Intraoperative radiation therapy for locally advanced and recurrent head and neck cancer.

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.

Retrospective Clinical Evaluation of a Decision-Support Software for Adaptive Radiotherapy of Head and Neck Cancer Patients.

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 (V95<95%) and adaptation (V95<93%) thresholds were set for PTVs, while OAR adaptation dosimetric endpoints of +10% (DE10) were set for all Dmax and Dmean 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 (CI95). Results: RTapp was able to address the needs of treatment adaptation. Specifically, we identified 18/27 studies (67%) for violating PTV coverage or parotid Dmean at EOT. Twelve PTVs had V95<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 Dmean dose constraints with a median increase of +2.60 Gy (range, 0.99-6.31 Gy) at EOT, including nine with DP>DE10. The differences between predicted and calculated PTV V95 and parotid Dmean was up to 7.6% (mean ± CI95, -2.7 ± 4.1%) and 5 Gy (mean ± CI95, 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.

Radiation Toxicity in Patients With Collagen Vascular Disease: A Meta-Analysis of Case-Control Studies.

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.

Estimating the tolerance of brachial plexus to hypofractionated stereotactic body radiotherapy: a modelling-based approach from clinical experience.

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.

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.

Initial Data Pooling for Radiation Dose-Volume Tolerance for Carotid Artery Blowout and Other Bleeding Events in Hypofractionated Head and Neck Retreatments.

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.

Biological Principles of Stereotactic Body Radiation Therapy (SBRT) and Stereotactic Radiation Surgery (SRS): Indirect Cell Death.

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.

Indirect cell death and the LQ model in SBRT and SRS.

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.

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.

Potential Clinical Significance of Overall Targeting Accuracy and Motion Management in the Treatment of Tumors That Move With Respiration: Lessons Learnt From a Quarter Century of Stereotactic Body Radiotherapy From Dose Response Models.

OBJECTIVE: To determine the long-term normal tissue complication probability with stereotactic body radiation therapy (SBRT) treatments for targets that move with respiration and its relation with the type of respiratory motion management (tracking vs. compression or gating). METHODS: A PubMed search was performed for identifying literature regarding dose, volume, fractionation, and toxicity (grade 3 or higher) for SBRT treatments for tumors which move with respiration. From the identified papers logistic or probit dose-response models were fitted to the data using the maximum-likelihood technique and confidence intervals were based on the profile-likelihood method in the dose-volume histogram (DVH) Evaluator. RESULTS: Pooled logistic and probit models for grade 3 or higher toxicity for aorta, chest wall, duodenum, and small bowel suggest a significant difference when live motion tracking was used for targeting tumors with move with respiration which was on the average 10 times lower, in the high dose range. CONCLUSION: Live respiratory motion management appears to have a better toxicity outcome when treating targets which move with respiration with very steep peripheral dose gradients. This analysis is however limited by sparsity of rigorous data due to poor reporting in the literature.

Combined radio-immunotherapy leads to complete clinical regression of stage IV Merkel cell carcinoma.

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.

National Cancer Database Analysis of the effect of brachytherapy on overall survival in patients with base of tongue cancer.

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.

Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma (INTRAGO): An Open-Label, Dose-Escalation Phase I/II Trial.

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.

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.

Extensive Cutaneous T-Cell Lymphoma of the Feet Treated with High-Dose-Rate Brachytherapy and External Beam Radiation.

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.

The effect of captopril on lipopolysaccharide-induced lung inflammation.

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.

Intraoperative Radiotherapy With INTRABEAM: Technical and Dosimetric Considerations.

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.

Relaxant effect of Curcuma longa on rat tracheal smooth muscle and its possible mechanisms.

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). EC50 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.

Stereotactic Radiation for Palliation of Skull Base Recurrences of Salivary Gland Carcinomas: Implications for Tumor Targeting.

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.

A novel surrogate to identify anatomical changes during radiotherapy of head and neck cancer patients.

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.