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1.  CHOD/BVAM CHEMOTHERAPY AND WHOLE-BRAIN RADIOTHERAPY FOR NEWLY DIAGNOSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA 
Purpose
To assess the efficacy and toxicity of chemotherapy consisting of cyclophosphamide, doxorubicin (Adriamycin), vincristine, and dexamethasone (CHOD) plus bis-chloronitrosourea (BCNU), cytosine arabinoside, and methotrexate (BVAM) followed by whole-brain irradiation (WBRT) for patients with primary central nervous system lymphoma (PCNSL).
Methods and Materials
Patients 70 years old and younger with newly diagnosed, biopsy-proven PCNSL received one cycle of CHOD followed by two cycles of BVAM. Patients then received WBRT, 30.6 Gy, if a complete response was evoked, or 50.4 Gy if the response was less than complete; both doses were given in 1.8-Gy daily fractions. The primary efficacy endpoint was 1-year survival.
Results
Thirty-six patients (19 men, 17 women) enrolled between 1995 and 2000. Median age was 60.5 years (range, 34 to 69 years). Thirty (83%) patients had baseline Eastern Cooperative Oncology Group performance scores of 0 to 1. All 36 patients were eligible for survival and response evaluations. Median time to progression was 12.3 months, and median survival was 18.5 months. The percentages of patients alive at 1, 2, and 3 years were 64%, 36%, and 33%, respectively. The best response was complete response in 10 patients and immediate progression in 7 patients. Ten (28%) patients had at least one grade 3 or higher neurologic toxicity.
Conclusions
This regimen did improve the survival of PCNSL patients but also caused substantial toxicity. The improvement in survival is less than that reported with high-dose methotrexate-based therapies.
doi:10.1016/j.ijrobp.2010.06.002
PMCID: PMC4335722  PMID: 20800387
Primary central nervous system lymphoma; Chemotherapy; Whole-brain radiotherapy
2.  Phase II Trial of Radiosurgery to Magnetic Resonance Spectroscopy–Defined High-Risk Tumor Volumes in Patients With Glioblastoma Multiforme 
Purpose
To determine the efficacy of a Gamma Knife stereotactic radiosurgery (SRS) boost to areas of high risk determined by magnetic resonance spectroscopy (MRS) functional imaging in addition to standard radiotherapy for patients with glioblastoma (GBM).
Methods and Materials
Thirty-five patients in this prospective Phase II trial underwent surgical resection or biopsy for a GBM followed by SRS directed toward areas of MRS-determined high biological activity within 2 cm of the postoperative enhancing surgical bed. The MRS regions were determined by identifying those voxels within the postoperative T2 magnetic resonance imaging volume that contained an elevated choline/N-acetylaspartate ratio in excess of 2:1. These voxels were marked, digitally fused with the SRS planning magnetic resonance image, targeted with an 8-mm isocenter per voxel, and treated using Radiation Therapy Oncology Group SRS dose guidelines. All patients then received conformal radiotherapy to a total dose of 60 Gy in 2-Gy daily fractions. The primary endpoint was overall survival.
Results
The median survival for the entire cohort was 15.8 months. With 75% of recursive partitioning analysis (RPA) Class 3 patients still alive 18 months after treatment, the median survival for RPA Class 3 has not yet been reached. The median survivals for RPA Class 4, 5, and 6 patients were 18.7, 12.5, and 3.9 months, respectively, compared with Radiation Therapy Oncology Group radiotherapy-alone historical control survivals of 11.1, 8.9, and 4.6 months. For the 16 of 35 patients who received concurrent temozolomide in addition to protocol radiotherapeutic treatment, the median survival was 20.8 months, compared with European Organization for Research and Treatment of Cancer historical controls of 14.6 months using radiotherapy and temozolomide. Grade 3/4 toxicities possibly attributable to treatment were 11%.
Conclusions
This represents the first prospective trial using selective MRS-targeted functional SRS combined with radiotherapy for patients with GBM. This treatment is feasible, with acceptable toxicity and patient survivals higher than in historical controls. This study can form the basis for a multicenter, randomized trial.
doi:10.1016/j.ijrobp.2012.01.020
PMCID: PMC4334318  PMID: 22445005
Radiosurgery; Glioblastoma; Gamma Knife; Magnetic resonance spectroscopy; Functional imaging; Prospective Phase II
3.  Is Diaphragm Motion a Good Surrogate for Liver Tumor Motion? 
Purpose
To evaluate the relationship between liver tumor motion and diaphragm motion.
Methods and Materials
Fourteen patients with hepatocellular carcinoma (10 of 14) or liver metastases (4 of 14) undergoing radiation therapy were included in this study. All patients underwent single-slice cine–magnetic resonance imaging simulations across the center of the tumor in 3 orthogonal planes. Tumor and diaphragm motion trajectories in the superior–inferior (SI), anterior–posterior (AP), and medial–lateral (ML) directions were obtained using an in-house-developed normalized cross-correlation–based tracking technique. Agreement between the tumor and diaphragm motion was assessed by calculating phase difference percentage, intraclass correlation coefficient, and Bland-Altman analysis (Diff). The distance between the tumor and tracked diaphragm area was analyzed to understand its impact on the correlation between the 2 motions.
Results
Of all patients, the mean (±standard deviation) phase difference percentage values were 7.1% ± 1.1%, 4.5% ± 0.5%, and 17.5% ± 4.5% in the SI, AP, and ML directions, respectively. The mean intraclass correlation coefficient values were 0.98 ± 0.02, 0.97 ± 0.02, and 0.08 ± 0.06 in the SI, AP, and ML directions, respectively. The mean Diff values were 2.8 ± 1.4 mm, 2.4 ± 1.1 mm, and 2.2 ± 0.5 mm in the SI, AP, and ML directions, respectively. Tumor and diaphragm motions had high concordance when the distance between the tumor and tracked diaphragm area was small.
Conclusions
This study showed that liver tumor motion had good correlation with diaphragm motion in the SI and AP directions, indicating diaphragm motion in the SI and AP directions could potentially be used as a reliable surrogate for liver tumor motion.
doi:10.1016/j.ijrobp.2014.07.028
PMCID: PMC4334361  PMID: 25223297
4.  Patterns of Care Among Patients Receiving Radiation Therapy for Bone Metastases at a Large Academic Institution 
Purpose
This study evaluates outcomes and patterns of care among patients receiving radiation therapy (RT) for bone metastases at a high-volume academic institution.
Methods and Materials
Records of all patients whose final RT course was for bone metastases from April 2007 to July 2012 were identified from electronic medical records. Chart review yielded demographic and clinical data. Rates of complicated versus uncomplicated bone metastases were not analyzed.
Results
We identified 339 patients whose final RT course was for bone metastases. Of these, 52.2% were male; median age was 65 years old. The most common primary was non-small-cell lung cancer (29%). Most patients (83%) were prescribed ≤10 fractions; 8% received single-fraction RT. Most patients (52%) had a documented goals of care (GOC) discussion with their radiation oncologist; hospice referral rates were higher when patients had such discussions (66% with vs 50% without GOC discussion, P=.004). Median life expectancy after RT was 96 days. Median survival after RT was shorter based on inpatient as opposed to outpatient status at the time of consultation (35 vs 136 days, respectively, P<.001). Hospice referrals occurred for 56% of patients, with a median interval between completion of RT and hospice referral of 29 days and a median hospice stay of 22 days.
Conclusions
These data document excellent adherence to American Society for Radiation Oncolology Choosing Wisely recommendation to avoid routinely using >10 fractions of palliative RT for bone metastasis. Nonetheless, single-fraction RT remains relatively uncommon. Participating in GOC discussions with a radiation oncologist is associated with higher rates of hospice referral. Inpatient status at consultation is associated with short survival.
doi:10.1016/j.ijrobp.2014.04.028
PMCID: PMC4332799  PMID: 25035214
5.  POSTMASTECTOMY RADIATION IMPROVES THE OUTCOME OF PATIENTS WITH LOCALLY ADVANCED BREAST CANCER WHO ACHIEVE A PATHOLOGIC COMPLETE RESPONSE TO NEOADJUVANT CHEMOTHERAPY 
Purpose
The aim of this study was to investigate the role of postmastectomy radiation therapy in women with breast cancer who achieved a pathologic complete response (pCR) to neoadjuvant chemotherapy.
Methods and Materials
We retrospectively identified 226 patients treated at our institution who achieved a pCR at surgery after receiving neoadjuvant chemotherapy. Of these, the 106 patients without inflammatory breast cancer who were treated with mastectomy were analyzed. The patients’ clinical stages at diagnosis were I in 2%, II in 31%, IIIA in 30%, IIIB in 25%, and IIIC in 11% (American Joint Committee on Cancer 2003 system). Of the patients, 92% received anthracycline-based chemotherapy, and 38% also received a taxane. A total of 72 patients received postmastectomy radiation therapy, and 34 did not. The actuarial rates of local-regional recurrence (LRR) and survival of the two groups were compared using the log-rank test.
Results
The median follow-up of surviving patients was 62 months. Use of radiation therapy did not affect the 10-year rates of LRR for patients with Stage I or II disease (the 10-year LRR rates were 0% for both groups). However, the 10-year LRR rate for patients with Stage III disease was significantly improved with radiation therapy (7.3% ± 3.5% with vs. 33.3% ± 15.7% without; p = 0.040). Within this cohort, use of radiation therapy was also associated with improved disease-specific and overall survival.
Conclusion
Postmastectomy radiation therapy provides a significant clinical benefit for breast cancer patients who present with clinical Stage III disease and achieve a pCR after neoadjuvant chemothearpy.
doi:10.1016/j.ijrobp.2007.01.023
PMCID: PMC4329732  PMID: 17418973
Neoadjuvant chemotherapy; Pathologic complete response; pCR; Breast cancer; Postmastectomy radiation
6.  TREATMENT OPTIMIZATION USING COMPUTED TOMOGRAPHY-DELINEATED TARGETS SHOULD BE USED FOR SUPRACLAVICULAR IRRADIATION FOR BREAST CANCER 
Background
The purpose of this study was to determine whether the use of optimized CT treatment planning offered better coverage of axillary level III (LIII)/supraclavicular (SC) targets than the empirically derived dose prescription that are commonly used.
Materials/Methods
Thirty-two consecutive breast cancer patients who underwent CT treatment planning of a SC field were evaluated. Each patient was categorized according to body mass index (BMI) classes: normal, overweight, or obese. The SC and LIII nodal beds were contoured, and four treatment plans for each patient were generated. Three of the plans used empiric dose prescriptions, and these were compared with a CT-optimized plan. Each plan was evaluated by two criteria: whether 98% of target volume receive >90% of prescribed dose and whether < 5% of the irradiated volume received 105% of prescribed dose.
Results
The mean depth of SC and LIII were 3.2 cm (range, 1.4–6.7 cm) and 3.1 (range, 1.7–5.8 cm). The depth of these targets varied according across BMI classes (p = 0.01). Among the four sets of plans, the CT-optimized plans were the most successful at achieving both of the dosimetry objectives for every BMI class (normal BMI, p = .003; overweight BMI, p < .0001; obese BMI, p < .001).
Conclusions
Across all BMI classes, routine radiation prescriptions did not optimally cover intended targets for every patient. Optimized CT-based treatment planning generated the most successful plans; therefore, we recommend the use of routine CT simulation and treatment planning of SC fields in breast cancer.
doi:10.1016/j.ijrobp.2007.05.075
PMCID: PMC4329762  PMID: 17889264
Supraclavicular; Axillary; Lymph node; Treatment planning; Computed tomography
7.  EFFECT OF POSTMASTECTOMY RADIOTHERAPY IN PATIENTS <35 YEARS OLD WITH STAGE II–III BREAST CANCER TREATED WITH DOXORUBICIN-BASED NEOADJUVANT CHEMOTHERAPY AND MASTECTOMY 
Purpose
Postmastectomy radiotherapy (PMRT) improves locoregional control (LRC) in patients with high-risk features after mastectomy. Young age continues to evolve as a potentially important risk factor. The objective of this study was to assess the benefits of PMRT in patients <35 years old treated with doxorubicin-based neoadjuvant chemotherapy for Stage II–III breast cancer.
Patients and Methods
We retrospectively analyzed 107 consecutive breast cancer patients <35 years old with Stage IIA–IIIC disease treated at our institution with doxorubicin-based neoadjuvant chemotherapy and mastectomy, with or without PMRT. The treatment groups were compared in terms of LRC and overall survival.
Results
Despite more advanced disease stages, the patients who received PMRT (n = 80) had greater rates of LRC (5-year rate, 88% vs. 63%, p = 0.001) and better overall survival (5-year rate, 67% vs. 48%, p = 0.03) than patients who did not receive PMRT (n = 27).
Conclusion
Among breast cancer patients <35 years old at diagnosis, the use of PMRT after doxorubicin-based neoadjuvant chemotherapy and mastectomy led to a statistically greater rate of LRC and overall survival compared with patients without PMRT. The benefit seen for PMRT in young patients provides valuable data to better tailor adjuvant, age-specific treatment decisions after mastectomy.
doi:10.1016/j.ijrobp.2007.05.029
PMCID: PMC4329785  PMID: 17855016
Radiation therapy; mastectomy; young age; neoadjuvant chemotherapy
8.  Phase 2 Study of Erlotinib Combined With Adjuvant Chemoradiation and Chemotherapy in Patients With Resectable Pancreatic Cancer 
Purpose
Long-term survival rates for patients with resected pancreatic ductal adenocarcinoma (PDAC) have stagnated at 20% for more than a decade, demonstrating the need to develop novel adjuvant therapies. Gemcitabine-erlotinib therapy has demonstrated a survival benefit for patients with metastatic PDAC. Here we report the first phase 2 study of erlotinib in combination with adjuvant chemoradiation and chemotherapy for resected PDAC.
Methods and Materials
Forty-eight patients with resected PDAC received adjuvant erlotinib (100 mg daily) and capecitabine (800 mg/m2 twice daily Monday-Friday) concurrently with intensity modulated radiation therapy (IMRT), 50.4 Gy over 28 fractions followed by 4 cycles of gemcitabine (1000 mg/m2 on days 1, 8, and 15 every 28 days) and erlotinib (100 mg daily). The primary endpoint was recurrence-free survival (RFS).
Results
The median follow-up time was 18.2 months (interquartile range, 13.8–27.1). Lymph nodes were positive in 85% of patients, and margins were positive in 17%. The median RFS was 15.6 months (95% confidence interval [CI], 13.4–17.9), and the median overall survival (OS) was 24.4 months (95% CI, 18.9–29.7). Multivariate analysis with adjustment for known prognostic factors showed that tumor diameter >3 cm was predictive for inferior RFS (hazard ratio, 4.01; P = .001) and OS (HR, 4.98; P = .02), and the development of dermatitis was associated with improved RFS (HR, 0.27; P = .009). During CRT and post-CRT chemotherapy, the rates of grade 3/4 toxicity were 31%/2% and 35%/8%, respectively.
Conclusion
Erlotinib can be safely administered with adjuvant IMRT-based CRT and chemotherapy. The efficacy of this regimen appears comparable to that of existing adjuvant regimens. Radiation Therapy Oncology Group 0848 will ultimately determine whether erlotinib produces a survival benefit in patients with resected pancreatic cancer.
doi:10.1016/j.ijrobp.2013.03.032
PMCID: PMC4322929  PMID: 23773391
9.  [No title available] 
PMCID: PMC3893711  PMID: 24411596
10.  [No title available] 
PMCID: PMC3905315  PMID: 24315566
11.  [No title available] 
PMCID: PMC3931463  PMID: 24411612
12.  [No title available] 
PMCID: PMC3947195  PMID: 24268788
13.  Dose Escalation of Total Marrow Irradiation with Concurrent Chemotherapy in Patients with Advanced Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation 
Purpose
We have demonstrated that toxicities are acceptable with total marrow irradiation (TMI) 16 Gy without chemotherapy or TMI 12 Gy and the reduced intensity regimen of fludarabine/melphalan in patients undergoing hematopoietic cell transplantation (HCT). This study reports on TMI combined with higher intensity chemotherapy regimens on two phase I trials in patients with advanced AML/ALL who would do poorly on standard intent-to-cure HCT regimens.
Methods
Trial 1: TMI on days -10 to -6, VP16 day -5 (60 mg/kg), and cyclophoshamide (CY) day -3 (100 mg/kg). TMI dose (Gy) was 12 (n=3), 13.5 (n=3) and 15 (n=6) at 1.5 Gy BID. Trial 2: Busulfan (BU) days -12 to -8 (800 uM min), TMI days -8 to -4, and VP16 day -3 (30 mg/kg). TMI dose (Gy) was 12 (n=18) and 13.5 (n=2) at 1.5 Gy BID.
Results
Trial 1: 12 patients; median age 33; 6 induction failure (IF), 6 first relapse (1RL); 9 with marrow blasts (10–98%), 5 with circulating blasts (24–85%) and 2 with chloromas. No dose limiting toxicities were observed. Eleven achieved CR at day 30. With a median follow-up 14.75 months, 5 remain in complete remission from 13.5–37.7 months. Trial 2: 20 patients; median age 41; 13 IF, 5 1RL, 2 in 2nd relapse; 19 with marrow blasts (3–100%) and 13 with peripheral blasts (6–63%). Grade 4 dose limiting toxicities were seen at 13.5 Gy (stomatitis and hepatotoxicity). Stomatitis was the most frequent toxicity in both trials.
Conclusions
TMI dose escalation to 15 Gy is possible when combined with CY/VP16 and is associated with acceptable toxicities and encouraging outcomes. TMI dose escalation is not possible with BU/VP16 due to dose-limiting toxicities. Future efforts will focus on whether further dose escalation with CY/VP16 is safe with the goal of improving disease control in this high risk population.
doi:10.1016/j.ijrobp.2012.03.033
PMCID: PMC4312108  PMID: 22592050
total marrow irradiation; bone marrow transplantation; total body irradiation; tomotherapy; acute leukemia
14.  Standardizing Naming Conventions in Radiation Oncology 
Purpose
The aim here is to report on the development of a standardized target and organ at risk naming convention for use in Radiation Therapy and to present the nomenclature for structure naming for inter-institutional data sharing, clinical trial repositories, integrated multi-institutional collaborative databases and quality control centers. This taxonomy should also enable improved plan benchmarking between clinical institutions and vendors and facilitation of automated treatment plan quality control.
Materials and Methods
The Advanced Technology Consortium (ATC), Washington University in St.Louis, Radiation Therapy Oncology Group (RTOG), Dutch Radiation Oncology Society (NVRO) and the Clinical Trials RT QA Harmonization Group collaborated in creating this new naming convention. The ICRU guidelines have been used to create standardized nomenclature for target volumes (CTV, ITV, PTV etc.), organs at risk (OAR), and planning organ at risk volumes (PRVs) in radiation therapy. The nomenclature also includes rules for specifying laterality and margins for various structures. The naming rules distinguish tumor and nodal PTVs, with correspondence to their respective tumor/nodal CTVs. It also provides rules for basic structure naming, as well as an option for more detailed names. Names of non-standard structures used mainly for plan optimization or evaluation (rings, islands of dose avoidance, islands where additional dose is needed (dose painting)) are identified separately.
Results
In addition to its use in 16 ongoing RTOG advanced technology clinical trial protocols and several new EORTC protocols, a pilot version of this naming convention has been evaluated using patient data sets with varying treatment sites. All structures in these data sets were satisfactorily identified using this nomenclature.
Conclusions
Use of standardized naming conventions is important to facilitate comparison of dosimetry across patient datasets. The guidelines presented here will facilitate international acceptance across a wide range of efforts, including groups organizing clinical trials, ROI, NVRO, IHE-RO, and DICOM.
doi:10.1016/j.ijrobp.2011.09.054
PMCID: PMC4306340  PMID: 22245204
Standardizing; Naming conventions; Structures; Target Volumes
15.  ADENOVIRAL E2F1 OVEREXPRESSION SENSITIZES LNCAP AND PC3 PROSTATE TUMOR CELLS TO RADIATION IN VIVO 
Purpose
We previously showed that E2F1 overexpression radiosensitizes prostate cancer cells in-vitro. Here, we demonstrate the radiosensitization efficacy of Ad-E2F1 in growing LNCaP (orthotopically) and PC3 (subcutaneously) nude mice xenograft tumors.
Methods and Materials
Adenoviral E2F1 was injected intra-tumorally in LNCaP (3×108 PFU) and PC3 (5×108 PFU) tumors treated with or without radiation. Tumor volumes (TV) were measured by MRI in LNCaP tumors, calipers in PC3 tumors and serum PSA levels by ELISA in LNCaP tumors. Apoptosis was measured by TUNEL staining and key proteins involved in cell death signaling were analyzed by Western blot.
Results
Intracellular overexpression of Ad-E2F1 had significant effect in the regression of TV and reducing the PSA relative to adenoviral luciferase (Ad-Luc) control. The in-vivo regressing effect of Ad-E2F1 on LNCaP tumor growth was significant (PSA-34 ng/ml/TV-142 mm3) compared to Ad-Luc control (PSA-59 ng/ml/TV-218 mm3; p<0.05). This effect was significantly enhanced by radiation therapy (PSA-16 ng/ml/TV-55 mm3 compared to Ad-Luc/PSA-42 ng/ml/TV-174 mm3; p<0.05). For PC3 tumors, the greatest effect was observed with Ad-E2F1 alone, there was little or no effect when RT was combined. However, addition of RT enhanced the level of in-situ apoptosis in PC3 tumors. Molecularly, Ad-E2F1 in a combination setting abrogated radiation induced BCL-2 protein and was associated with an increase in activated BAX, together caused a potent radiosensitizing effect irrespective of p53 and AR functional status.
Conclusions
We show here for the first time that ectopic overexpression of E2F1 in-vivo using an adenoviral vector significantly inhibits orthotopic p53wild-type LNCaP and subcutaneous p53null PC3 tumors in nude mice. Furthermore, we demonstrate that E2F1 strongly sensitizes LNCaP tumors to RT. These findings suggest that E2F1 overexpression can sensitize prostate tumor cells in-vivo independent of p53 or androgen receptor status.
doi:10.1016/j.ijrobp.2010.08.013
PMCID: PMC4299462  PMID: 21195876
Ad-E2F1; Prostate cancer; Radiation; LNCaP; PC3
16.  [No title available] 
PMCID: PMC4292925  PMID: 25304799
17.  The association between RT-induced changes in lung tissue density and global lung function 
Purpose
To assess the association between RT-induced changes in computed tomography (CT)-defined lung tissue density and pulmonary function tests (PFTs).
Methods and Materials
Patients receiving incidental partial lung irradiation were prospectively assessed for global (PFTs) and regional (CT and SPECT [single photon emission computed tomography] scans) lung function pre- and serially post-RT. The percent reductions in PFTs and the average changes in lung density were compared (Pearson correlations) in the overall group and subgroups based on various clinical factors. Comparisons were also made between the CT- and SPECT-based computations using U test.
Results
From 1991–2004, 343 patients were enrolled. Of these, 111 patients had a total of 203 concurrent post-RT evaluations of changes in lung density and PFTs available for analyses, and 81 patients had a total of 141 concurrent post-RT SPECT images as well. The average increases in lung density were related to the percent reductions in PFTs, albeit with modest correlation coefficients (r) (range, 0.20 ~ 0.43). The analyses also indicate that the association between lung density and PFT changes is essentially equivalent to the corresponding association with SPECT-defined lung perfusion.
Conclusion
There is a weak quantitative association between the degree of increase in lung density as defined by CT and percent reduction in PFTs.
doi:10.1016/j.ijrobp.2008.08.053
PMCID: PMC4287218  PMID: 19084355
Radiation induced lung injury; Lung density; Computed tomography; Pulmonary function tests; Single photon emission computed tomography defined lung perfusion
18.  Interobserver Variability in Target Definition for Hepatocellular Carcinoma With and Without Portal Vein Thrombus: Radiation Therapy Oncology Group Consensus Guidelines 
Purpose
Defining hepatocellular carcinoma (HCC) gross tumor volume (GTV) requires multimodal imaging, acquired in different perfusion phases. The purposes of this study were to evaluate the variability in contouring and to establish guidelines and educational recommendations for reproducible HCC contouring for treatment planning.
Methods and Materials
Anonymous, multiphasic planning computed tomography scans obtained from 3 patients with HCC were identified and distributed to a panel of 11 gastrointestinal radiation oncologists. Panelists were asked the number of HCC cases they treated in the past year. Case 1 had no vascular involvement, case 2 had extensive portal vein involvement, and case 3 had minor branched portal vein involvement. The agreement between the contoured total GTVs (primary + vascular GTV) was assessed using the generalized kappa statistic. Agreement interpretation was evaluated using Landis and Koch’s interpretation of strength of agreement. The S95 contour, defined using the simultaneous truth and performance level estimation (STAPLE) algorithm consensus at the 95% confidence level, was created for each case.
Results
Of the 11 panelists, 3 had treated >25 cases in the past year, 2 had treated 10 to 25 cases, 2 had treated 5 to 10 cases, 2 had treated 1 to 5 cases, 1 had treated 0 cases, and 1 did not respond. Near perfect agreement was seen for case 1, and substantial agreement was seen for cases 2 and 3. For case 2, there was significant heterogeneity in the volume identified as tumor thrombus (range 0.58–40.45 cc). For case 3, 2 panelists did not include the branched portal vein thrombus, and 7 panelists contoured thrombus separately from the primary tumor, also showing significant heterogeneity in volume of tumor thrombus (range 4.52–34.27 cc).
Conclusions
In a group of experts, excellent agreement was seen in contouring total GTV. Heterogeneity exists in the definition of portal vein thrombus that may impact treatment planning, especially if differential dosing is contemplated. Guidelines for HCC GTV contouring are recommended.
doi:10.1016/j.ijrobp.2014.03.041
PMCID: PMC4285340  PMID: 24969794
19.  Modeling Pathologic Response of Esophageal Cancer to Chemoradiotherapy Using Spatial-Temporal 18F-FDG PET Features, Clinical Parameters, and Demographics 
International journal of radiation oncology, biology, physics  2013;88(1):10.1016/j.ijrobp.2013.09.037.
Purpose
To construct predictive models using comprehensive tumor features for the evaluation of tumor response to neoadjuvant chemoradiotherapy (CRT) in patients with esophageal cancer.
Methods and Materials
This study included 20 patients who underwent trimodality therapy (CRT + surgery) and had 18F-FDG PET/CT scans both before and after CRT. Four groups of tumor features were examined: (1) conventional PET/CT response measures (SUVmax, tumor diameter, etc.); (2) clinical parameters (TNM stage, histology, etc.) and demographics; (3) spatial-temporal PET features, which characterize tumor SUV intensity distribution, spatial patterns, geometry, and associated changes resulting from CRT; and (4) all features combined. An optimal feature set was identified with recursive feature selection and cross-validations. Support vector machine (SVM) and logistic regression (LR) models were constructed for prediction of pathologic tumor response to CRT, using cross-validations to avoid model over-fitting. Prediction accuracy was assessed via area under the receiver operating characteristic curve (AUC), and precision was evaluated via confidence intervals (CIs) of AUC.
Results
When applied to the 4 groups of tumor features, the LR model achieved AUCs (95% CI) of 0.57 (0.10), 0.73 (0.07), 0.90 (0.06), and 0.90 (0.06). The SVM model achieved AUCs (95% CI) of 0.56 (0.07), 0.60 (0.06), 0.94 (0.02), and 1.00 (no misclassifications). Using spatial–temporal PET features combined with conventional PET/CT measures and clinical parameters, the SVM model achieved very high accuracy (AUC 1.00) and precision (no misclassifications), significantly better than using conventional PET/CT measures or clinical parameters and demographics alone. For groups with a large number of tumor features (groups 3 and 4), the SVM model achieved significantly higher accuracy than the LR model,
Conclusions
The SVM model using all features including spatial–temporal PET features accurately and precisely predicted pathologic tumor response to CRT in esophageal cancer.
doi:10.1016/j.ijrobp.2013.09.037
PMCID: PMC3875172  PMID: 24189128
20.  Roles of sensory nerves in the regulation of radiation-induced structural and functional changes in the heart 
International journal of radiation oncology, biology, physics  2014;88(1):10.1016/j.ijrobp.2013.10.014.
Purpose
Radiation-induced heart disease (RIHD) is a chronic severe side effect of radiotherapy of intrathoracic and chest wall tumors. The heart contains a dense network of sensory neurons that are not only involved in monitoring of cardiac events such as ischemia/reperfusion, but also play a role in cardiac tissue homeostasis, preconditioning, and repair. The purpose of this study was to examine the role of sensory nerves in RIHD.
Methods and Materials
Male Sprague-Dawley rats were administered capsaicin to permanently ablate sensory nerves, two weeks before local image-guided heart X-ray irradiation with a single dose of 21 Gy. During the 6-months follow up time, heart function was assessed with high resolution echocardiography. At 6 months after irradiation, cardiac structural and molecular changes were examined with histology, immunohistochemistry, and Western-Blots.
Results
Capsaicin-pretreatment blunted the effects of radiation on myocardial fibrosis and mast cell infiltration and activity. On the other hand, capsaicin-pretreatment caused a small but significant reduction in cardiac output at 6 months after irradiation. Capsaicin did not alter the effects of radiation on cardiac macrophage number or indicators of autophagy and apoptosis.
Conclusions
These results suggest that sensory nerves, while playing a predominantly protective role in radiation-induced cardiac function changes, may eventually enhance radiation-induced myocardial fibrosis and mast cell activity.
doi:10.1016/j.ijrobp.2013.10.014
PMCID: PMC3868013  PMID: 24331664
21.  GENDER TRENDS IN RADIATION ONCOLOGY IN THE UNITED STATES: A 30 YEAR ANALYSIS 
International journal of radiation oncology, biology, physics  2013;88(1):10.1016/j.ijrobp.2013.09.025.
Purpose/Objective
Although considerable research exists regarding the role of women in the medical profession in the United States, little work has described the participation of women in academic radiation oncology. We examined women’s participation in authorship of radiation oncology literature, a visible and influential activity that merits specific attention.
Methods and Materials
We examined the gender of first and senior U.S. physician-authors of articles published in the Red Journal in 1980, 1990, 2000, 2004, 2010 and 2012. The significance of trends over time was evaluated using logistic regression. Results were compared to female representation in journals of general medicine and other major medical specialties. Findings were also placed in the context of trends in the representation of women among radiation oncology faculty and residents over the last three decades, using AAMC data.
Results
The proportion of women among Red Journal first authors increased from 13.4% in 1980 to 29.7% in 2012, and the proportion among senior authors increased from 3.2% to 22.6%. The proportion of women among radiation oncology full-time faculty increased from 11% to 26.7% from 1980 to 2012. The proportion of women among radiation oncology residents increased from 27.1% to 33.3% from 1980 to 2010.
Conclusion
Female first and senior authorship in the Red Journal has increased significantly, as has women’s participation among full-time faculty, but women remain under-represented among radiation oncology residents as compared to their representation in the medical student body. Understanding such trends is necessary to develop appropriately targeted interventions to improve gender equity in radiation oncology.
doi:10.1016/j.ijrobp.2013.09.025
PMCID: PMC3880121  PMID: 24189127
gender; radiation oncology; publications; career development; medical profession; medical education
22.  Interfraction Displacement of Primary Tumor and Involved Lymph Nodes Relative to Anatomical Landmarks in Image–guided Radiotherapy of Locally Advanced Lung Cancer 
Purpose
Image-guided radiotherapy for patients with locally advanced lung cancer relies on bony landmarks and carina or - if visible - the primary tumor (PT) for daily patient alignment, neglecting potential variations in the relative position of PT and involved lymph nodes (LN). This study analyzes PT and LN position changes relative to each other and relative to anatomical landmarks during conventionally fractionated radiotherapy.
Methods and Materials
In 12 patients with locally advanced non-small cell lung cancer PT, LN, carina and one thoracic vertebra were manually contoured on weekly 4D fan beam CTs. Systematic and random interfraction displacements of all contoured structures were identified in the three cardinal directions, resulting setup margins were calculated. Time trends and the effect of volume changes on displacements were analyzed.
Results
Three-dimensional displacement vectors and systematic/random interfraction displacements were smaller for carina than vertebra both for PT and LN. For PT, mean 3D displacement vectors with carina-based alignment were 7 mm/SD 4 mm versus 9 mm/SD 5 mm with bony anatomy (p<0.0001). For LN, smaller displacements were found with carina- (5 mm/SD 3 mm, p<0.0001) and vertebra-based (6 mm/SD 3 mm, p=0.002) alignment compared to using PT for setup (8 mm/SD 5 mm). Primary tumor and LN displacements relative to bone and carina were independent (p>0.05). Displacements between PT and bone (p=0.04), and between PT and LN (p=0.01) were significantly correlated with PT volume regression. Displacements between LN and carina were correlated with LN volume change (p=0.03).
Conclusions
Carina-based setup results in a more reproducible PT and LN alignment than bony anatomy setup. Considering the independence of PT and LN displacement and the impact of volume regression on displacements over time, repeated CT imaging even with primary tumorbased alignment is recommended in locally advanced disease.
doi:10.1016/j.ijrobp.2013.09.050
PMCID: PMC3895914  PMID: 24239387
Lung cancer; Mediastinal lymph nodes; Interfraction displacement; Conventional radiotherapy; Image guidance
23.  Standing on the shoulders of giants: Results from the Radiation Oncology Academic Development and Mentorship Assessment Project (ROADMAP) 
Purpose
To analyze survey information regarding mentorship practices and cross-correlate the results with objective metrics of academic productivity among academic radiation oncologists at U.S. ACGME-accredited residency training programs.
Methods and Materials
An IRB-approved survey for the Radiation Oncology Academic Development and Mentorship Assessment Project (ROADMAP) was sent to 1031 radiation oncologists employed at an ACGME-accredited residency training program and administered using Research Electronic Data Capture (REDCap). Data collected included demographics, presence of mentorship as well as the nature of specific mentoring activities. Productivity metrics, including number of publications, number of citations, h-index, and date of first publication were collected for each survey respondent from a commercially available online database (Web of Science, Thompson Reuters- v5.9), and m-index was calculated.
Results
158 academic RO completed the survey, 96 of whom reported having an academic/scientific mentor. Faculty with a mentor had higher numbers of publications, citations, h- and m-indices. Differences in gender and race/ethnicity were not associated with significant differences in mentorship rates, but those with a mentor were more likely to have a Ph.D. and were more likely to have more time protected for research. Bivariate fit regression modeling showed a positive correlation between a mentor’s h-index and their mentee’s h-index (R2=0.16; p<0.001). Linear regression also showed significant correlates of higher h-index, in addition to having a mentor (p=0.001), included a longer career duration (p<0.001), and having fewer patients on treatment (p=0.02).
Conclusions
Mentorship is widely believed to be important to career development and academic productivity. These results emphasize the importance of identifying and striving to overcome potential barriers to effective mentorship.
doi:10.1016/j.ijrobp.2013.09.035
PMCID: PMC4085773  PMID: 24210670
radiation oncology; education; mentorship; publication; productivity
24.  A Prospective Study of the Utility of Magnetic Resonance Imaging in Determining Candidacy for Partial Breast Irradiation 
Purpose
Retrospective data have demonstrated that breast magnetic resonance imaging (MRI) may change a patient's eligibility for partial breast irradiation (PBI) by identifying multicentric, multifocal, or contralateral disease. The objective of the current study was to prospectively determine the frequency with which MRI identifies occult disease and to establish clinical factors associated with a higher likelihood of MRI prompting changes in PBI eligibility.
Methods and Materials
At The University of Chicago, women with breast cancer uniformly undergo MRI in addition to mammography and ultrasonography. From June 2009 through May 2011, all patients were screened prospectively in a multidisciplinary conference for PBI eligibility based on standard imaging, and the impact of MRI on PBI eligibility according to National Surgical Adjuvant Breast and Bowel Project protocol B-39/Radiation Therapy Oncology Group protocol 0413 entry criteria was recorded. Univariable analysis was performed using clinical characteristics in both the prospective cohort and in a separate cohort of retrospectively identified patients. Pooled analysis was used to derive a scoring index predictive of the risk that MRI would identify additional disease.
Results
A total of 521 patients were screened for PBI eligibility, and 124 (23.8%) patients were deemed eligible for PBI based on standard imaging. MRI findings changed PBI eligibility in 12.9% of patients. In the pooled univariable analysis, tumor size ≥2 cm on mammography or ultrasonography (P=.02), age <50 years (P=.01), invasive lobular histology (P=.01), and HER-2/neu amplification (P=.01) were associated with a higher likelihood of MRI changing PBI eligibility. A predictive score was generated by summing the number of significant risk factors. Patients with a score of 0, 1, 2, and 3 had changes to eligibility based on MRI findings in 2.8%, 13.2%, 38.1%, and 100%, respectively (P<.0001).
Conclusions
MRI identified additional disease in a significant number of patients eligible for PBI, based on standard imaging. Clinical characteristics may be useful in directing implementation of MRI in the staging of PBI candidates.
doi:10.1016/j.ijrobp.2012.06.014
PMCID: PMC4280848  PMID: 22836047
25.  Physician Evaluation of Internet Health Information on Proton Therapy for Prostate Cancer 
Purpose
Many patients considering prostate cancer (PCa) treatment options report seeking proton beam therapy (PBT) based in part on information readily available on the Internet. There is, however, potential for considerable variation in Internet health information (IHI). We thus evaluated the characteristics, quality, and accuracy of IHI on PBT for PCa.
Methods and Materials
We undertook a qualitative research study using snowball-purposive sampling in which we evaluated the top 50 Google search results for “proton prostate cancer.” Quality was evaluated on a 5-point scale using the validated 15-question DISCERN instrument. Accuracy was evaluated by comparing IHI with the best available evidence.
Results
Thirty-seven IHI websites were included in the final sample. These websites most frequently were patient information/support resources (46%), were focused exclusively on PBT (51%), and had a commercial affiliation (38%). There was a significant difference in quality according to the type of IHI. Substantial inaccuracies were noted in the study sample compared with best available or contextual evidence.
Conclusions
There are shortcomings in quality and accuracy in consumer-oriented IHI on PBT for PCa. Providers must be prepared to educate patients how to critically evaluate IHI related to PBT for PCa to best inform their treatment decisions.
doi:10.1016/j.ijrobp.2012.10.039
PMCID: PMC4277870  PMID: 23245278

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