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: PurposeTo study the potential risk factors, including radiotherapy (RT) for contralateral breast cancer (CBC), in patients treated for early-stage breast cancer.: Methods and materialsThe Surveillance, Epidemiology, and End Results database (1973–1996) was used to study the incidence of CBC after breast cancer. The Cox proportional hazards regression model was used to estimate the relative risk (RR) of CBC, with adjustment for confounders, including age, race, histologic subtype, and use of RT. Information on the use of hormonal therapy and chemotherapy was not available in the Surveillance, Epidemiology, and End Results database.: ResultsA CBC was documented in 5679 (4.2%) of the 134,501 localized invasive or intraductal breast cancer patients surviving at least 3 months. The 10- and 20-year actuarial rate of CBC was 6.1% and 12%, respectively. In multivariate analysis, medullary carcinoma (RR = 1.18, 95% confidence interval [CI] 1.02–1.37), black race (RR = 1.20, 95% CI 1.08–1.33), and age >55 years at initial diagnosis (RR = 1.15, 95% CI 1.08–1.22) were associated with increased CBC risk. A total of 1234 (3.3%) of 37,379 patients who received RT developed CBC, and 4445 (4.6%) of 97,122 patients who did not receive RT developed CBC. Overall, RT was not associated with an increased risk of CBC (RR = 1.04, 95% CI 0.97–1.10) in multivariate analysis. The CBC risk associated with RT varied substantially with the length of follow-up. During the first 5 years of follow-up, RT was not associated with an increased CBC risk (age-adjusted RR = 0.96, 95% CI 0.88–1.04). For patients surviving for >5 years, RT was associated with a 14% increase in CBC risk (RR = 1.14, 95% CI 1.03–1.26). The increased CBC risk with RT was evident in patients aged <45 years (RR = 1.32, p = 0.01) and >55 years (RR = 1.15, p = 0.04) at initial diagnosis. The 5-, 10-, 15-, and 20-year actuarial rate of CBC was 2.9%, 6.5%, 10.2%, and 13.4%, respectively, for patients with RT; the corresponding rates were 3.0%, 6.0%, 8.9%, and 11.8% for patients without RT. The absolute increase in CBC risk associated with RT was 0.5%, 1.3%, and 1.6% in the 10-, 15-, and 20-year actuarial rate, respectively.: ConclusionCBC is not uncommon after breast cancer, especially for certain subsets of patients. RT was associated with a very small increased long-term CBC risk. This minimal increase in CBC risk should not affect clinical decision-making in treatment selection for patients with localized invasive breast cancer or ductal carcinoma in situ. Unnecessary radiation exposure to the contralateral breast should be avoided for all patients with early-stage breast cancer. [Copyright &y& Elsevier]

Purpose: Several retrospective series have reported that patients with collagen vascular disease (CVD) are at increased risk of radiation (RT) toxicity. However, the evidence is mixed, and many series lack control groups. We performed a meta-analysis including only case-cohort or randomized studies that examined the risk of RT toxicity for patients with CVD compared with controls.Methods and Materials: Meta-analysis of Observational Studies in Epidemiology guidelines were used to perform a comprehensive search identifying case-control or randomized studies reporting RT toxicity outcomes for patients with CVD versus controls. Data were synthesized from studies reporting grade 2 to 3 or more (G2/3 +) acute and late RT toxicities. Results were analyzed with fixed effects meta-analysis on the random-effects model for between-study heterogeneity; otherwise, the fixed-effects model was used. Hazard ratio or odds ratio (OR) were the effect-size estimators, as appropriate.Results: Ten studies were included, with 4028 patients (CVD: 406, control: 3622). Patients with CVD had higher rates of acute G2/3 + toxicity (26.2% vs 16.5%, OR [odds ratio] 2.01; P < .001) and late G2/3 + toxicity (18.4% vs 10.1%, OR 2.37; P < .001). Higher rates of late G2/3 + toxicity were observed for CVD patients with systemic lupus erythematous (21% vs 9.7%; OR 2.55, P = .03), systemic scleroderma (31.8% vs 9.7%, OR 3.85; P = .03), rheumatoid arthritis (11.7% vs 8.4%, OR = 2.56; P = .008), and those irradiated to the pelvis/abdomen (32.2% vs 11.9%, OR 3.29; P = .001), breast (14.7% vs 4.4%, OR 3.51; P = .003), thorax (12.5% vs 8.7%, OR 3.46; P < .001), and skin (14.6% vs 5.2%, OR 2.59; P = .02). Late grade 5 toxicities were significantly higher for patients with CVD, although absolute rates were low (3.9% vs 0.6%, OR = 7.81; P = .01).Conclusions: Moderate and severe toxicities are more likely in patients with CVD, with variable risk depending on toxicity grade, CVD subtype, treatment site, and dose. Severe toxicities are uncommon. These factors should be considered when informing patients of treatment-related risks and monitoring for morbid treatment sequelae. [ABSTRACT FROM AUTHOR]

Background: Brachial plexopathy is a potentially serious complication from stereotactic body radiation therapy (SBRT) that has not been widely studied. Therefore, we compared datasets from two different institutions and generated a brachial plexus dose-response model, to quantify what dose constraints would be needed to minimize the effect on normal tissue while still enabling potent therapy for the tumor.Methods: Two published SBRT datasets were pooled and modeled from patients at Indiana University and the Richard L. Roudebush Veterans Administration Medical Center from 1998 to 2007, as well as the Karolinska Institute from 2008 to 2013. All patients in both studies were treated with SBRT for apically located lung tumors localized superior to the aortic arch. Toxicities were graded according to Common Terminology Criteria for Adverse Events, and a probit dose response model was created with maximum likelihood parameter fitting.Results: This analysis includes a total of 89 brachial plexus maximum point dose (Dmax) values from both institutions. Among the 14 patients who developed brachial plexopathy, the most common complications were grade 2, comprising 7 patients. The median follow-up was 30 months (range 6.1-72.2) in the Karolinska dataset, and the Indiana dataset had a median of 13 months (range 1-71). Both studies had a median range of 3 fractions, but in the Indiana dataset, 9 patients were treated in 4 fractions, and the paper did not differentiate between the two, so our analysis is considered to be in 3-4 fractions, one of the main limitations. The probit model showed that the risk of brachial plexopathy with Dmax of 26 Gy in 3-4 fractions is 10%, and 50% with Dmax of 70 Gy in 3-4 fractions.Conclusions: This analysis is only a preliminary result because more details are needed as well as additional comprehensive datasets from a much broader cross-section of clinical practices. When more institutions join the QUANTEC and HyTEC methodology of reporting sufficient details to enable data pooling, our field will finally reach an improved understanding of human dose tolerance. [ABSTRACT FROM AUTHOR]

Purpose: Dose-volume data for injury to carotid artery and other major vessels in stereotactic body radiation therapy (SBRT)/SABR head and neck reirradiation were reviewed, modeled, and summarized.Methods and Materials: A PubMed search of the English-language literature (stereotactic and carotid and radiation) in April 2018 found 238 major vessel maximum point doses in 6 articles that were pooled for logistic modeling. Two subsequent studies with dose-volume major vessel data were modeled separately for comparison. Attempts were made to separate carotid blowout syndrome from other bleeding events (BE) in the analysis, but we acknowledge that all except 1 data set has some element of BE interspersed.Results: Prior radiation therapy (RT) dose was not uniformly reported per patient in the studies included, but a course on the order of conventionally fractionated 70 Gy was considered for the purposes of the analysis (with an approximately ≥6-month estimated interval between prior and subsequent treatment in most cases). Factors likely associated with reduced risk of BE include nonconsecutive daily treatment, lower extent of circumferential tumor involvement around the vessel, and no surgical manipulation before or after SBRT.Conclusions: Initial data pooling for reirradiation involving the carotid artery resulted in 3 preliminary models compared in this Hypofractionated Treatment Effects in the Clinic (HyTEC) report. More recent experiences with alternating fractionation schedules and additional risk-reduction strategies are also presented. Complications data for the most critical structures such as spinal cord and carotid artery are so limited that they cannot be viewed as strong conclusions of probability of risk, but rather, as a general guideline for consideration. There is a great need for better reporting standards as noted in the High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic introductory paper. [ABSTRACT FROM AUTHOR]

Purpose: To review the radiobiological mechanisms of stereotactic body radiation therapy stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS).Methods and Materials: We reviewed previous reports and recent observations on the effects of high-dose irradiation on tumor cell survival, tumor vasculature, and antitumor immunity. We then assessed the potential implications of these biological changes associated with SBRT and SRS.Results: Irradiation with doses higher than approximately 10 Gy/fraction causes significant vascular injury in tumors, leading to secondary tumor cell death. Irradiation of tumors with high doses has also been reported to increase the antitumor immunity, and various approaches are being investigated to further elevate antitumor immunity. The mechanism of normal tissue damage by high-dose irradiation needs to be further investigated.Conclusions: In addition to directly killing tumor cells, high-dose irradiation used in SBRT and SRS induces indirect tumor cell death via vascular damage and antitumor immunity. Further studies are warranted to better understand the biological mechanisms underlying the high efficacy of clinical SBRT and SRS and to further improve the efficacy of SBRT and SRS. [ABSTRACT FROM AUTHOR]

Background: Rosa damascena (R.D) is an aromatic plant with numerous therapeutic effects including cardiovascular effect. The mechanism cardiovascular effect of R.D is unclear and suggested mediated through renin–angiotensin system (RAS). Therefore, in this study, the role of hydroalcoholic extract of R.D on acute hypertension induced by AngII was evaluated. Methods: After anesthesia, femoral artery and vein of rats were cannulated for recording cardiovascular responses and drug injection, respectively. Systolic blood pressure (SBP), mean arterial blood pressure (MAP), and heart rate (HR) were recorded continuously by power lab software. Rats were divided into saline, AngII (50 ng/kg), AngII + Losartan (10 mg/kg), and three groups of R.D extract (250, 500, and 1000 mg/kg). Losartan and AngII were administered intravenously and the other ones intraperitoneal. In the R.D groups, 30 min after injection of the extract, AngII was injected and the maximum changes in SBP, MAP, and HR were calculated and compared to that in control and AngII groups. Results: Results show that AngII significantly increased SBP, MAP, and decreased HR than the control group which was blocked by losartan. SBP and MAP in R.D + AngII groups were significantly lower than AngII alone (P < 0.05 –P < 0.001). Only MAP in higher dose (1000 mg/kg) was significantly lower than low dose (250 mg/kg; P < 0.05). Two higher doses also significantly decreased bradycardia induced by AngII (P < 0. 01). Conclusions: The preventive effect of hydroalcoholic extract of R.D on cardiovascular parameters maybe is mediated by suppression of AngII activity. [ABSTRACT FROM AUTHOR]

Cutaneous T-cell lymphoma (CTCL) is a chronic, debilitating disease that has a severe impact on quality of life. We present a patient with multiple CTCL lesions on the bilateral feet, which impaired his ability to ambulate. His lesions on both feet were successfully treated with a total of 8 Gy in two fractions via high-dose-rate surface brachytherapy using the Freiburg Flap applicator. The deeper aspects of the bulkier lesions on the left foot were boosted with electron beam therapy. The radiation therapy was well tolerated, and the patient was able to regain his mobility after completing radiation therapy. To our knowledge, there are few reports utilizing brachytherapy in treating CTCL. Our case describes treatment of larger, more extensive CTCL lesions than previously reported. [ABSTRACT FROM AUTHOR]

Purpose: As an angiotensin converting enzyme (ACE) inhibitor, the effects of captopril on inflammation has been previously examined. Captopril has been shown to have anti-inflammatory and antioxidant effects. Imbalance in the oxidant/antioxidant system is one of the major causes of inflammation. In the present study, the effects of captopril on total and differential white blood cells (WBC), oxidative stress andlung histopathological changes produced by lipopolysaccharide (LPS) were investigated in rat. Materials and Method: The rats were divided into: control (saline-treated), LPS (1 mg/kg), 12.5, 25 or 50 mg/kg captopril-treated before LPS administration (LPS+Cap12.5, LPS+Cap25 and LPS+Cap50) and Cap-treated, 50 mg/kg before saline administration (as positive control group)groups. The levels of total and percentage of differential WBC in blood, and the oxidative stress index in the serum were evaluated. Lung histopathological changes were also examined. Results: In the LPS group, total WBC count, percentage of neutrophils, basophils, eosinophils, and monocytes in the blood, oxidative stress indices in serum, lung pathological changes were significantly higher than the control group (p < 0.05 to p < 0.001). Pathological changes of lung, serum oxidative stress indices of LPS+Cap50 group, total WBC counts of LPS+Cap25 and LPS+Cap50 groups, as well as percentage of neutrophils, monocytes, and basophils in LPS+Cap50 group and percentage of eosinophils in LPS+Cap50 and LPS+Cap25 groups, were significantly decreased compared to the LPS group (p < 0.05 to p < 0.001). Conclusion: The results of this study showed that captopril dose-dependently reduced total and differential WBC counts, while it improved serum oxidant/antioxidant biomarkers and histopathological changes in LPS-treated rats. These results indicate a therapeutic potential for captopril on systemic inflammation and oxidative stress against LPS-induced lung injuries. [ABSTRACT FROM AUTHOR]

Purpose To develop a novel method to monitor external anatomical changes in head and neck cancer patients in order to triage possible adaptive radiotherapy needs. Methods The presented approach aims to provide information on internal anatomical changes based on variations observed in external anatomy. Setup Cone Beam Computed Tomography (CBCT) images are processed to produce an accurate external contour of the patient's skin. After registering the CBCTs to the reference planning CT, the external contours from each CBCT are transferred to the initial - first week - CBCT. Contour radii, defined as the distances between an external contour and the isocenter projection in each CBCT slice, are calculated for each scan over the full 360 degrees. The changes in external anatomy are then quantified by the difference in radial distance between the external contours of any secondary CBCT relative to the initial CBCT. Finally, the radial difference is displayed in cylindrical coordinates as a 2D intensity map to highlight regions of interests with significant changes. Weekly CBCT scans from 15 head and neck patients were retrospectively analyzed to demonstrate the utility of this approach as a proof of principle. External changes suggested by the 2D radial difference map of an example patient after 23 fractions were then correlated with the changes in the gross tumor volumes and organs at risks. The resulting dosimetric effects were evaluated. An interactive standalone software application has been developed to facilitate the generation and the interpretation of the 2D intensity map. Results The 2D radial difference maps provided qualitative and quantitative information, such as the location and the magnitude of external contour changes and the rate at which these deviations occur. Out of the 15 patients, 10 presented clear evidence of general external volume shrinkage due to weight loss, and nine patients had at least one site of local shrinkage. Only two patients showed no signs of anatomical change during their entire treatment course. For the example patient, the mean (±σ) radial difference was 6.7 (±3.0) mm for the left parotid and 7.3 (±2.5) mm for the right parotid. The mean dose to the left and right parotids increased from 20.1 Gy to 30 Gy and from 16.3 Gy to 29.6 Gy, respectively. Conclusion This novel method provides an efficient tool to visualize 3D external anatomical changes on a single 2D map. It quickly pinpoints the location of differences in anatomy during the course of radiotherapy, which can help physicians determine if a treatment plan needs to be adapted. The interactive graphic user interface developed in this study will be evaluated in an adaptive radiotherapy workflow for head and neck patients in a future prospective trial. [ABSTRACT FROM AUTHOR]

Background Approximately 3 to 13% of salivary carcinomas recur at the skull base. We report our experience treating these recurrences with stereotactic radiation. Methods In total, 14 patients with skull base recurrence of salivary gland carcinoma were identified. Patient characteristics, treatment parameters, response to treatment, local recurrence-free/overall survival, and patterns of failure were studied. Results All 12 symptomatic patients experienced palliation of symptoms. Two grade 3 toxicities were observed. Local recurrence-free survival after skull base treatment was 28 months (74 months after allowing for additional course of salvage radiotherapy). Overall survival was 153 months from primary diagnosis and 67 months from first skull base failure. Of 13 treatment failures, 8 occurred at margins; the rest were infield. All intracranial failures occurred along meningeal surfaces. Conclusions Stereotactic radiation provides well-tolerated palliation for the majority of patients, but with a high rate of local failure. Due to the propensity for meningeal failures, we suggest increasing margins along the meningeal surfaces when treating these patients. [ABSTRACT FROM AUTHOR]

Purpose and Objectives: To quantify, through an observer study, the reduction in metal artifacts on cone beam computed tomographic (CBCT) images using a projection-interpolation algorithm, on images containing metal artifacts from dental fillings and implants in patients treated for head and neck (H&N) cancer.Methods and Materials: An interpolation-substitution algorithm was applied to H&N CBCT images containing metal artifacts from dental fillings and implants. Image quality with respect to metal artifacts was evaluated subjectively and objectively. First, 6 independent radiation oncologists were asked to rank randomly sorted blinded images (before and after metal artifact reduction) using a 5-point rating scale (1 = severe artifacts; 5 = no artifacts). Second, the standard deviation of different regions of interest (ROI) within each image was calculated and compared with the mean rating scores.Results: The interpolation-substitution technique successfully reduced metal artifacts in 70% of the cases. From a total of 60 images from 15 H&N cancer patients undergoing image guided radiation therapy, the mean rating score on the uncorrected images was 2.3 ± 1.1, versus 3.3 ± 1.0 for the corrected images. The mean difference in ranking score between uncorrected and corrected images was 1.0 (95% confidence interval: 0.9-1.2, P<.05). The standard deviation of each ROI significantly decreased after artifact reduction (P<.01). Moreover, a negative correlation between the mean rating score for each image and the standard deviation of the oral cavity and bilateral cheeks was observed.Conclusion: The interpolation-substitution algorithm is efficient and effective for reducing metal artifacts caused by dental fillings and implants on CBCT images, as demonstrated by the statistically significant increase in observer image quality ranking and by the decrease in ROI standard deviation between uncorrected and corrected images. [ABSTRACT FROM AUTHOR]

Background Recent reports demonstrate impaired tumor re-oxygenation 24–48 h 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 60 Gy/5 fractions). 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 23.7 months, 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. [ABSTRACT FROM AUTHOR]

Purpose To compare hyperfractionation versus standard fractionation for T2N0 vocal cord carcinoma in a randomized controlled trial. Methods and Materials Patients with T2 vocal cord cancer were stratified by substage (T2a vs T2b) and randomly assigned to receive either hyperfractionation (HFX) to 79.2 Gy in 66 fractions of 1.2 Gy given twice a day, or standard fractionation (SFX) to 70 Gy in 35 fractions given once a day. The trial was designed to detect a 55% reduction in the local failure hazard rate with 80% statistical power. Results Between April 1996 and July 2003, a total of 250 patients were enrolled. Of 239 patients analyzable for outcomes, 94% were male, 83% had a Karnofsky performance status of 90-100, and 62% had T2a tumor. Median follow-up for all surviving patients was 7.9 years (range, 0.6-13.1 years). The 5-year local control (LC) rate was 8 points higher but not statistically significant (P=.14 for HFX [78%] vs SFX [70%]), corresponding to a 30% hazard rate reduction. The 5-year disease-free survival (DFS) was 49% versus 40% (P=.13) and overall survival (OS) was 72% versus 63% (P=.29). HFX was associated with higher rates of acute skin, mucosal, and laryngeal toxicity. Grade 3-4 late effects were similar with a 5-year cumulative incidence of 8.5% (3.4%-13.6%) after SFX and 8.5% (3.4%-13.5%) after HFX. Conclusions The 5-year local control was modestly higher with HFX compared to SFX for T2 glottic carcinoma, but the difference was not statistically significant. These results are consistent with prior studies of hyperfractionation showing a benefit in local control. Substaging by T2a versus T2b carries prognostic value for DFS and OS. For cost and convenience reasons other altered fractionation schedules have been adopted in routine practice. [ABSTRACT FROM AUTHOR]

Purpose: A prospective feasibility study was conducted to investigate the utility of dual-energy (DE) imaging compared to conventional x-ray imaging for patients undergoing kV-based image guided radiation therapy (IGRT) for lung cancer. Methods and Materials: An institutional review board-approved feasibility study enrolled patients with lung cancer undergoing IGRT and was initiated in September 2011. During daily setup, 2 sequential respiration-gated x-ray images were obtained using an on-board imager. Imaging was composed of 1 standard x-ray image at 120 kVp (1 mAs) and a second image obtained at 60 kVp (4 mAs). Weighted logarithmic subtraction of the 2 images was performed offline to create a soft tissue-selective DE image. Conventional and DE images were evaluated by measuring relative contrast and contrast-to-noise ratios (CNR) and also by comparing spatial localization, using both approaches. Imaging dose was assessed using a calibrated ion chamber. Results: To date, 10 patients with stage IA to IIIA lung cancer were enrolled and 57 DE images were analyzed. DE subtraction resulted in complete suppression of overlying bone in all 57 DE images, with an average improvement in relative contrast of 4.7 ± 3.3 over that of 120 kVp x-ray images (P<.0002). The improvement in relative contrast with DE imaging was seen for both smaller (gross tumor volume [GTV] ≤5 cc) and larger tumors (GTV >5 cc), with average relative contrast improvement ratios of 3.4 ± 4.1 and 5.4 ± 3.6, respectively. Moreover, the GTV was reliably localized in 95% of the DE images versus 74% of the single energy (SE images, (P=.004). Mean skin dose per DE image set was 0.44 ± 0.03 mGy versus 0.43 ± 0.03 mGy, using conventional kV imaging parameters. Conclusions: Initial results of this feasibility study suggest that DE thoracic imaging may enhance tumor localization in lung cancer patients receiving kV-based IGRT without increasing imaging dose. [ABSTRACT FROM AUTHOR]

Purpose: To study various standardized uptake value (SUV)-based approaches to ascertain the best strategy for delineating metabolic tumor volumes (MTV). Methods and Materials: Twenty-two consecutive previously treated esophageal cancer patients with positron emission tomography (PET) imaging and computed tomography (CT)-based radiotherapy plans were studied. At the level of the tumor epicenter, MTVs were delineated at 11 different thresholds: SUV ≥2, ≥2.5, ≥3, ≥3.5 (SUV(n)); ≥40%, ≥45%, and ≥50% of the maximum (SUV(n%)); and mean liver SUV + 1, 2, 3, and 4 standard deviations (SUV(Lnσ)). The volume ratio and conformality index were determined between MTVs, and the corresponding CT/endoscopic ultrasound-based gross tumor volume (GTV) at the epicenter. Means were analyzed by one-way analysis of variance for repeated measures and further compared using a paired t test for repeated measures. Results: The mean conformality indices ranged from 0.33 to 0.48, being significantly (p < 0.05) closest to 1 at SUV(2.5) (0.47 ± 0.03) and SUV(L4σ) (0.48 ± 0.03). The mean volume ratios ranged from 0.39 to 2.82, being significantly closest to 1 at SUV(2.5) (1.18 ± 0.36) and SUV(L4σ) (1.09 ± 0.15). The mean value of the SUVs calculated using the SUV(L4σ) approach was 2.4. Conclusions: Regardless of the SUV thresholding method used (i.e., absolute or relative to liver mean), a threshold of approximately 2.5 yields the highest conformality index and best approximates the CT-based GTV at the epicenter. These findings may ultimately aid radiation oncologists in the delineation of the entire GTV in esophageal cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: Patients with non–small-cell lung cancer (NSCLC) in the Radiation Therapy Oncology Group (RTOG) 93-11 trial received radiation doses of 70.9, 77.4, 83.8, or 90.3 Gy. The locoregional control and survival rates were similar among the various dose levels. We investigated the effect of the gross tumor volume (GTV) on the outcome. Methods and Materials: The GTV was defined as the sum of the volumes of the primary tumor and involved lymph nodes. The tumor response, median survival time (MST), and progression-free survival (PFS) were analyzed separately for smaller (≤45 cm3) vs. larger (>45 cm3) tumors. Results: The distribution of the GTV was as follows: ≤45 cm3 in 79 (49%) and >45 cm3 in 82 (51%) of 161 patients. The median GTV was 47.3 cm3. N0 status and female gender were associated with better tumor responses. Patients with smaller (≤45 cm3) tumors achieved a longer MST and better PFS than did patients with larger (>45 cm3) tumors (29.7 vs. 13.3 months, p < 0.0001; and 15.8 vs. 8.3 months, p < 0.0001, respectively). Increasing the radiation dose had no effect on the MST or PFS. On multivariate analysis, only a smaller GTV was a significant prognostic factor for improved MST and PFS (hazard ratio [HR], 2.12, p = 0.0002; and HR, 2.0, p = 0.0002, respectively). The GTV as a continuous variable was also significantly associated with the MST and PFS (HR, 1.59, p < 0.0001; and HR, 1.39, p < 0.0001, respectively). Conclusions: Radiation dose escalation up to 90.3 Gy did not result in improved MST or PFS. The tumor responses were greater in node-negative patients and women. An increasing GTV was strongly associated with decreased MST and PFS. Future radiotherapy trials patients might need to use stratification by tumor volume. [Copyright &y& Elsevier]

Purpose: To evaluate the effect of tumor bulk on local control and survival of patients with T1 glottic cancer. Methods and Materials: Effects of tumor bulk, T-stage, anterior-commissure involvement, treatment duration, and fraction size were analyzed in 208 patients; 136 had small tumors and 72 had bulky tumors. Anterior-commissure was involved in 54 patients. Treatment duration ranged from 39 to 64 days and fraction size ranged from 1.8 to 2.0 Gy. Median follow-up was 5.1 years. Results: Five-year actuarial local control rates were 86.1% and 91.4% after radiotherapy and salvage laryngectomy. On univariate analysis, local control rates were 92.6% and 73.6% for small and bulky tumors (p = 0.03), 89.6% and 75.9% for patients without and with anterior-commissure involvement (p = 0.01), 92.6% and 75.6% when treatment duration was ≤50 days and >50 days (p = 0.04), and 90.2% and 76.4% with 2 Gy and 1.8 Gy (p = 0.02) per fraction. On multivariate analysis, tumor bulk was the only significant factor that affected local control (p = 0.007). Ultimate local control rates after salvage were 97.1% and 80.5% for patients with small and bulky tumors. Disease-free survival rates at 5 years for small and bulky tumors were 96.3% and 84.7% (p = 0.001). Median duration to recurrence for small tumors was 30 months as compared with 11 months for bulky tumors. Conclusion: Tumor bulk is a highly significant prognostic factor for radiation control of T1 glottic cancer. Patients with bulky tumors had lower local control and disease-free survival rates and shorter duration to recurrence than those with small tumors. [Copyright &y& Elsevier]

Purpose: To develop standardized correlates of [18F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) standard uptake value (SUV) to computed tomography (CT)-based window and levels. Methods and Materials: Nineteen patients with non–small-cell lung cancer who underwent imaging with positron emission tomography (PET) and CT were selected. A method of standardizing SUV within CT planning software was developed. A scale factor, determined by a sensitivity calibration of the PET scanner, converts voxel counts to activity per gram in tissue, allowing SUVs to be correlated to CT window and levels. A method of limiting interobserver variations was devised to enhance “edges” of regions of interest based on SUV thresholds. The difference in gross tumor volumes (GTVs) based on CT, PET SUV ≥ 2.5, and regions of 40% maximum SUV were analyzed. Results: The mean SUV was 9.3. Mean GTV volumes were 253 cc for CT, 221 cc for SUV ≥ 2.5, and 97 cc for SUV40%Max. Average volume difference was −259% between ≥2.5 SUV and CT and −162% between SUV40%Max and CT. Percent difference between GTV ≥ 2.5 SUV and SUV40%Max remained constant beyond SUV > 7. For SUVs 4–6, best correlation among SUV thresholds occurred at volumes near 90 cc. Mean percent change from GTVs contoured according to CT (GTV CT) was −260% for GTV2.5 and −162% for GTV40%Max. Using the SUV40%Max threshold resulted in a significant alteration of volume in 98% of patients, while the SUV2.5 threshold resulted in an alteration of volume in 58% of patients. Conclusions: Our method of correlating SUV to W/L thresholds permits accurate displaying of SUV in coregistered PET/CT studies. The optimal SUV thresholds to contour GTV depend on maximum tumor SUV and volume. Best correlation occurs with SUVs >6 and small volumes <100 cc. At SUVs >7, differences between the SUV threshold filters remain constant. Because of variability in volumes obtained by using SUV40%Max, we recommend using SUV ≥ 2.5 for radiotherapy planning in non–small-cell lung cancer. [Copyright &y& Elsevier]

Purpose: To evaluate prospectively the acute and late morbidities from a multiinstitutional three-dimensional radiotherapy dose-escalation study for inoperable non–small-cell lung cancer. Methods and materials: A total of 179 patients were enrolled in a Phase I–II three-dimensional radiotherapy dose-escalation trial. Of the 179 patients, 177 were eligible. The use of concurrent chemotherapy was not allowed. Twenty-five patients received neoadjuvant chemotherapy. Patients were stratified at escalating radiation dose levels depending on the percentage of the total lung volume that received >20 Gy with the treatment plan (V20). Patients with a V20 <25% (Group 1) received 70.9 Gy in 33 fractions, 77.4 Gy in 36 fractions, 83.8 Gy in 39 fractions, and 90.3 Gy in 42 fractions, successively. Patients with a V20 of 25–36% (Group 2) received doses of 70.9 Gy and 77.4 Gy, successively. The treatment arm for patients with a V20 ≥37% (Group 3) closed early secondary to poor accrual (2 patients) and the perception of excessive risk for the development of pneumonitis. Toxicities occurring or persisting beyond 90 days after the start of radiotherapy were scored as late toxicities. The estimated toxicity rates were calculated on the basis of the cumulative incidence method. Results: The following acute Grade 3 or worse toxicities were observed for Group 1: 70.9 Gy (1 case of weight loss), 77.4 Gy (nausea and hematologic toxicity in 1 case each), 83.8 Gy (1 case of hematologic toxicity), and 90.3 Gy (3 cases of lung toxicity). The following acute Grade 3 or worse toxicities were observed for Group 2: none at 70.9 Gy and 2 cases of lung toxicity at 77.4 Gy. No patients developed acute Grade 3 or worse esophageal toxicity. The estimated rate of Grade 3 or worse late lung toxicity at 18 months was 7%, 16%, 0%, and 13% for Group 1 patients receiving 70.9, 77.4, 83.8, or 90.3 Gy, respectively. Group 2 patients had an estimated late lung toxicity rate of 15% at 18 months for both 70.9 and 77.4 Gy. The prognostic factors for late pneumonitis in multivariate analysis were the mean lung dose and V20. The estimated rate of late Grade 3 or worse esophageal toxicity at 18 months was 8%, 0%, 4%, and 6%, for Group 1 patients receiving 70.9, 77.4, 83.8, 90.3 Gy, respectively, and 0% and 5%, respectively, for Group 2 patients receiving 70.9 and 77.4 Gy. The dyspnea index scoring at baseline and after therapy for functional impairment, magnitude of task, and magnitude of effort revealed no change in 63%, functional pulmonary loss in 23%, and pulmonary improvement in 14% of patients. The observed locoregional control and overall survival rates were each similar among the study arms within each dose level of Groups 1 and 2. Locoregional control was achieved in 50–78% of patients. Thirty-one patients developed regional nodal failure. The location of nodal failure in relationship to the RT volume was documented in 28 of these 31 patients. Twelve patients had isolated elective nodal failures. Fourteen patients had regional failure in irradiated nodal volumes. Two patients had both elective nodal and irradiated nodal failure. Conclusions: The radiation dose was safely escalated using three-dimensional conformal techniques to 83.8 Gy for patients with V20 values of <25% (Group 1) and to 77.4 Gy for patients with V20 values between 25% and 36% (Group 2), using fraction sizes of 2.15 Gy. The 90.3-Gy dose level was too toxic, resulting in dose-related deaths in 2 patients. Elective nodal failure occurred in <10% of patients. [Copyright &y& Elsevier]

Background and purpose: The appropriate application of 3-D CRT and IMRT for HNSCC requires a standardization of the procedures for the delineation of the target volumes. Over the past few years, two proposals—the so-called Brussels guidelines from Gre´goire et al., and the so-called Rotterdam guidelines from Nowak et al.—emerged from the literature for the delineation of the neck node levels. Detailed examination of these proposals however revealed some important discrepancies.Materials and methods: Within this framework, the Brussels and Rotterdam groups decided to review their guidelines and derive a common set of recommendations for delineation of neck node levels. This proposal was then discussed with representatives of major cooperative groups in Europe (DAHANCA, EORTC, GORTEC) and in North America (NCIC, RTOG), which, after some additional refinements, have endorsed them. The objective of the present article is to present the consensus guidelines for the delineation of the node levels in the node-negative neck.Results and conclusions: First a short discussion of the discrepancies between the previous Brussels and the Rotterdam guidelines is presented. The general philosophy of the consensus guidelines and the methodology used to resolve the various discrepancies are then described. The consensus proposal is then presented and representative CTVs that are consistent with these guidelines are illustrated on CT sections. Last, the limitations of the consensus guidelines are discussed and some concerns about the direct applications of these guidelines to the node-positive neck and the post-operative neck are described. [Copyright &y& Elsevier]

: BackgroundLiterature regarding incidence of site-specific second cancers after laryngeal cancer is limited. Risk factors associated with second primaries are unknown.: MethodsSecond primaries after laryngeal cancer in the SEER database (1973–1996) were analyzed for incidence, relative risk compared with the general population, and potential risk factors, including radiotherapy. Information on chemotherapy and tobacco smoking was not available in the SEER database.: ResultsOf 20,074 laryngeal cancer patients surviving at least 3 months, 3533 (17.6%) developed second cancers. The cumulative risk of developing a second cancer was 26% at 10 years and 47% at 20 years. Compared with age-adjusted, gender, and tumor-specific rates in the general population, laryngeal cancer patients had higher risks of second cancers overall (observed-to-expected ratio [O/E] = 1.68, 95% confidence interval [CI] = 1.58–1.79), head-and-neck (4.81 [4.31–5.58]), esophageal (3.99 [3.29–4.83]), and lung (3.56 [3.34–3.79]) cancer. Advanced age at initial diagnosis was associated with increased risks of second cancers (p = 0.0001). Radiotherapy was associated with increased risk of second cancers overall (relative risk [RR] = 1.10 [1.02–1.18], p = 0.012), especially second cancers of the lung (RR = 1.18, [1.05–1.33], p = 0.006) and possibly second cancers of the head and neck (RR = 1.26, [0.99–1.60], p = 0.061). Radiotherapy was associated with a 68% excess risk (RR = 1.68, [1.16–2.43], p = 0.007) of developing a second head-and-neck cancer in patients who survived more than 5 years. Second primary was associated with a poor survival (p = 0.0001).: ConclusionsSecond cancers after laryngeal cancer are common, especially for long-term survivors. Radiotherapy was associated with a small increased risk of developing second cancers overall and long-term risk of head-and-neck cancers. This data should be interpreted with caution in light of the lack of information on chemotherapy and tobacco smoking in the SEER database. Prevention and early detection are indicated. [Copyright &y& Elsevier]

Purpose: To implement the “plan-do-check-act” (PDCA) cycle for the continual quality improvement of normal tissue contours used for radiation therapy treatment planning. Methods and Materials: The CT scans of patients treated for tumors of the brain, head and neck, thorax, pancreas and prostate were selected for this study. For each scan, a radiation oncologist and a diagnostic radiologist, outlined the normal tissues (“gold” contours) using Radiation Therapy Oncology Group (RTOG) guidelines. A total of 30 organs were delineated. Independently, 5 board-certified dosimetrists and 1 trainee then outlined the same organs. Metrics used to compare the agreement between the dosimetrists'' contours and the gold contours included the Dice Similarity Coefficient (DSC), and a penalty function using distance to agreement. Based on these scores, dosimetrists were re-trained on those organs in which they did not receive a passing score, and they were subsequently re-tested. Results: Passing scores were achieved on 19 of 30 organs evaluated. These scores were correlated to organ volume. For organ volumes <8 cc, the average DSC was 0.61 vs organ volumes ≥8 cc, for which the average DSC was 0.91 (P=.005). Normal tissues that had the lowest scores included the lenses, optic nerves, chiasm, cochlea, and esophagus. Of the 11 organs that were considered for re-testing, 10 showed improvement in the average score, and statistically significant improvement was noted in more than half of these organs after education and re-assessment. Conclusions: The results of this study indicate the feasibility of applying the PDCA cycle to assess competence in the delineation of individual organs, and to identify areas for improvement. With testing, guidance, and re-evaluation, contouring consistency can be obtained across multiple dosimetrists. Our expectation is that continual quality improvement using the PDCA approach will ensure more accurate treatments and dose assessment in radiotherapy treatment planning and delivery. [Copyright &y& Elsevier]

The purpose of the present study was to present a single institution experience with intraoperative radiation therapy (IORT) for patients with head and neck cancer (HNC). The present study included all patients with HNC treated consecutively with IORT at Loyola University Medical Center between January 2014 and December 2018. Charts were reviewed for patient and tumor characteristics, IORT technical details, IORT-induced adverse events and treatment outcomes. The study included 23 eligible patients. Median patient age was 66 years (range, 34-91 years). Tumor sites included the parotid gland (43%), lymph nodes (43%), oral tongue (9%) and ear (4%). A total of 48% of patients received IORT upfront with or without postoperative adjuvant external beam radiation therapy (EBRT), whereas 52% received salvage IORT after local tumor recurrence. The median prescribed IORT dose was 7.5 Gy (range, 5-14 Gy) in a single fraction prescribed to 5 mm depth with flat applicators (median diameter, 5 cm). A total of 92% of patients did not experience wound healing complications. One patient (4%) developed postoperative acute thromboembolic stroke and a second patient (4%) experienced protracted wound healing. At a median follow up of 36 months (range, 2-81 months), overall survival was 52%. In addition, 48% of patients were reported to have no evidence of disease, and although two had died of unrelated causes, 13% of patients were alive with disease and 39% died with the disease. The local-regional recurrence rate was 39% (median time to local recurrence, 11 months; range, 1-34 months), the rate of distant metastasis was 35% (median time to distant metastasis, 16 months; range, 4-40 months), and 21% of patients had both local-regional recurrence and distant metastases. The percentages of local-regional recurrence and distant metastases among patients receiving salvage IORT were 58 and 50% respectively, compared with 18 and 18% respectively in those receiving upfront IORT with or without adjuvant EBRT. In the present single institution retrospective study, it was concluded that IORT for patients with locally advanced and recurrent HNC was a safe treatment modality, with tumor control comparable to historical IORT data. Larger prospective studies are needed to further assess the utility of IORT in the management of locally advanced and recurrent HNC., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Chiodo et al.)

Purpose: This study aimed to evaluate the clinical need for an automated decision-support software platform for adaptive radiation therapy (ART) of head and neck cancer (HNC) patients., Methods: We tested RTapp (SegAna), a new ART software platform for deciding when a treatment replan is needed, to investigate a set of 27 HNC patients' data retrospectively. For each fraction, the software estimated key components of ART such as daily dose distribution and cumulative doses received by targets and organs at risk (OARs) from daily 3D imaging in real-time. RTapp also included a prediction algorithm that analyzed dosimetric parameter (DP) trends against user-specified thresholds to proactively trigger adaptive re-planning up to four fractions ahead. The DPs evaluated for ART were based on treatment planning dose constraints. Warning (V 95 <95%) and adaptation (V 95 <93%) thresholds were set for PTVs, while OAR adaptation dosimetric endpoints of +10% (DE 10 ) were set for all D max and D mean DPs. Any threshold violation at end of treatment (EOT) triggered a review of the DP trends to determine the threshold-crossing fraction Fx when the violations occurred. The prediction model accuracy was determined as the difference between calculated and predicted DP values with 95% confidence intervals (CI 95 )., Results: RTapp was able to address the needs of treatment adaptation. Specifically, we identified 18/27 studies (67%) for violating PTV coverage or parotid D mean at EOT. Twelve PTVs had V 95 <95% (mean coverage decrease of -6.8 ± 2.9%) including six flagged for adaptation at median Fx = 6 (range, 1-16). Seventeen parotids were flagged for exceeding D mean dose constraints with a median increase of +2.60 Gy (range, 0.99-6.31 Gy) at EOT, including nine with DP>DE 10 . The differences between predicted and calculated PTV V 95 and parotid D mean was up to 7.6% (mean ± CI 95 , -2.7 ± 4.1%) and 5 Gy (mean ± CI 95 , 0.3 ± 1.6 Gy), respectively. The most accurate predictions were obtained closest to the threshold-crossing fraction. For parotids, the results showed that Fx ranged between fractions 1 and 23, with a lack of specific trend demonstrating that the need for treatment adaptation may be verified for every fraction., Conclusion: Integrated in an ART clinical workflow, RTapp aids in predicting whether specific treatment would require adaptation up to four fractions ahead of time., Competing Interests: Dr. Anand Santhanam is a co-founder of Segana Inc., the company who developed the RTapp software platform evaluated in this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gros, Santhanam, Block, Emami, Lee and Joyce.)

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Stang et al.)

Context: Curcumin, the active component of Curcuma longa L. (Zingiberaceae), exhibits a wide variety of biological activities including vasodilation and anti-inflammation. Objective: The relaxant effect of curcumin in tracheal smooth muscle (TSM) was not examined so far, thus, this study was designed to assess the relaxant effect of curcumin on rat TSM and examine the underlying mechanism(s) responsible for this effect. Materials and methods: TSM was contracted by KCl (60 mM) or methacholine (10 μM), and cumulative concentrations of curcumin (12.5, 25, 50, and 100 mg/mL) or theophylline (0.2, 0.4, 0.6, and 0.8 mM, as positive control) were added to organ bath. The relaxant effect of curcumin was examined in non-incubated or incubated tissues with atropine (1 μM), chlorpheniramine (1 μM), indomethacin (1 μM), and papaverine (100 μM). Results: In non-incubated TSM, curcumin showed significant relaxant effects on KCl-induced contraction in a concentration-dependent manner ( p  < 0.001 for all concentrations). The relaxant effects of curcumin 12.5, 25, and 50 mg/mL were significantly lower in atropine-incubated tissue compared to non-incubated TSM ( p  < 0.05 to p  < 0.001). A significant difference was observed in EC 50 between atropine-incubated (48.10 ± 2.55) and non-incubated (41.65 ± 1.81) tissues ( p  < 0.05). Theophylline showed a significant relaxant effect on both KCl and methacholine-induced contraction in a concentration-dependent manner ( p  < 0.001 for all cases). Conclusions: The results indicated a relatively potent relaxant effect of curcumin on TSM, which was less marked than the effect of theophylline. Calcium channel blocking and/or potassium channel opening properties of curcumin may be responsible for TSM relaxation.

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Harris et al.)

High-dose hypofractionated SBRT and SRS indirectly kills substantial fractions of tumor cells via causing vascular damage. The LQ formula may work well for certain clinical cases of SBRT and SRS when the indirect/additional tumor cell death secondary to vascular damage is small. However, when the indirect cell death is extensive, the LQ model will underestimate the clinical outcome of SBRT and SRS., Competing Interests: Authors’ disclosure of potential conflicts of interest The authors have nothing to disclose., (© 2020 Old City Publishing, Inc.)

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumour of the skin. While localised disease carries an overall favourable prognosis, metastatic disease is associated with poor clincal outcomes. Most cases of metastatic MCC are managed with systemic chemotherapy or immunotherapy, though 5-year survival for these patients remains a dismal 17%. Here, we present the case of a 79-year-old man with MCC of the right ear with metastases to regional lymph nodes, ipsilateral parotid gland and thoracic spine. He was treated with a combination of first-line radiotherapy and concurrent immune checkpoint inhibition (avelumab), which led to complete clinical regression of disease with minimal adverse effects. This observation suggests that combined radio-immunotherapy warrants larger-scale investigation for use in patients with unresectable MCC., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We performed an analysis of the National Cancer Database (NCDB) to evaluate overall survival (OS) in patients with base of tongue (BOT) cancer treated with external beam radiation therapy (EBRT) combined with brachytherapy (BT)., Methods: The tongue NCDB Participant User File was used to obtain demographic and clinical patient data. The Kaplan-Meier method was used to determine OS. Significance was determined using univariable and multivariable Cox proportional hazards models., Results: At 3 years, OS was 69.6%, 77.1%, and 63.7% for patients treated with EBRT (n = 27 954), EBRT + BT (n = 209), or BT alone (n = 154), respectively (P = .01). On multivariable analysis, the instantaneous hazard of death for patients receiving EBRT + BT was 25% (Hazard ratio [HR] = 0.75, 95% CI: 0.58-0.98) lower than patients receiving only EBRT (P = .03)., Conclusions: The addition of BT to EBRT in BOT cancer has an OS benefit., (© 2019 Wiley Periodicals, Inc.)

Background: The median time to recurrence of glioblastoma (GB) following multimodal treatment is ∼7 mo. Nearly all cancers recur locally, suggesting that augmenting local treatments may improve outcomes., Objective: To investigate whether intraoperative radiotherapy (IORT) to the resection cavity is safe and effective., Methods: INTRAGO was a phase I/II trial to evaluate the safety and tolerability of IORT with 20 to 40 Gy of low-energy photons in addition to standard radiochemotherapy (ClinicalTrials.gov ID, NCT02685605). The primary endpoint was safety as per occurrence of dose-limiting toxicities. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). We also performed an exploratory analysis of the local PFS (L-PFS), defined as recurrence within 1 cm of the treated margin., Results: Fifteen patients were treated at 3 dose levels. Of these, 13 underwent incomplete resection, 6 had unresected satellites, and 3 did not receive per-protocol treatment (PPT). The MGMT promoter was unmethylated in 10 patients. The median follow-up was 13.8 mo. The majority of grade 3 to 5 adverse events were deemed unrelated to IORT. Five cases of radionecrosis were observed, 2 were classified as grade 3 events. Other grade 3 events judged related to radiotherapy (external-beam radiotherapy and/or IORT) were wound dehiscence (n = 1), CSF leakage (n = 1), cyst formation (n = 1). No IORT-related deaths occurred. The median PFS was 11.2 mo (95% confidence interval [CI]: 5.4-17.0) for all patients and 11.3 mo (95% CI: 10.9-11.6) for those receiving PPT. The median L-PFS was 14.3 mo (95% CI: 8.4-20.2) for all patients and 17.8 mo (95% CI: 9.7-25.9) for those receiving PPT. The median OS was 16.2 mo (95% CI: 11.1-21.4) for all patients and 17.8 mo (95% CI: 13.9-21.7) for those receiving PPT., Conclusion: These data suggest that IORT is associated with manageable toxicity. Considering the limitations of a 15-patient phase I/II trial, further studies aimed at assessing an outcome benefit are warranted.

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., (Published by Elsevier Inc.)

Purpose: We evaluate dose characteristics and clinical applications of treatment accessories used in intraoperative radiotherapy (IORT) and make site-specific recommendations for their optimal use., Methods and Materials: Dose measurements were performed for a low energy (50 kV) X-ray INTRABEAM source. For spherical, flat, surface, and needle applicators, the following dosimetric parameters were measured: depth-dose (DD) profiles, surface dose (Ds), output factors (OF), and target dose homogeneity (DH). Optical density versus exposure calibration films were employed to obtain 2-dimensional dose distributions in planes parallel and perpendicular to beam direction. Film results were verified via repeat dose measurements with a parallel-plate ionization chamber in a custom water tank. The impact of applicator design on dose distributions was evaluated., Results: Spherical applicators are commonly used for treating the inner-surface of breast lumpectomy cavity. Flat and surface applicators provide uniform planar dose for head and neck, abdomen, and pelvis targets. Needle applicators are designed for kypho-IORT of spinal metastasis. Typically, larger applicators produce a more homogeneous target dose region with lower surface dose, but require longer treatment times. For 4-cm diameter spherical, flat, and surface applicators, dose rates (DR) at their respective prescription points were found to be: 0.8, 0.3, and 2.2 Gy/min, respectively. The DR for a needle applicator was 7.04 Gy/min at 5 mm distance from the applicator surface. Overall, film results were in excellent agreement with ion-chamber data., Conclusion: IORT may be delivered with a variety of site-specific applicators. Appropriate applicator use is paramount for safe, effective, and efficient IORT delivery. Results of this study should help clinicians assure optimized target dose coverage and reduced normal tissue exposure.

Background: The aim of this study was investigation of the effects of Nigella sativa (NS) seeds on hypothyroid pregnant rats and their progenies., Materials and Methods: Hypothyroidism was induced by propylthiouracil (PTU) 0.03% in drinking water. Female rats were divided into seven groups: control, PTU, PTU-NS (100, 200, and 400 mg/kg), and NS (100 and 400 mg/kg). All treatments were done 20 days before mating and during pregnancy. The weight of rat dams and progenies, number of progenies and serum T4, estradiol and prolactin (PRL) levels in rat dams were measured for all groups., Results: Serum T4 in all PTU-NS groups before mating was significantly increased versus PTU group. Body weight of rat dams before mating in all groups of PTU-NS was increased versus PTU group by P < 0.001, P < 0.05, and P < 0.001, respectively and in NS 100 and NS 400 was increased versus control group ( P < 0.001). The number of offspring was significantly decreased in PTU and PTU-NS versus control group. The weight of progenies in NS 400 was higher than control group ( P < 0.001) and was increased in PTU-NS 200 and PTU-NS 400 versus PTU group by P < 0.001 and P < 0.05, respectively. Serum PRL level in rat dams in control, PTU, and PTU-NS groups were not statistically different between groups but significantly increased in NS 400 group when compared to control group. Estradiol levels were not significantly different in rat dams at 5 days after delivery., Conclusion: These results demonstrated that feeding of rat dams with NS extract before mating has positive protective effects on progenies. These effects may be due to antioxidant properties of NS in reducing oxidative stress and thyroid damages induced by PTU., Competing Interests: There are no conflicts of interest.

Context: Turmeric is a spice obtained from the root of Curcuma longa L. (Zingiberaceae) with anti-aging, anticancer, anti-Alzheimer's disease, antioxidant and other medicinal properties., Objective: The relaxant effect of C. longa on rat tracheal smooth muscle and its possible mechanisms were investigated in this study., Materials and Methods: The relaxant effects of four cumulative concentrations of hydro-ethanol extract of C. longa (6.25, 12.5, 25, 50 mg/mL) were studied on tracheal smooth muscle precontracted by methacholine or KCl in non-incubated or incubated with different substances including propranolol, diltiazem, L-NAME, glibenclamide, atropine, chlorpheniramine, indomethacin and papaverine. The duration of the study was 84 days., Results: In non-incubated tracheal smooth muscle, the extract of C. longa showed significant concentration-dependent relaxant effects (p < 0.001 for all concentrations on both KCl and methacholine-induced contraction). There was no significant difference in the relaxant effects between C. longa and theophylline in both methacholine and KCl-induced contraction conditions. In tissues incubated with propranolol, diltiazem, L-NAME and glibenclamide on methacholine-induced contraction and in tissues incubated with atropine, chlorpheniramine, indomethacin and papaverine on KCl-induced contraction, the extract also showed significant concentration-dependent relaxant effects (p < 0.001). EC 50 values of C. longa between non-incubated (16.22 ± 0.62) and incubated tissues (atropine: 13.03 ± 0.55, chlorpheniramine: 12.94 ± 0.68, indomethacin: 14.80 ± 0.57 and papaverine: 16.16 ± 1.42) were not significantly different., Conclusions: Tracheal smooth muscle relaxant effects of C. longa, were comparable to those of theophylline, which could be due to the presence of methylxanthines or its possible interaction with non-adrenergic non-cholinergic nervous system.

Objective: To investigate the effects of adaptive radiotherapy on dosimetric, clinical, and toxicity outcomes for patients with head and neck cancer undergoing chemoradiotherapy with intensity-modulated radiotherapy., Methods: Fifty-one patients with advanced head and neck cancer underwent definitive chemoradiotherapy with the original plan optimized to deliver 70.2 Gy. All patients were resimulated at a median dose of 37.8 Gy (range, 27.0-48.6 Gy) due to changes in tumor volume and/or patient weight loss (>15% from baseline). Thirty-four patients underwent adaptive replanning for their boost planning (21.6 Gy). The dosimetric effects of the adaptive plan were compared to the original plan and the original plan copied on rescan computed tomography. Acute and late toxicities and tumor local control were assessed. Gross tumor volume reduction rate was calculated., Results: With adaptive replanning, the maximum dose to the spinal cord, brain stem, mean ipsilateral, and contralateral parotid had a median reduction of -4.5%, -3.0%, -6.2%, and -2.5%, respectively (median of 34 patients). Median gross tumor volume and boost planning target volume coverage improved by 0.8% and 0.5%, respectively. With a median follow-up time of 17.6 months, median disease-free survival and overall survival was 14.8 and 21.1 months, respectively. Median tumor volume reduction rate was 35.2%. For patients with tumor volume reduction rate ≤35.2%, median disease-free survival was 8.7 months, whereas it was 16.9 months for tumor volume reduction rate >35.2%. Four patients had residual disease after chemoradiotherapy, whereas 64.7% (20 of 34) of patients achieved locoregional control., Conclusion: Implementation of adaptive radiotherapy in head and neck cancer offers benefits including improvement in tumor coverage and decrease in dose to organs at risk. The tumor volume reduction rate during treatment was significantly correlated with disease-free survival and overall survival.

Purpose: To evaluate a method for reducing metal artifacts, arising from dental fillings, on cone-beam computed tomography images., Materials and Methods: A projection interpolation algorithm is applied to cone-beam computed tomography images containing metal artifacts from dental fillings. This technique involves identifying metal regions in individual cone-beam computed tomography projections and interpolating the surrounding values to remove the metal from the projection data. Axial cone-beam computed tomography images are then reconstructed, resulting in a reduction in the streak artifacts produced by the metal. Both phantom and patient imaging data are used to evaluate this technique., Results: The interpolation substitution technique successfully reduced metal artifacts in all cases. Corrected images had fewer or no streak artifacts compared to their noncorrected counterparts. Quantitatively, regions of interest containing the artifacts showed reduced variance in the corrected images versus the uncorrected images. Average pixel values in regions of interest around the metal object were also closer in value to nonmetal regions after artifact reduction. Artifact correction tended to perform better on patient images with less complex metal objects versus those with multiple large dental fillings., Conclusion: The interpolation substitution is potentially an efficient and effective technique for reducing metal artifacts caused by dental fillings on cone-beam computed tomography image. This technique may be effective in reducing such artifacts in patients with head and neck cancer receiving daily image-guided radiotherapy., (© The Author(s) 2015.)

Objective: The purpose of this study was to determine dose delivered to individual mandibular tooth-bearing regions during adjuvant intensity-modulated radiotherapy for laryngeal cancers., Study Design: Twenty patients with laryngeal cancer treated with intensity-modulated radiotherapy were included. Individual mandibular tooth-borne areas were manually contoured. Average doses were calculated for individual teeth., Results: Doses to individual teeth increased with more posterior location. Highest dose was observed for third molar (M3) (43.1 Gy; P < .001). Doses to molars and premolars correlated with T- and N-stage (P = .007; P < .001, respectively). For ipsilateral nodal disease, there was no difference between the doses to ipsilateral teeth and contralateral teeth. Only in N2 c tumors, dose was above our threshold for extraction for M3 only (51.5 Gy)., Conclusions: T- and N-stage drive dose to individual mandibular tooth-borne areas. With the exception of the posterior molars, particularly in node-positive patients, radiation exposure falls below the threshold reported for pre-RT tooth extractions (50 Gy). We concluded that a more conservative approach to prophylactic tooth extraction with a greater emphasis on dental management may be warranted for the prevention of osteoradionecrosis in patients with laryngeal cancer receiving adjuvant RT., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This editorial comments on the study by Tallet et al. which reported on the incidence of ipsilateral second breast cancers (BC) detected by preoperative magnetic resonance imaging (MRI) in patients being considered for intraoperative radiotherapy (IORT). Any second BC was detected in 7% of patients; an ipsilateral BC was detected in 4% of patients, precluding them from IORT. The authors comment that in view of detection of a substantial rate of ipsilateral BCs by preoperative MRI, this exam should be used routinely for staging patients being considered for IORT.

Metastatic involvement of the cranial base and jugular foramen generally presents with headache and lower cranial neuropathy but may escape early diagnosis. In this report, a patient developed a jugular foramen syndrome as the initial presentation of metastatic lung cancer soon after being diagnosed and treated surgically for extracranial atherosclerotic internal carotid artery disease. With the appropriate diagnosis established, he underwent local fractionated radiation therapy and systemic chemotherapy but succumbed to the disease. This report analyses metastatic disease affecting the cranial base and in particular, the jugular foramen, with a discussion of the clinical syndromes that accompany this rare condition.

Background: This phase I study was designed to determine the maximum tolerated dose (MTD) and preliminary efficacy of docetaxel with concurrent radiotherapy (RT), in high-risk squamous cell carcinoma of the head and neck., Patients and Methods: Eligible patients had resected squamous cell carcinoma of the head and neck, histologically involved lymph nodes, and/or extranodal disease, and/or involved surgical margins and performance status 0 to 1. Treatment included weekly docetaxel with concurrent RT in a dose-finding study; a subsequent small cohort of patients was treated using the MTD of docetaxel., Results: Twenty patients were enrolled. Planned accrual was 25, but the study was closed prematurely because of slow accrual. The MTD was 15 mg/m2. Dose-limiting toxicity was oral stomatitis. Therapy was well tolerated. Five patients experienced locoregional relapse at a median follow-up of 32 months., Conclusion: Docetaxel with concurrent RT has acceptable toxicity. This approach warrants further investigation in a phase II trial.

Objective: The study objective was to determine survival and functional results in patients who underwent transoral laser excision of base of tongue squamous cell carcinoma., Study Design: This was a case series with chart review., Subjects and Methods: Patients with biopsy-proven base of tongue squamous cell carcinoma primarily treated with transoral laser excision and followed for at least 24 months were included. Disease-specific and overall survival data were determined. Quality-of-life data were obtained using the University of Washington Quality of Life instrument., Results: Of the 71 patients treated, one (1.4%), nine (12.7%), seven (9.9%), and 54 (76.1%) were stage I, II, III, and IV, respectively, at diagnosis. At 24 months, overall survival was 90 percent; disease-specific survival was 94 percent. Locoregional recurrence occurred in 10 percent. Given the low number of deaths, no significance was detectable between survival and gender, overall stage, tumor size, nodal status, or adjuvant therapy. Quality-of-life data, obtained for 46 patients, revealed the majority of patients had mild or no pain, minimally impaired to normal swallowing, and normal speech., Conclusion: Transoral laser excision offers an acceptable treatment approach in terms of survival and quality of life for patients with base of tongue squamous cell carcinoma.