; use of metformin was not significant (p = 0.34). There was no difference in grade ≥2 radiation pneumonitis between metformin users vs non-users (p = 0.51) Conclusion In this retrospective sample of lung SBRT patients, we did not detect a meaningful effect of concurrent metformin use on PFS. Since SBRT and conventional RT may have different cell kill mechanisms, the previously described beneficial effects of metformin may not apply in a hypofractionated setting. These results should be validated in an independent dataset, and we await the results of ongoing clinical trials.

Cervical cancer in Eastern Europe: review and proceedings from the Cervical Cancer Research Conference.

Cervical cancer is the third most common cancer among women worldwide, with a disproportionately high burden of disease in less-developed regions of the world. The Cervix Cancer Research Network was founded by the Gynecologic Cancer InterGroup with a mission to improve outcomes in cervical cancer by enhancing international access to clinical trials, specifically in under-represented, underdeveloped areas. The Cervix Cancer Research Network held its third international educational symposium in Bucharest in 2018 and is the subject of this report. The purpose of this symposium was to advance the international understanding of cervical cancer treatment patterns, to foster recruitment to Cervix Cancer Research Network clinical trials, and identify key Cervix Cancer Research Network clinical trial concepts to improve cervical cancer care worldwide.

Pretreatment Factors Influencing Radiation Pneumonitis after Stereotactic Body Radiation Therapy in the Treatment of Lung Cancer.

Objective Radiation pneumonitis (RP) is a dose-limiting toxicity that affects the treatment of lung cancer. Data on factors predictive of developing symptomatic RP after stereotactic body radiation therapy (SBRT) are limited. We reviewed data to identify pretreatment factors predictive of the development of symptomatic RP in patients' lung cancer treated with SBRT. Methods Data were collected on 296 patients treated with SBRT for lung cancer. Factors available at time of consultation were analyzed for the development of symptomatic RP, defined as CTCAE v. 4.0 ≥ Grade 2. The factors analyzed included patient demographic, tumor-specific, and pretreatment pulmonary function data. Univariate and multivariate analyses were performed to assess for predictive factors. Results Median follow-up was 22 months. The rate of symptomatic RP was 16%. Univariate analysis showed an increased rate of symptomatic RP with treatments to the right lung (22% vs. 9%, p = 0.007), driven primarily by an increased rate of symptomatic RP when treating the right lower lobe (RLL) vs. other lobes (31 vs. 13%, p = 0.03). Patients with a history of prior lung directed therapy were also more likely to develop symptomatic RP (12% vs. 24%, p = 0.008). These statistical differences were retained on multivariate analysis. Conclusion SBRT to the right lung, especially the RLL, and to patients with a history of prior lung-directed therapy increases the risk of developing symptomatic RP after SBRT. Further studies on ways to predict and prevent symptomatic RP are needed.

Predictors of Distant Failure After Stereotactic Body Radiation Therapy for Stages I to IIA Non-Small-Cell Lung Cancer.

PURPOSE: The use of stereotactic body radiation therapy (SBRT) has emerged as an effective treatment modality for patients with early-stage non-small-cell lung cancer (NSCLC), with excellent local control rates. Despite this, there is a predominant pattern of distant failure. We sought to identify factors that help predict which patients with stages I to IIA NSCLC treated with SBRT are at highest risk of distant failure, so that we may utilize these factors in the future to help determine which patients may benefit from the addition of systemic therapies. PATIENTS AND METHODS: We retrospectively reviewed 292 patients treated with SBRT for early stage NSCLC from 2006 to 2016 at 2 institutions. Patients were classified by T stage, tumor size, location and histology, pretreatment positron emission tomography/computed tomography (PET/CT) standardized uptake value (SUV), smoking status, and age. The primary endpoint of the study was distant failure. We aimed to analyze if patient characteristics could be identified that predicted for distant failure through the use of competing risk analysis. RESULTS: The median follow-up was 21.9 months. The median dose of radiation and fractionation delivered was 50 Gy (range, 45-65 Gy) in 5 fractions (range, 3-13 fractions). The median patient age was 72.8 years (interquartile range, 65.4-79.7 years). The 2-year distant failure was 22.0%, and overall survival at 2 years was found to be 61.0%. For every 1-year increase in patient age, the hazard of distant failure at any given time was 3% lower (hazard ratio, 0.97; 95% confidence interval, 0.94-0.99; P = .04). None of the remaining characteristics emerged as significant risk factors for distant failure on univariable or multivariable analysis. CONCLUSIONS: Overall, our cohort had distant failure and survival rates comparable with what has been described in the literature. Although we were unable to identify factors outside of age that correlated to risk of distant failure, this topic warrants further investigation, as distant failure is the primary pattern of failure with SBRT when used as the primary management for early-stage NSCLC. Additional molecular studies are needed to further inform on the role of systemic therapy in patients with early-stage NSCLC to improve clinical outcomes.

Local control dependence on consecutive vs. nonconsecutive fractionation in lung stereotactic body radiation therapy.

BACKGROUND: Recent reports demonstrate impaired tumor re-oxygenation 24-48h after stereotactic body radiation therapy (SBRT), suggesting that non-consecutive treatment delivery may be advantageous. To test this hypothesis clinically, we compared local control in patients treated in consecutive daily fractions vs. nonconsecutive fractions. METHODS: We retrospectively reviewed 107 lung SBRT patients (117 tumors) treated for T1-T2N0 NSCLC with LINAC based SBRT (50 or 60Gy/5fractions). Patients were characterized as having been treated in consecutive daily fractions vs. in non-consecutive fractions. Local control, survival and toxicity end points (CTCAE V4.0) were compared. Propensity score matching and Cox regression analyses were performed in order to determine the effect of fractionation on local control. RESULTS: With a median follow up of 23.7months, 3-year local control was superior at 93.3% vs. 63.6% in the non-consecutive and consecutive group, respectively (p=0.001). Multivariate analysis and propensity score matching showed that consecutive fractionation was an independent predictor of local failure. Overall survival trended toward improvement in the non-consecutive group, but this was not statistically significant (p=0.188). Development of any grade 2 toxicity was not significantly different between the two groups (p=0.75). CONCLUSION: Five-fraction SBRT delivered over non-consecutive days imparts superior LC and similar toxicity compared to consecutive fractionation. These results should be validated in independent datasets and in a prospective fashion.

Daily isoflurane exposure increases barbiturate insensitivity in medullary respiratory and cortical neurons via expression of ε-subunit containing GABA ARs.

The parameters governing GABAA receptor subtype expression patterns are not well understood, although significant shifts in subunit expression may support key physiological events. For example, the respiratory control network in pregnant rats becomes relatively insensitive to barbiturates due to increased expression of ε-subunit-containing GABAARs in the ventral respiratory column. We hypothesized that this plasticity may be a compensatory response to a chronic increase in inhibitory tone caused by increased central neurosteroid levels. Thus, we tested whether increased inhibitory tone was sufficient to induce ε-subunit upregulation on respiratory and cortical neurons in adult rats. Chronic intermittent increases in inhibitory tone in male and female rats was induced via daily 5-min exposures to 3% isoflurane. After 7d of treatment, phrenic burst frequency was less sensitive to barbiturate in isoflurane-treated male and female rats in vivo. Neurons in the ventral respiratory group and cortex were less sensitive to pentobarbital in vitro following 7d and 30d of intermittent isoflurane-exposure in both male and female rats. The pentobarbital insensitivity in 7d isoflurane-treated rats was reversible after another 7d. We hypothesize that increased inhibitory tone in the respiratory control network and cortex causes a compensatory increase in ε-subunit-containing GABAARs.

Leukemia Cutis of the Face, Scalp, and Neck Treated with Non-coplanar Split Field Volumetric Modulated Arc Therapy: A Case Report.

Malignancies with a superficial involvement of the scalp present a unique technical challenge for radiation treatment planning. As an example of this, leukemic infiltration of the superficial skin as the only presentation of the disease is a rare entity. For such cases, radiation oncologists have typically treated with 3D conformal radiotherapy with matched electron fields, a technique that can lead to significant dose inhomogeneity. In this report, we describe the case of a patient with leukemia cutis with a superficial involvement of the scalp, face, and shoulders that was treated with volumetric modulated arc radiotherapy, with an impressive clinical response.

Increased GABA(A) receptor ε-subunit expression on ventral respiratory column neurons protects breathing during pregnancy.

GABAergic signaling is essential for proper respiratory function. Potentiation of this signaling with allosteric modulators such as anesthetics, barbiturates, and neurosteroids can lead to respiratory arrest. Paradoxically, pregnant animals continue to breathe normally despite nearly 100-fold increases in circulating neurosteroids. ε subunit-containing GABA(A)Rs are insensitive to positive allosteric modulation, thus we hypothesized that pregnant rats increase ε subunit-containing GABA(A)R expression on brainstem neurons of the ventral respiratory column (VRC). In vivo, pregnancy rendered respiratory motor output insensitive to otherwise lethal doses of pentobarbital, a barbiturate previously used to categorize the ε subunit. Using electrode array recordings in vitro, we demonstrated that putative respiratory neurons of the preBötzinger Complex (preBötC) were also rendered insensitive to the effects of pentobarbital during pregnancy, but unit activity in the VRC was rapidly inhibited by the GABA(A)R agonist, muscimol. VRC unit activity from virgin and post-partum females was potently inhibited by both pentobarbital and muscimol. Brainstem ε subunit mRNA and protein levels were increased in pregnant rats, and GABA(A)R ε subunit expression co-localized with a marker of rhythm generating neurons (neurokinin 1 receptors) in the preBötC. These data support the hypothesis that pregnancy renders respiratory motor output and respiratory neuron activity insensitive to barbiturates, most likely via increased ε subunit-containing GABA(A)R expression on respiratory rhythm-generating neurons. Increased ε subunit expression may be critical to preserve respiratory function (and life) despite increased neurosteroid levels during pregnancy.

The effect of age and tongue exercise on BDNF and TrkB in the hypoglossal nucleus of rats.

Age-associated changes in tongue musculature may contribute to dysphagia. One possible treatment is tongue exercise. Exercise induces synaptic plasticity by increasing neurotrophic factors in spinal cord and limb musculature. However, effects of exercise on neurotrophic factors in the cranial sensorimotor system are unknown. Our purpose was to examine the effects of age and exercise on brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the rat hypoglossal nucleus. Young, middle-aged, and old rats were assigned to exercise or no-exercise control conditions. Exercise animals were trained to perform a tongue press task for 8 weeks. Samples from the hypoglossal nucleus were analyzed for BDNF and TrkB immunoreactivity. Baseline maximum tongue forces were similar in all age groups and increased significantly following exercise. BDNF immunoreactivity did not show a significant decrease with age in control group. However, in the exercise group, BDNF was significantly increased in young animals. TrkB immunoreactivity decreased significantly with age in control group, but did not change with exercise. BDNF and TrkB immunoreactivity levels were positively correlated with exercise in young and middle aged animals, but were negatively or weakly correlated with exercise in old animals and with a lack of exercise in no-exercise controls. Tongue exercise was associated with increased tongue forces in rats at all ages. While increases in BDNF and TrkB levels associated with exercise may play a role in mechanisms contributing to increased tongue forces in young and middle-aged rats, other mechanisms may be involved in increased tongue forces observed in old rats.