Jordan Kharofa

Selective Serotonin Reuptake Inhibitors and Risk of Hemorrhagic Stroke

Background and Purpose— Selective serotonin reuptake inhibitors (SSRI) are widely prescribed. Several reports have observed an increased bleeding risk associated with SSRI use, which is hypothesized to be secondary to their antiplatelet effect. Methods— We tested the hypothesis that SSRIs increase the risk for or potentiate the risk of hemorrhagic stroke associated with antiplatelets and anticoagulants. Results— In multivariate analysis, we found no increased risk associated with SSRI use for intracerebral hemorrhage (odds ratio=1.1, 95% CI: 0.7 to 1.8; P=0.63) or subarachnoid hemorrhage (odds ratio=0.6, 95% CI: 0.4 to 1.0; P=0.054). In addition, potentiation of risk with warfarin or antiplatelets was not observed. Conclusions— Further studies with larger populations would be needed to exclude a small increase in intracranial hemorrhage risk with SSRI use.

Decreased Risk of Radiation Pneumonitis With Incidental Concurrent Use of Angiotensin-Converting Enzyme Inhibitors and Thoracic Radiation Therapy

PURPOSE Angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models. The aim of this study was to evaluate whether ACE inhibitors decrease the risk of radiation pneumonitis in lung cancer patients receiving thoracic irradiation. METHODS AND MATERIALS Patients with Stage I through III small-cell and non-small-cell lung cancer treated definitively with radiation from 2004-2009 at the Clement J. Zablocki Veterans Affairs Medical Center were retrospectively reviewed. Acute pulmonary toxicity was quantified within 6 months of completion of treatment according to the Common Terminology Criteria for Adverse Events version 4. The use of ACE inhibitors, nonsteroidal anti-inflammatory drugs, inhaled glucocorticosteroids, statins, and angiotensin receptor blockers; dose-volume histogram parameters; and patient factors were assessed for association with Grade 2 or higher pneumonitis. RESULTS A total of 162 patients met the criteria for inclusion. The majority of patients had Stage III disease (64%) and received concurrent chemotherapy (61%). Sixty-two patients were identified as ACE inhibitor users (38%). All patients had acceptable radiation plans based on dose-volume histogram constraints (V20 [volume of lung receiving at least 20 Gy] ≤37% and mean lung dose ≤20 Gy) with the exception of 2 patients who did not meet both criteria. Grade 2 or higher pulmonary toxicity occurred in 12 patients (7.4%). The rate of Grade 2 or higher pneumonitis was lower in ACE inhibitor users vs. nonusers (2% vs. 11%, p = 0.032). Rates of Grade 2 or higher pneumonitis were significantly increased in patients aged greater than 70 years (16% vs. 2%, p = 0.005) or in whom V5 (volume of lung receiving at least 5 Gy) was 50% or greater (13% vs. 4%, p = 0.04). V10 (volume of lung receiving at least 10 Gy), V20, V30 (volume of lung receiving at least 30 Gy), and mean lung dose were not independently associated with Grade 2 or higher pneumonitis. CONCLUSION ACE inhibitors may decrease the incidence of radiation pneumonitis in patients receiving thoracic radiation for lung cancer. These findings are consistent with preclinical evidence and should be prospectively evaluated.

Neoadjuvant Chemoradiation with IMRT in Resectable and Borderline Resectable Pancreatic Cancer

PURPOSE Neoadjuvant chemoradiation is an alternative to the surgery-first approach for resectable pancreatic cancer (PDA) and represents the standard of care for borderline resectable (BLR). MATERIALS AND METHODS All patients with resectable and BLR PDA treated with neoadjuvant chemoradiation using IMRT between 1/2009 and 11/2011 were reviewed. Patients were treated to a customized CTV which included the primary mass and regional vessels. RESULTS Neoadjuvant chemoradiation was completed in 69 patients (39 BLR and 30 resectable). Induction chemotherapy was used in 32 (82%) of the 39 patients with BLR disease prior to chemoXRT. All resectable patients were treated with chemoXRT alone. Following neoadjuvant treatment, 48 (70%) of the 69 patients underwent successful pancreatic resection with 47 (98%) being margin negative (RO). In 30 of the BLR patients who had arterial abutment or SMV occlusion, 19 (63%) were surgically resected and all had RO resections. The cumulative incidence of local failure at 1 and 2 years was 2% (95% CI 0-6%) and 9% (95% CI 0.6-17%) respectively. The median overall survival for all patients, patients undergoing resection, and patients without resection were 20, 26 and 11 months respectively. Sixteen (23%) of the 69 patients are alive without disease with a median follow-up of 47 months (36-60). CONCLUSION Neoadjuvant chemoXRT can facilitate a margin negative resection in patients with localized PCa.

Continuous-course reirradiation with concurrent carboplatin and paclitaxel for locally recurrent, nonmetastatic squamous cell carcinoma of the head-and-neck.

PURPOSE To examine the efficacy and toxicity of continuous-course, conformal reirradiation with weekly paclitaxel and carboplatin for the treatment of locally recurrent, nonmetastatic squamous cell carcinoma of the head and neck (SCCHN) in a previously irradiated field. METHODS AND MATERIALS Patients treated with continuous course-reirradiation with concurrent carboplatin and paclitaxel at the Medical College of Wisconsin and the Clement J. Zablocki VA from 2001 through 2009 were retrospectively reviewed. Patients included in the analysis had prior radiation at the site of recurrence of at least 45 Gy. The analysis included patients who received either intensity-modulated radiotherapy (RT) or three-dimensional conformal RT techniques. All patients received weekly concurrent carboplatin (AUC2) and paclitaxel (30-50 mg/m(2)). RESULTS Thirty-eight patients with nonmetastatic SCCHN met the entry criteria for analysis. The primary sites at initial diagnosis were oropharyngeal or laryngeal in most patients (66%). Median reirradiation dose was 60 Gy (range, 54-70 Gy). Acute toxicity included Grade 2 neutropenia (5%), Grade 3 neutropenia (15%), and Grade 1/2 thrombocytopenia (8%). No deaths occurred from hematologic toxicity. Chemotherapy doses held (50%) was more prevalent than radiation treatment break (8%). Sixty-eight percent of patients required a gastrostomy tube in follow-up. Significant late toxicity was experienced in 6 patients (16%): 1 tracheoesophageal fistula, 1 pharyngocutaneous fistula, 3 with osteoradionecrosis, and 1 patient with a lingual artery bleed. Patients treated with three-dimensional conformal RT had more frequent significant late toxicites than patients treated with intensity-modulated RT (44% and 7% respectively, p < 0.05). The median time to progression was 7 months and progression-free rates at 1, 2, and 5 years was 44%, 34%, and 29% respectively. The median overall survival was 16 months. Overall survival at 1, 3, and 5 years was 54%, 31%, and 20% respectively. CONCLUSIONS Continuous-course, conformal reirradiation with weekly paclitaxel and carboplatin has an acceptable toxicity profile and offers a potentially curative option in a subset of patients with few other options.

Symptomatic Radiation Pneumonitis in Elderly Patients Receiving Thoracic Irradiation

PURPOSE Advanced age has been associated with increased risk of radiation pneumonitis. The purpose of this study was to examine the clinical and dosimetric predictors of radiation pneumonitis in elderly patients relative to younger patients treated with thoracic radiation therapy for lung cancer. METHODS Two hundred fifty-six consecutive patients with stage I-III small cell and non-small-cell lung cancer treated with definitive radiation with or without concurrent chemotherapy, between 2004 and 2009, were reviewed. Pneumonitis was graded by using the Common Terminology Criteria for Adverse Events version 4. Clinical parameters and dosimetric variables were assessed in univariate and multivariate analysis to evaluate predictors of grade ≥2 pneumonitis in patients age ≥70 years and age <70 years. RESULTS There were 99 patients age ≥70 and 157 patients age <70 years old. Pneumonitis occurred in 32 patients (grade 2 [22], grade 3 [7], grade 4 [3], grade 5 [1]). On multivariate analysis, the V5 Gy (P = .005) and age ≥70 years (P = .001) predicted for grade ≥2 pneumonitis, whereas angiotensin converting enzyme inhibitor use was associated with decreased risk (P = .02). Pneumonitis grade ≥3 occurred in 10% (n = 10/99) of patients age ≥70 years and in 1% (n = 1/157) of patients <70 years (P = .001). In patients with a V20 Gy >31%, the incidence of grade ≥3 pneumonitis was 33% (n = 4/12) in elderly patients compared with 2% (n = 1/44) in younger patients (P = .005). CONCLUSIONS Elderly patients were observed to have an increased risk of symptomatic pneumonitis. Radiation dose parameters remain useful in this population; however, the threshold for clinically acceptable pneumonitis may be lower than in younger patients. angiotensin converting enzyme inhibitors use may mitigate radiation pneumonitis.

Does radiologic response correlate to pathologic response in patients undergoing neoadjuvant therapy for borderline resectable pancreatic malignancy

In patients with borderline resectable pancreas cancers, clinicians frequently consider radiographic response as the primary driver of whether patients should be offered surgical intervention following neoadjuvant therapy (NT). We sought to determine any correlation between radiographic and pathologic response rates following NT.

Patient-reported outcomes in patients with nonmelanomatous skin cancers of the face treated with orthovoltage radiation therapy: a cross-sectional survey.

Patients confronted with various treatment options for the treatment of nonmelanomatous skin cancers in visible areas of the face may not be fully informed of the expected outcomes associated with treatment. Radiation therapy may be particularly advantageous in treating lesions in which surgical resection would risk poor cosmetic outcomes. Results from several large series demonstrate local recurrence rates of <10% with the use of radiation therapy (1-4). Despite reports of local control rates comparable to those associated with surgical resection, few studies have addressed cosmetic endpoints following radiation therapy. No studies have assessed patient-reported outcomes. The purpose of the survey was to evaluate patient-reported outcomes following orthovoltage radiation therapy for skin cancers of the face (SCF).

Downstaging therapy followed by liver transplantation for hepatocellular carcinoma beyond Milan criteria

Background. Orthotopic liver transplantation is a curative treatment for hepatocellular carcinoma within Milan criteria, but these criteria preclude many patients from transplant candidacy. Recent studies have demonstrated that downstaging therapy can reduce tumor burden to meet conventional criteria. The present study reports a single‐center experience with tumor downstaging and its effects on post–orthotopic liver transplantation outcomes. Methods. All patients with hepatocellular carcinoma who were evaluated by our multidisciplinary liver services team from 2012 to 2016 were identified (N = 214). Orthotopic liver transplantation candidates presenting outside of Milan criteria at initial radiographic diagnosis and/or an initial alpha‐fetoprotein >400 ng/mL were categorized as at high risk for tumor recurrence and post‐transplant mortality. Results. Of the 214 patients newly diagnosed with hepatocellular carcinoma, 73 (34.1%) eventually underwent orthotopic liver transplantation. The majority of patients who did not undergo orthotopic liver transplantation were deceased or lost to follow‐up (47.5%), with 14 of 141 (9.9%) currently listed for transplantation. Among transplanted patients, 21 of 73 (28.8%) were considered high‐risk candidates. All 21 patients were downstaged to within Milan criteria with an alpha‐fetoprotein <400 ng/mL before orthotopic liver transplantation, through locoregional therapies. Recurrence of hepatocellular carcinoma was higher but acceptable between downstaged high‐risk and traditional candidates (9.5% vs 1.9%; P > .05) at a median follow‐up period of 17 months. Downstaged high‐risk candidates had a similar overall survival compared with those transplanted within Milan criteria (log‐rank P > .05). Conclusions. In highly selected cases, patients with hepatocellular carcinoma outside of traditional criteria for orthotopic liver transplantation may undergo downstaging therapy in a multidisciplinary fashion with excellent post‐transplant outcomes. These data support an aggressive downstaging approach for selected patients who would otherwise be deemed ineligible for transplantation.

Magnetic Resonance Imaging-Guided High–Dose Rate Brachytherapy for Cervical Cancer

Introduction Cervical cancer represents 0.8% of all new cancer cases and in 2012 there was an estimated 249,512 women living with cervical cancer in the United States. Concurrent chemoradiation followed by brachytherapy represents the standard of care in patients with International Federation of Gynecology and Obstetrics stage IB2 to IVA tumors (tumors larger than 4 cm or with parametrial involvement). During the first phase of treatment, patients receive external beam radiotherapy (EBRT) to the pelvis specifically targeting the cervix, uterus, and regional lymphatics. Patients typically receive 45-50.4 Gy with concurrentweekly cisplatin over 5weeks. This is followed by brachytherapy where applicators are placed in close proximity to the tumor typically via an intracavitary approach for temporary loading of a radioactive source. Brachytherapy plays a crucial role in the management of invasive cervical cancer. It has a rapid dose fall off allowing the tumor to receive a high dose while relatively sparing nearby structures such as the bladder, sigmoid, and rectum. Brachytherapy delivery options have evolved over time and can be delivered through multiple (typically 5) outpatient procedures using a high–dose rate source or during 2 inpatient stays using a low–dose rate source. By taking advantage of the geometric andphysical properties of brachytherapy, the central principle is to escalate the tumor dose to a curative rangewhileminimizing the dose and toxicity to the surrounding organs at risk (rectum, bladder, and sigmoid). Over time with advances in imaging, brachytherapy treatment planning has evolved tomeet these goals. In the early era, brachytherapy was planned using 2-dimensional images (Fig. 1). Defined points in space were used to evaluate the quality of brachytherapy implants and to estimate the tumor dose and dose to organs at risk. With the widespread use of computed tomography (CT) within radiation oncology departments, CT-based planning (Fig. 2) is now feasible. The

Results of the 2013 Association of Residents in Radiation Oncology Career Planning Survey of Practicing Physicians in the United States

PURPOSE The goal of this study was to develop insights about the job application process for graduating radiation oncology residents from the perspective of those involved in hiring. METHODS In May and June 2013, a nationwide electronic survey was sent to 1,671 practicing radiation oncologists in academic and private practice settings. Descriptive statistics are reported. In addition, subgroup analysis was performed. RESULTS Surveys were completed by 206 physicians. Ninety-six percent were willing to hire individuals directly from residency. Participants believed that the first half of the fourth postgraduate year is the most appropriate time for residents to begin networking and the beginning of the fifth postgraduate year is the most appropriate time to begin contacting practices in pursuit of employment. Seventy percent began interviewing 4 to 9 months before the job start date, and 84% interviewed ≤6 candidates per available position. The 5 most important factors to participants when evaluating prospective candidates were (from most to least important) work ethic, personality, interview impression, experience in intensity-modulated radiation therapy, and flexibility. Factors that participants believed should be most important to candidates when evaluating practices included a collegial environment; emphasis on best patient care; quality of equipment, physics, dosimetry, and quality assurance; quality of the support staff and facility; and a multidisciplinary approach to patient care. Those in academics rated research-related factors higher than those in private practice, who rated business-related factors higher. CONCLUSIONS The perspectives of practicing physicians on the job application process are documented to provide a comprehensive resource for current and future residents and employers.