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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,657 records · Page 92
All sourcesNASA NTRSDOE OSTI
DOE OSTI2011

Targeted Intraoperative Radiotherapy for Breast Cancer in Patients in Whom External Beam Radiation Is Not Possible

Purpose: External beam radiation therapy (EBRT) following wide local excision of the primary tumor is the standard treatment in early breast cancer. In some circumstances this procedure is not possible or is contraindicated or difficult. The purpose of this study was to determine the safety and efficacy of targeted intraoperative radiotherapy (TARGIT) when EBRT is not feasible. Methods and Materials: We report our experience with TARGIT in three centers (Australia, Germany, and the United Kingdom) between 1999 and 2008. Patients at these centers received a single radiation dose of 20 Gy to the breast tissue in contact with the applicator (or 6 Gy at 1-cm distance), as they could not be given EBRT and were keen to avoid mastectomy. Results: Eighty patients were treated with TARGIT. Reasons for using TARGIT were 21 patients had previously received EBRT, and 31 patients had clinical reasons such as systemic lupus erythematosus, motor neuron disease, Parkinson's disease, ankylosing spondylitis, morbid obesity, and cardiovascular or severe respiratory disease. Three of these patients received percutaneous radiotherapy without surgery; 28 patients were included for compelling personal reasons, usually on compassionate grounds. After a median follow-up of 38 months, only two local recurrences were observed, an annual local recurrence rate of 0.75% (95% confidence interval, 0.09%-2.70%). Conclusions: While we await the results of the randomized trial (over 2,000 patients have already been recruited), TARGIT is an acceptable option but only in highly selected cases that cannot be recruited in the trial and in whom EBRT is not feasible/possible.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Radiation Therapy and Late Mortality From Second Sarcoma, Carcinoma, and Hematological Malignancies After a Solid Cancer in Childhood

Purpose: To compare patterns of long-term deaths due to secondary carcinomas, sarcomas, and hematological malignancies occurring after childhood cancer in a cohort of patients followed over a median of 28 years. Methods and Materials: The study included 4,230 patients treated at eight institutions, who were at least 5-year survivors of a first cancer, representing 105,670 person-years of observation. Complete clinical, chemotherapeutic, and radiotherapeutic data were recorded, and the integral radiation dose was estimated for 2,701 of the 2,948 patients who had received radiotherapy. The integral dose was estimated for the volume inside the beam edges. The causes of death obtained from death certificates were validated. Results: In total, 134 events were due to second malignant neoplasm(s) (SMN). We found that the standardized mortality ratio decreased with increasing follow-up for second carcinomas and sarcomas, whereas the absolute excess risk (AER) increased for a second carcinoma but decreased for second sarcomas. There was no clear variation in SMN and AER for hematological malignancies. We found a significant dose-response relationship between the radiation dose received and the mortality rate due to a second sarcoma and carcinoma. The risk of death due to carcinoma and sarcoma as SMN was 5.2-fold and 12.5-fold higher, respectively, in patients who had received a radiation dose exceeding 150 joules. Conclusions: Among patients who had received radiotherapy, only those having received the highest integral radiation dose actually had a higher risk of dying of a second carcinoma or sarcoma.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms (SNPs) Associated With the Development of Erectile Dysfunction in African-American Men After Radiotherapy for Prostate Cancer

Purpose: To identify single nucleotide polymorphisms (SNPs) associated with erectile dysfunction (ED) among African-American prostate cancer patients treated with external beam radiation therapy. Methods and Materials: A cohort of African-American prostate cancer patients treated with external beam radiation therapy was observed for the development of ED by use of the five-item Sexual Health Inventory for Men (SHIM) questionnaire. Final analysis included 27 cases (post-treatment SHIM score {<=}7) and 52 control subjects (post-treatment SHIM score {>=}16). A genome-wide association study was performed using approximately 909,000 SNPs genotyped on Affymetrix 6.0 arrays (Affymetrix, Santa Clara, CA). Results: We identified SNP rs2268363, located in the follicle-stimulating hormone receptor (FSHR) gene, as significantly associated with ED after correcting for multiple comparisons (unadjusted p = 5.46 x 10{sup -8}, Bonferroni p = 0.028). We identified four additional SNPs that tended toward a significant association with an unadjusted p value < 10{sup -6}. Inference of population substructure showed that cases had a higher proportion of African ancestry than control subjects (77% vs. 60%, p = 0.005). A multivariate logistic regression model that incorporated estimated ancestry and four of the top-ranked SNPs was a more accurate classifier of ED than a model that included only clinical variables. Conclusions: To our knowledge, this is the first genome-wide association study to identify SNPs associated with adverse effects resulting from radiotherapy. It is important to note that the SNP that proved to be significantly associated with ED is located within a gene whose encoded product plays a role in male gonad development and function. Another key finding of this project is that the four SNPs most strongly associated with ED were specific to persons of African ancestry and would therefore not have been identified had a cohort of European ancestry been screened. This study demonstrates the feasibility of a genome-wide approach to investigate genetic predisposition to radiation injury.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Epidermal Growth Factor Receptor Expression Modulates Antitumor Efficacy of Vandetanib or Cediranib Combined With Radiotherapy in Human Glioblastoma Xenografts

Purpose: The purpose of this study was to determine the ability of radiation therapy (RT) combined with the tyrosine kinase inhibitors (TKI) vandetanib (antiepidermal growth factor receptor [EGFR] plus antivascular endothelial growth factor receptor [anti-VEGFR]) and cediranib (anti-VEGFR) to inhibit glioblastoma multiforme (GBM) growth. A secondary aim was to investigate how this regimen is modulated by tumor EGFR expression. Methods and Materials: Radiosensitivity was assessed by clonogenic cell survival assay. VEGF secretion was quantified by enzyme-linked immunosorbent assay. GBM (U87MG wild-type EGFR [wtEGFR] and U87MG EGFR-null) xenografts were treated with vandetanib, cediranib, and RT, alone or in combinations. Excised tumor sections were stained for proliferative and survival biomarkers. Results: In vitro, U87MG wtEGFR and U87 EGFR-null cells had similar growth kinetics. Neither TKI affected clonogenic cell survival following RT. However, in vivo, exogenous overexpression of wtEGFR decreased tumor doubling time (T2x) in U87MG xenografts (2.70 vs. 4.41 days for U87MG wtEGFR vs. U87MG vector, respectively). In U87MG EGFR-null cells, TKI combined with radiation was no better than radiation therapy alone. In U87MG wtEGFR, RT in combination with vandetanib (but not with cediranib) significantly increased tumor T2x compared with RT alone (T2x, 10.4 days vs. 4.8 days; p < 0.001). In vivo, growth delay correlated with suppression of pAkt, survivin, and Ki67 expression in tumor samples. The presence of EGFR augmented RT-stimulated VEGF release; this effect was inhibited by vandetanib. Conclusions: EGFR expression promoted tumor growth in vivo but not in vitro, suggesting a microenvironmental effect. GBM xenografts expressing EGFR exhibited greater sensitivity to both cediranib and vandetanib than EGFR-null tumors. Hence EGFR status plays a major role in determining a tumor's in vivo response to radiation combined with TKI, supporting a 'personalized' approach to GBM management.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Assessment of Tumor Radioresponsiveness and Metastatic Potential by Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Purpose: It has been suggested that gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may provide clinically useful biomarkers for personalized cancer treatment. In this preclinical study, we investigated the potential of DCE-MRI as a noninvasive method for assessing the radioresponsiveness and metastatic potential of tumors. Methods and Materials: R-18 melanoma xenografts growing in BALB/c nu/nu mice were used as experimental tumor models. Fifty tumors were subjected to DCE-MRI, and parametric images of K{sup trans} (the volume transfer constant of Gd-DTPA) and v{sub e} (the fractional distribution volume of Gd-DTPA) were produced by pharmacokinetic analysis of the DCE-MRI series. The tumors were irradiated after the DCE-MRI, either with a single dose of 10 Gy for detection of radiobiological hypoxia (30 tumors) or with five fractions of 4 Gy in 48 h for assessment of radioresponsiveness (20 tumors). The host mice were then euthanized and examined for lymph node metastases, and the primary tumors were resected for measurement of cell survival in vitro. Results: Tumors with hypoxic cells showed significantly lower K{sup trans} values than tumors without significant hypoxia (p < 0.0001, n = 30), and K{sup trans} decreased with increasing cell surviving fraction for tumors given fractionated radiation treatment (p < 0.0001, n = 20). Tumors in metastasis-positive mice had significantly lower K{sup trans} values than tumors in metastasis-negative mice (p < 0.0001, n = 50). Significant correlations between v{sub e} and tumor hypoxia, radioresponsiveness, or metastatic potential could not be detected. Conclusions: R-18 tumors with low K{sup trans} values are likely to be resistant to radiation treatment and have a high probability of developing lymph node metastases. The general validity of these observations should be investigated further by studying preclinical tumor models with biological properties different from those of the R-18 tumors.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Molecular Profiling to Optimize Treatment in Non-Small Cell Lung Cancer: A Review of Potential Molecular Targets for Radiation Therapy by the Translational Research Program of the Radiation Therapy Oncology Group

Therapeutic decisions in non-small cell lung cancer (NSCLC) have been mainly based on disease stage, performance status, and co-morbidities, and rarely on histological or molecular classification. Rather than applying broad treatments to unselected patients that may result in survival increase of only weeks to months, research efforts should be, and are being, focused on identifying predictive markers for molecularly targeted therapy and determining genomic signatures that predict survival and response to specific therapies. The availability of such targeted biologics requires their use to be matched to tumors of corresponding molecular vulnerability for maximum efficacy. Molecular markers such as epidermal growth factor receptor (EGFR), K-ras, vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), and anaplastic lymphoma kinase (ALK) represent potential parameters guide treatment decisions. Ultimately, identifying patients who will respond to specific therapies will allow optimal efficacy with minimal toxicity, which will result in more judicious and effective application of expensive targeted therapy as the new paradigm of personalized medicine develops.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

How Radiation Oncologists Would Disclose Errors: Results of a Survey of Radiation Oncologists and Trainees

Purpose: To analyze error disclosure attitudes of radiation oncologists and to correlate error disclosure beliefs with survey-assessed disclosure behavior. Methods and Materials: With institutional review board exemption, an anonymous online survey was devised. An email invitation was sent to radiation oncologists (American Society for Radiation Oncology [ASTRO] gold medal winners, program directors and chair persons of academic institutions, and former ASTRO lecturers) and residents. A disclosure score was calculated based on the number or full, partial, or no disclosure responses chosen to the vignette-based questions, and correlation was attempted with attitudes toward error disclosure. Results: The survey received 176 responses: 94.8% of respondents considered themselves more likely to disclose in the setting of a serious medical error; 72.7% of respondents did not feel it mattered who was responsible for the error in deciding to disclose, and 3.9% felt more likely to disclose if someone else was responsible; 38.0% of respondents felt that disclosure increased the likelihood of a lawsuit, and 32.4% felt disclosure decreased the likelihood of lawsuit; 71.6% of respondents felt near misses should not be disclosed; 51.7% thought that minor errors should not be disclosed; 64.7% viewed disclosure as an opportunity for forgiveness from the patient; and 44.6% considered the patient's level of confidence in them to be a factor in disclosure. For a scenario that could be considerable, a non-harmful error, 78.9% of respondents would not contact the family. Respondents with high disclosure scores were more likely to feel that disclosure was an opportunity for forgiveness (P=.003) and to have never seen major medical errors (P=.004). Conclusions: The surveyed radiation oncologists chose to respond with full disclosure at a high rate, although ideal disclosure practices were not uniformly adhered to beyond the initial decision to disclose the occurrence of the error.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Potential of Hybrid Computational Phantoms for Retrospective Heart Dosimetry After Breast Radiation Therapy: A Feasibility Study

Purpose: Current retrospective cardiovascular dosimetry studies are based on a representative patient or simple mathematic phantoms. Here, a process of patient modeling was developed to personalize the anatomy of the thorax and to include a heart model with coronary arteries. Methods and Materials: The patient models were hybrid computational phantoms (HCPs) with an inserted detailed heart model. A computed tomography (CT) acquisition (pseudo-CT) was derived from HCP and imported into a treatment planning system where treatment conditions were reproduced. Six current patients were selected: 3 were modeled from their CT images (A patients) and the others were modelled from 2 orthogonal radiographs (B patients). The method performance and limitation were investigated by quantitative comparison between the initial CT and the pseudo-CT, namely, the morphology and the dose calculation were compared. For the B patients, a comparison with 2 kinds of representative patients was also conducted. Finally, dose assessment was focused on the whole coronary artery tree and the left anterior descending coronary. Results: When 3-dimensional anatomic information was available, the dose calculations performed on the initial CT and the pseudo-CT were in good agreement. For the B patients, comparison of doses derived from HCP and representative patients showed that the HCP doses were either better or equivalent. In the left breast radiation therapy context and for the studied cases, coronary mean doses were at least 5-fold higher than heart mean doses. Conclusions: For retrospective dose studies, it is suggested that HCP offers a better surrogate, in terms of dose accuracy, than representative patients. The use of a detailed heart model eliminates the problem of identifying the coronaries on the patient's CT.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Statistical Modeling of the Eye for Multimodal Treatment Planning for External Beam Radiation Therapy of Intraocular Tumors

Purpose: Ocular anatomy and radiation-associated toxicities provide unique challenges for external beam radiation therapy. For treatment planning, precise modeling of organs at risk and tumor volume are crucial. Development of a precise eye model and automatic adaptation of this model to patients' anatomy remain problematic because of organ shape variability. This work introduces the application of a 3-dimensional (3D) statistical shape model as a novel method for precise eye modeling for external beam radiation therapy of intraocular tumors. Methods and Materials: Manual and automatic segmentations were compared for 17 patients, based on head computed tomography (CT) volume scans. A 3D statistical shape model of the cornea, lens, and sclera as well as of the optic disc position was developed. Furthermore, an active shape model was built to enable automatic fitting of the eye model to CT slice stacks. Cross-validation was performed based on leave-one-out tests for all training shapes by measuring dice coefficients and mean segmentation errors between automatic segmentation and manual segmentation by an expert. Results: Cross-validation revealed a dice similarity of 95% {+-} 2% for the sclera and cornea and 91% {+-} 2% for the lens. Overall, mean segmentation error was found to be 0.3 {+-} 0.1 mm. Average segmentation time was 14 {+-} 2 s on a standard personal computer. Conclusions: Our results show that the solution presented outperforms state-of-the-art methods in terms of accuracy, reliability, and robustness. Moreover, the eye model shape as well as its variability is learned from a training set rather than by making shape assumptions (eg, as with the spherical or elliptical model). Therefore, the model appears to be capable of modeling nonspherically and nonelliptically shaped eyes.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Risk of Salivary Gland Cancer After Childhood Cancer: A Report From the Childhood Cancer Survivor Study

Purpose: To evaluate effects of radiation therapy, chemotherapy, cigarette smoking, and alcohol consumption on the risk of second primary salivary gland cancer (SGC) in the Childhood Cancer Survivor Study (CCSS). Methods and Materials: Standardized incidence ratios (SIR) and excess absolute risks (EAR) of SGC in the CCSS were calculated using incidence rates from Surveillance, Epidemiology, and End Results population-based cancer registries. Radiation dose to the salivary glands was estimated based on medical records. Poisson regression was used to assess risks with respect to radiation dose, chemotherapy, smoking, and alcohol consumption. Results: During the time period of the study, 23 cases of SGC were diagnosed among 14,135 childhood cancer survivors. The mean age at diagnosis of the first primary cancer was 8.3 years, and the mean age at SGC diagnosis was 24.8 years. The incidence of SGC was 39-fold higher in the cohort than in the general population (SIR = 39.4; 95% CI = 25.4-57.8). The EAR was 9.8 per 100,000 person-years. Risk increased linearly with radiation dose (excess relative risk = 0.36/Gy; 95% CI = 0.06-2.5) and remained elevated after 20 years. There was no significant trend of increasing risk with increasing dose of chemotherapeutic agents, pack-years of cigarette smoking, or alcohol intake. Conclusion: Although the cumulative incidence of SGC was low, childhood cancer survivors treated with radiation experienced significantly increased risk for at least 2 decades after exposure, and risk was positively associated with radiation dose. Results underscore the importance of long-term follow up of childhood cancer survivors for the development of new malignancies.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Radiation, Atherosclerotic Risk Factors, and Stroke Risk in Survivors of Pediatric Cancer: A Report From the Childhood Cancer Survivor Study

Purpose: To test the hypotheses that (1) the increased risk of stroke conferred by childhood cranial radiation therapy (CRT) persists into adulthood; and (2) atherosclerotic risk factors further increase the stroke risk in cancer survivors. Methods and Materials: The Childhood Cancer Survivor Study is a multi-institutional retrospective cohort study of 14,358 5-year survivors of childhood cancer and 4023 randomly selected sibling controls with longitudinal follow-up. Age-adjusted incidence rates of self-reported late-occurring (≥5 years after diagnosis) first stroke were calculated. Multivariable Cox proportional hazards models were used to identify independent stroke predictors. Results: During a mean follow-up of 23.3 years, 292 survivors reported a late-occurring stroke. The age-adjusted stroke rate per 100,000 person-years was 77 (95% confidence interval [CI] 62-96), compared with 9.3 (95% CI 4-23) for siblings. Treatment with CRT increased stroke risk in a dose-dependent manner: hazard ratio 5.9 (95% CI 3.5-9.9) for 30-49 Gy CRT and 11.0 (7.4-17.0) for 50+ Gy CRT. The cumulative stroke incidence in survivors treated with 50+ Gy CRT was 1.1% (95% CI 0.4-1.8%) at 10 years after diagnosis and 12% (95% CI 8.9-15.0%) at 30 years. Hypertension increased stroke hazard by 4-fold (95% CI 2.8-5.5) and in black survivors by 16-fold (95% CI 6.9-36.6). Conclusion: Young adult pediatric cancer survivors have an increased stroke risk that is associated with CRT in a dose-dependent manner. Atherosclerotic risk factors enhanced this risk and should be treated aggressively.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Dosimetric and Radiobiological Consequences of Computed Tomography–Guided Adaptive Strategies for Intensity Modulated Radiation Therapy of the Prostate

Purpose: To examine a range of scenarios for image-guided adaptive radiation therapy of prostate cancer, including different schedules for megavoltage CT imaging, patient repositioning, and dose replanning. Methods and Materials: We simulated multifraction dose distributions with deformable registration using 35 sets of megavoltage CT scans of 13 patients. We computed cumulative dose–volume histograms, from which tumor control probabilities and normal tissue complication probabilities (NTCPs) for rectum were calculated. Five-field intensity modulated radiation therapy (IMRT) with 18-MV x-rays was planned to achieve an isocentric dose of 76 Gy to the clinical target volume (CTV). The differences between D{sub 95}, tumor control probability, V{sub 70Gy}, and NTCP for rectum, for accumulated versus planned dose distributions, were compared for different target volume sizes, margins, and adaptive strategies. Results: The CTV D{sub 95} for IMRT treatment plans, averaged over 13 patients, was 75.2 Gy. Using the largest CTV margins (10/7 mm), the D{sub 95} values accumulated over 35 fractions were within 2% of the planned value, regardless of the adaptive strategy used. For tighter margins (5 mm), the average D{sub 95} values dropped to approximately 73.0 Gy even with frequent repositioning, and daily replanning was necessary to correct this deficit. When personalized margins were applied to an adaptive CTV derived from the first 6 treatment fractions using the STAPLE (Simultaneous Truth and Performance Level Estimation) algorithm, target coverage could be maintained using a single replan 1 week into therapy. For all approaches, normal tissue parameters (rectum V{sub 70Gy} and NTCP) remained within acceptable limits. Conclusions: The frequency of adaptive interventions depends on the size of the CTV combined with target margins used during IMRT optimization. The application of adaptive target margins (<5 mm) to an adaptive CTV determined 1 week into therapy minimizes the need for subsequent dose replanning.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

Burnout in United States Academic Chairs of Radiation Oncology Programs

Purpose: The aims of this study were to determine the self-reported prevalence of burnout in chairs of academic radiation oncology departments, to identify factors contributing to burnout, and to compare the prevalence of burnout with that seen in other academic chair groups. Methods and Materials: An anonymous online survey was administered to the membership of the Society of Chairs of Academic Radiation Oncology Programs (SCAROP). Burnout was measured with the Maslach Burnout Inventory-Human Services Survey (MBI-HSS). Results: Questionnaires were returned from 66 of 87 chairs (76% response rate). Seventy-nine percent of respondents reported satisfaction with their current positions. Common major stressors were budget deficits and human resource issues. One-quarter of chairs reported that it was at least moderately likely that they would step down in the next 1 to 2 years; these individuals demonstrated significantly higher emotional exhaustion. Twenty-five percent of respondents met the MBI-HSS criteria for low burnout, 75% for moderate burnout, and none for high burnout. Group MBI-HSS subscale scores demonstrated a pattern of moderate emotional exhaustion, low depersonalization, and moderate personal accomplishment, comparing favorably with other specialties. Conclusions: This is the first study of burnout in radiation oncology chairs with a high response rate and using a validated psychometric tool. Radiation oncology chairs share similar major stressors to other chair groups, but they demonstrate relatively high job satisfaction and lower burnout. Emotional exhaustion may contribute to the anticipated turnover in coming years. Further efforts addressing individual and institutional factors associated with burnout may improve the relationship with work of chairs and other department members.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

Support Vector Machine-Based Prediction of Local Tumor Control After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer

Background: Several prognostic factors for local tumor control probability (TCP) after stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) have been described, but no attempts have been undertaken to explore whether a nonlinear combination of potential factors might synergistically improve the prediction of local control. Methods and Materials: We investigated a support vector machine (SVM) for predicting TCP in a cohort of 399 patients treated at 13 German and Austrian institutions. Among 7 potential input features for the SVM we selected those most important on the basis of forward feature selection, thereby evaluating classifier performance by using 10-fold cross-validation and computing the area under the ROC curve (AUC). The final SVM classifier was built by repeating the feature selection 10 times with different splitting of the data for cross-validation and finally choosing only those features that were selected at least 5 out of 10 times. It was compared with a multivariate logistic model that was built by forward feature selection. Results: Local failure occurred in 12% of patients. Biologically effective dose (BED) at the isocenter (BED{sub ISO}) was the strongest predictor of TCP in the logistic model and also the most frequently selected input feature for the SVM. A bivariate logistic function of BED{sub ISO} and the pulmonary function indicator forced expiratory volume in 1 second (FEV1) yielded the best description of the data but resulted in a significantly smaller AUC than the final SVM classifier with the input features BED{sub ISO}, age, baseline Karnofsky index, and FEV1 (0.696 ± 0.040 vs 0.789 ± 0.001, P<.03). The final SVM resulted in sensitivity and specificity of 67.0% ± 0.5% and 78.7% ± 0.3%, respectively. Conclusions: These results confirm that machine learning techniques like SVMs can be successfully applied to predict treatment outcome after SBRT. Improvements over traditional TCP modeling are expected through a nonlinear combination of multiple features, eventually helping in the task of personalized treatment planning.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

Influence of Double-Strand Break Repair on Radiation Therapy-Induced Acute Skin Reactions in Breast Cancer Patients

Purpose: Curative radiation therapy (RT)-induced toxicity poses strong limitations for efficient RT and worsens the quality of life. The parameter that explains when and to what extent normal tissue toxicity in RT evolves would be of clinical relevance because of its predictive value and may provide an opportunity for personalized treatment approach. Methods and Materials: DNA double-strand breaks and repair were analyzed by microscopic γ-H2AX foci analysis in peripheral lymphocytes from 38 healthy donors and 80 breast cancer patients before RT, a 2 Gy challenge dose of x-ray exposed in vitro. Results: The actual damage (AD) at 0.25, 3, and 6 hours and percentage residual damage (PRD) at 3 and 6 hours were used as parameters to measure cellular radiosensitivity and correlated with RT-induced acute skin reactions in patients stratified as non-overresponders (NOR) (Radiation Therapy Oncology Group [RTOG] grade <2) and overresponders (OR) (RTOG grade ≥2). The results indicated that the basal and induced (at 0.25 and 3 hours) γ-H2AX foci numbers were nonsignificant (P>.05) between healthy control donors and the NOR and OR groups, whereas it was significant between ORs and healthy donors at 6 hours (P<.001). There was a significantly higher PRD in OR versus NOR (P<.05), OR versus healthy donors (P<.001) and NOR versus healthy donors (P<.01), supported further by the trend analysis (r=.2392; P=.0326 at 6 hours). Conclusions: Our findings strongly suggest that the measurement of PRD by performing γ-H2AX foci analysis has the potential to be developed into a clinically useful predictive assay.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

Phase 1 Trial of Bevacizumab With Concurrent Chemoradiation Therapy for Squamous Cell Carcinoma of the Head and Neck With Exploratory Functional Imaging of Tumor Hypoxia, Proliferation, and Perfusion

Purpose: A phase 1 trial was completed to examine the safety and feasibility of combining bevacizumab with radiation and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (HNSCC) treated with curative intent. Additionally, we assessed the capacity of bevacizumab to induce an early tumor response as measured by a series of biological imaging studies. Methods and Materials: All patients received a single induction dose of bevacizumab (15 mg/kg) delivered 3 weeks (±3 days) before the initiation of chemoradiation therapy. After the initial dose of bevacizumab, comprehensive head and neck chemoradiation therapy was delivered with curative intent to 70 Gy in 33 fractions with concurrent weekly cisplatin at 30 mg/m{sup 2} and bevacizumab every 3 weeks (weeks 1, 4, 7) with dose escalation from 5 to 10 to 15 mg/kg. All patients underwent experimental imaging with [{sup 18}F]fluorothymidine positron emission tomography (FLT-PET) (proliferation), [{sup 61}Cu]Cu-diacetyl-bis(N4-methylthiosemicarbazone) PET (Cu-ATSM-PET) (hypoxia), and dynamic contrast-enhanced computed tomography (DCE-CT) (perfusion) at 3 time points: before bevacizumab monotherapy, after bevacizumab monotherapy, and during the combined therapy course. Results: Ten patients were enrolled. All had stage IV HNSCC, all achieved a complete response to treatment, and 9 of 10 remain alive, with a mean survival time of 61.3 months. All patients experienced grade 3 toxicity, but no dose-limiting toxicities or significant bleeding episodes were observed. Significant reductions were noted in tumor proliferation (FLT-PET), tumor hypoxia (Cu-ATSM-PET), and DCE-CT contrast enhancement after bevacizumab monotherapy, with further decreases in FLT-PET and Cu-ATSM-PET during the combined therapy course. Conclusions: The incorporation of bevacizumab into comprehensive chemoradiation therapy regimens for patients with HNSCC appears safe and feasible. Experimental imaging demonstrates measureable changes in tumor proliferation, hypoxia, and perfusion after bevacizumab monotherapy and during chemoradiation therapy. These findings suggest opportunities to preview the clinical outcomes for individual patients and thereby design personalized therapy approaches in future trials.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

Second Malignancies After Adjuvant Radiation Therapy for Early Stage Breast Cancer: Is There Increased Risk With Addition of Regional Radiation to Local Radiation?

Purpose: This study was undertaken to determine whether there was an increased risk of second malignancies (SM), particularly lung cancer, in early stage breast cancer patients treated with the addition of nodal fields to breast and/or chest wall radiation therapy (RT). Materials and Methods: Subjects were stage I/II female breast cancer patients 20 to 79 years of age, diagnosed between 1989 and 2005 and treated with adjuvant RT at our institution. Patients were included if they survived and did not have SM within 3 years of diagnosis. Standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated to compare SM incidence to cancer incidence in the general sex- and age-matched populations. Secondary malignancy risks in patients treated with local RT (LRT) to the breast/chest wall were compared to those in patients treated with locoregional RT (LRRT) to the breast/chest wall and regional nodes, using multivariate regression analysis (MVA) to account for covariates. Results: The cohort included 12,836 patients with a median follow-up of 8.4 years. LRRT was used in 18% of patients. The SIR comparing patients treated with LRT to the general population was 1.29 (CI: 1.21-1.38). No statistically significant increased incidence of in-field malignancies (SIR, 1.04; CI: 0.87-1.23) and lung cancers (SIR, 1.06; CI: 0.88-1.26) was detected. The SIR comparing patients treated with LRRT to the general population was 1.39 (CI: 1.17-1.64). No statistically significant increased incidence of in-field malignancies (SIR, 1.26; CI: 0.77-1.94) and lung cancers (SIR, 1.27; CI: 0.76-1.98) was detected. On MVA comparing LRRT to LRT, the adjusted hazard ratio was 1.20 for in-field malignancies (CI: 0.68-2.16) and 1.26 for lung cancer (CI: 0.67-2.36). The excess attributable risk (EAR) to regional RT was 3.1 per 10,000 person years (CI: −8.7 to 9.9). Conclusions: No statistically significant increased risk of second malignancy was detected after LRRT relative to that for LRT. The upper limit of the EAR was approximately 1% at 10 years.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

A Validated Prediction Model for Overall Survival From Stage III Non-Small Cell Lung Cancer: Toward Survival Prediction for Individual Patients

Purpose: Although patients with stage III non-small cell lung cancer (NSCLC) are homogeneous according to the TNM staging system, they form a heterogeneous group, which is reflected in the survival outcome. The increasing amount of information for an individual patient and the growing number of treatment options facilitate personalized treatment, but they also complicate treatment decision making. Decision support systems (DSS), which provide individualized prognostic information, can overcome this but are currently lacking. A DSS for stage III NSCLC requires the development and integration of multiple models. The current study takes the first step in this process by developing and validating a model that can provide physicians with a survival probability for an individual NSCLC patient. Methods and Materials: Data from 548 patients with stage III NSCLC were available to enable the development of a prediction model, using stratified Cox regression. Variables were selected by using a bootstrap procedure. Performance of the model was expressed as the c statistic, assessed internally and on 2 external data sets (n=174 and n=130). Results: The final multivariate model, stratified for treatment, consisted of age, gender, World Health Organization performance status, overall treatment time, equivalent radiation dose, number of positive lymph node stations, and gross tumor volume. The bootstrapped c statistic was 0.62. The model could identify risk groups in external data sets. Nomograms were constructed to predict an individual patient's survival probability ( (www.predictcancer.org)). The data set can be downloaded at (https://www.cancerdata.org/10.1016/j.ijrobp.2015.02.048). Conclusions: The prediction model for overall survival of patients with stage III NSCLC highlights the importance of combining patient, clinical, and treatment variables. Nomograms were developed and validated. This tool could be used as a first building block for a decision support system.

62 RADIOLOGY AND NUCLEAR MEDICINE↗