Sarah E. Hegarty

A Phase I Study of the Combination of Sorafenib With Temozolomide and Radiation Therapy for the Treatment of Primary and Recurrent High-Grade Gliomas

PURPOSE Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. METHODS AND MATERIALS This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m(2)) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). RESULTS Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population. CONCLUSIONS Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide.

Prognostic Factors and Outcomes After Definitive Treatment of Female Urethral Cancer: A Population-based Analysis

OBJECTIVE To evaluate the prognostic factors and outcomes for a large observational cohort of female patients with urethral cancer in the Surveillance, Epidemiology, and End Results database. METHODS We identified 722 women diagnosed with urethral cancer from 1983 to 2008 in the Surveillance, Epidemiology, and End Results database. Descriptive statistics were used to explore the epidemiology, standard treatment practices, and tumor characteristics. A total of 359 women with nonmetastatic primary urethral cancer were identified for cancer-specific and survival analysis. Kaplan-Meier plots and log-rank tests were performed for each potential covariate. A multivariate Cox proportional hazards model was performed to evaluate age, demographic factors, T stage, nodal status, histologic findings, surgery, and radiotherapy. RESULTS The median overall survival time was 42 months (95% confidence interval 35-57), and the 5- and 10-year overall survival rate was 43% and 32%, respectively. The median cancer-specific survival (CSS) time was 78 months, and the 5- and 10-year CSS rate was 53% and 46%, respectively. On multivariate analysis, black race, Stage T3-T4 tumors compared with T1, node-positive disease, nonsquamous histologic features, and advanced age were associated with shortened CSS. Surgery was associated with longer CSS. Black patients presented with a statistically significant greater T stage. CONCLUSION Advanced age, T stage, node-positive disease, nonsquamous histologic features, and black race were associated with reduced CSS, and surgical resection was associated with longer CSS. We found that black patients present with more advanced tumors and have shorter CSS than white women with urethral cancer.

Radiation Therapy after Radical Prostatectomy for Prostate Cancer: Evaluation of Complications and Influence of Radiation Timing on Outcomes in a Large, Population-Based Cohort

Purpose To evaluate the influence of timing of salvage and adjuvant radiation therapy on outcomes after prostatectomy for prostate cancer. Methods Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified prostate cancer patients diagnosed during 1995–2007 who had one or more adverse pathological features after prostatectomy. The final cohort of 6,137 eligible patients included men who received prostatectomy alone (n = 4,509) or with adjuvant (n = 894) or salvage (n = 734) radiation therapy. Primary outcomes were genitourinary, gastrointestinal, and erectile dysfunction events and survival after treatment(s). Results Radiation therapy after prostatectomy was associated with higher rates of gastrointestinal and genitourinary events, but not erectile dysfunction. In adjusted models, earlier treatment with adjuvant radiation therapy was not associated with increased rates of genitourinary or erectile dysfunction events compared to delayed salvage radiation therapy. Early adjuvant radiation therapy was associated with lower rates of gastrointestinal events that salvage radiation therapy, with hazard ratios of 0.80 (95% CI, 0.67–0.95) for procedure-defined and 0.70 (95% CI, 0.59, 0.83) for diagnosis-defined events. There was no significant difference between ART and non-ART groups (SRT or RP alone) for overall survival (HR = 1.13 95% CI = (0.96, 1.34) p = 0.148). Conclusions Radiation therapy after prostatectomy is associated with increased rates of gastrointestinal and genitourinary events. However, earlier radiation therapy is not associated with higher rates of gastrointestinal, genitourinary or sexual events. These findings oppose the conventional belief that delaying radiation therapy reduces the risk of radiation-related complications.

Adjuvant Versus Salvage Radiation Therapy for Prostate Cancer Patients With Adverse Pathologic Features: Comparative Analysis of Long-term Outcomes.

Objectives:To compare long-term outcomes of men with adverse pathologic features after adjuvant radiation therapy (ART) versus salvage radiation therapy (SRT) after radical prostatectomy at our institution. Methods:Patients treated with postprostatectomy radiation therapy with pT3 tumors, or pT2 with positive surgical margins, were identified. Cumulative freedom from biochemical failure (FFBF), freedom from metastatic failure (FFMF), and overall survival rates were estimated utilizing the Kaplan-Meier method. Multivariate analyses were performed to determine independent prognostic factors correlated with study endpoints. Propensity score analyses were performed to adjust for confounding because of nonrandom treatment allocation. Results:A total of 186 patients with adverse pathologic features treated with ART or SRT were identified. The median follow-up time after radical prostatectomy was 103 and 88 months after completion of radiation therapy. The Kaplan-Meier estimates for 10-year FFBF was 73% and 41% after ART and SRT, respectively (log-rank, P=0.0001). Ten-year FFMF was higher for patients who received ART versus SRT (98.6% vs. 80.9%, P=0.0028). On multivariate analyses there was no significant difference with respect to treatment group in terms of FFBF, FFMF, and overall survival after adjusting for propensity score. Conclusions:Although unadjusted analyses showed improved FFBF with ART, the propensity score-adjusted analyses demonstrated that long-term outcomes of patients treated with ART and SRT do not differ significantly. These results, with decreased effect size of ART after adjusting for propensity score, demonstrate the potential impact of confounding on observational research.

Comparative effectiveness research for prostate cancer radiation therapy: current status and future directions

Comparative effectiveness research aims to help clinicians, patients and policymakers make informed treatment decisions under real-world conditions. Prostate cancer patients have multiple treatment options, including active surveillance, androgen deprivation therapy, surgery and multiple modalities of radiation therapy. Technological innovations in radiation therapy for prostate cancer have been rapidly adopted into clinical practice despite relatively limited evidence for effectiveness showing the benefit for one modality over another. Comparative effectiveness research has become an essential component of prostate cancer research to help define the benefits, risks and effectiveness of the different radiation therapy modalities currently in use for prostate cancer treatment.

Early results of prostate cancer radiation therapy: an analysis with emphasis on research strategies to improve treatment delivery and outcomes

BackgroundThere is scant data regarding disease presentation and treatment response among black men living in Africa. In this study we evaluate disease presentation and early clinical outcomes among Ghanaian men with prostate cancer treated with external beam radiotherapy (EBRT).MethodsA total of 379 men with prostate cancer were referred to the National Center for Radiotherapy, Ghana from 2003 to 2009. Data were collected regarding patient-and tumor-related factors such as age, prostate specific antigen (PSA), Gleason score (GS), clinical stage (T), and use of androgen deprivation therapy (ADT). For patients who received EBRT, freedom from biochemical failure (FFbF) was evaluated using the Kaplan-Meier method.ResultsOf 379 patients referred for treatment 69.6% had initial PSA (iPSA) > 20 ng/ml, and median iPSA was 39.0 ng/ml. A total of 128 men, representing 33.8% of the overall cohort, were diagnosed with metastatic disease at time of referral. Among patients with at least 2 years of follow-up after EBRT treatment (n=52; median follow-up time: 38.9 months), 3- and 5-year actuarial FFbF was 73.8% and 65.1% respectively. There was significant association between higher iPSA and GS (8–10 vs. ≤7, p < 0.001), and T stage (T3/4 vs. T1/2, p < 0.001).ConclusionsThis is the largest series reporting on outcomes after prostate cancer treatment in West Africa. That one-third of patients presented with metastatic disease suggests potential need for earlier detection to permit curative-intent therapy. Data from this study will aid in the strategic development of prostate cancer research roadmap in Ghana.

Comparison of 2 stitches vs 1 stitch for transvaginal cervical cerclage for preterm birth prevention

OBJECTIVE The objective of the study was to compare the efficacy and outcomes of 2 vs 1 stitch at the time of cervical cerclage placement for preterm birth prevention. STUDY DESIGN This was a retrospective cohort study of women with singleton gestation undergoing history- or ultrasound-indicated transvaginal cervical cerclage prior to 24 weeks. The primary outcome was delivery at less than 37 weeks. The secondary outcomes included gestational age at delivery at less than 35, less than 34, less than 32, less than 28, and less than 24 weeks, perioperative details at the time of cerclage placement and removal, and maternal and neonatal outcomes. Comparison was made between patients with 2 vs 1 stitch at the time of cerclage placement. History- and ultrasound-indicated cerclages were analyzed separately. RESULTS Four hundred forty-four patients met inclusion criteria, 237 being history indicated (2 stitches, n = 86, 1 stitch, n = 151), and 207 ultrasound indicated (2 stitches, n = 117, 1 stitch, n = 90). Gestational age at delivery at less than 37 weeks was not significantly different between the 2 groups for both history- and ultrasound-indicated cerclage, even after adjusting for demographic differences and suture type (39% vs 35%; adjusted odds ratio, 1.38; 95% confidence interval, 0.64-3.01; and 44% vs 49%; adjusted odds ratio, 0.66; 95% confidence interval, 0.27-1.61, respectively). CONCLUSION Two stitches at the time of cerclage do not appear to improve pregnancy outcome either in the history- or the ultrasound-indicated procedures, compared with 1 stitch.

Olfactory function in migraine both during and between attacks.

Introduction People with migraine often report being osmophobic, both during and between acute migraine attacks. It is not clear, however, whether such reports are associated with changes in olfaction such as hyperosmia, as measured by psychophysical testing. In this case-control study we quantitatively assessed olfactory identification ability, which correlates with threshold tests of olfactory acuity, in patients with migraine at baseline (no headache), during migraine episodes, and after a treated attack and compared the test scores to those of matched control subjects. Methods Fifty episodic migraine subjects and 50 and sex- and age-matched controls without headache were tested. All completed the University of Pennsylvania Smell Identification Test (UPSIT), a standardized and well-validated olfactory test. Results At baseline, the UPSIT scores did not differ significantly between the migraine and control study groups (median paired score difference: −1, p = 0.18). During migraine attacks, a minority of migraine subjects (eight of 42) developed microsmia (i.e. lower test scores by at least four points), suggesting that, as compared to their matched controls, olfactory acuity was somewhat impaired during migraine attacks (p = 0.02). This difference was less pronounced and not statistically significant after a successfully treated attack (p = 0.15). Discussion People with episodic migraine were found to have similar olfactory function as age- and sex-matched controls, but a minority exhibit microsmia or hyposmia during acute attacks. The cause of this dysfunction is unknown, but could relate to autonomic symptoms, limbic system activation, or disorders of higher order sensory processing.

Treatment‐related complications of radiation therapy after radical prostatectomy: comparative effectiveness of intensity‐modulated versus conformal radiation therapy

Intensity‐modulated radiation therapy (IMRT) is frequently utilized after prostatectomy without strong evidence for an improvement in outcomes compared to conformal radiation therapy (RT). We analyzed a large group of patients treated with RT after radical prostatectomy (RP) to compare complications after IMRT and CRT. The Surveillance, Epidemiology and End Results (SEER)‐Medicare database was queried to identify male Medicare beneficiaries aged 66 years or older who underwent prostatectomy with 1+ adverse pathologic features and received postprostatectomy RT between 1995 and 2007. Chi‐square test was used to compare baseline characteristics between the treatment groups. First complication events, based upon administrative procedure or diagnosis codes occurring >1 year after start of RT, were compared for IMRT versus CRT groups. Propensity score adjustment was performed to adjust for potential confounders. Multivariable Cox proportional hazards models of time to first complication were performed. A total of 1686 patients were identified who received RT after RP (IMRT = 634, CRT = 1052). Patients treated with IMRT were more likely to be diagnosed after 2004 (P < 0.001), have minimally invasive prostatectomy (P < 0.001) and have positive margins (P = 0.019). IMRT use increased over time. After propensity score adjustment, IMRT was associated with lower rate of gastrointestinal (GI) complications, and higher rate of genitourinary‐incontinence complications, compared to CRT. The observed outcomes after IMRT must be considered when determining the optimal approach for postprostatectomy RT and warrant additional study.

Adenoma Detection in Excellent Versus Good Bowel Preparation for Colonoscopy

Goal: To determine whether Excellent bowel cleansing is superior to Good for the detection of adenomas. Background: High quality colonoscopy requires Adequate bowel preparation. However, it is unknown whether adenoma detection differs between subcategories of Adequate cleansing. Study: We utilized a retrospective, cross-sectional study design to obtain data about patients undergoing colonoscopy at a single university center between August 31, 2011 and September 1, 2012. Primary outcome was adenoma detection rate (ADR), the percentage of patients with ≥1 adenoma. Secondary outcomes included adenomas per colonoscopy, adenoma distribution (proximal vs. distal), and detection of advanced adenomas, sessile serrated polyps (SSP), and cancer. Results: The electronic medical record of 5113 consecutive colonoscopies with Good or Excellent preparation was queried for preparation quality, colonoscopy indication, demographics, medical history, and history of adenoma and colon cancer. Exclusion criteria were age below 18 years, inflammatory bowel disease, or familial polyposis. Adenoma detection was not superior with Excellent cleansing as compared with Good for ADR [respectively, 26% vs. 29%, odds ratio 0.97 (0.85, 1.11), P=0.618] or adenomas per colonoscopy [respectively, 0.437 vs. 0.499, incidence rate ratio (IRR) 0.98 (0.90, 1.07), P=0.705]. Excellent cleansing demonstrated superior detection of SSPs [IRR 1.66 (1.14, 2.40), P=0.008] and advanced adenomas [IRR 1.37 (1.09, 1.72), P=0.007] but not colon cancer [odds ratio 0.286 (0.083, 0.985), P=0.0474]. Conclusions: ADR is not significantly different between the Adequate subcategories of Excellent and Good. However, Excellent cleansing is associated with superior detection of advanced adenomas and SSPs. If confirmed, achieving an Excellent preparation may improve colonoscopy performance in the proximal colon where SSPs primarily occur.