An assessment of urethral radiation exposure in the treatment of endometrial and rectal cancers.

INTRODUCTION AND HYPOTHESIS: Female survivors of endometrial and rectal cancers have increased risk of urinary incontinence. Survivors with prior radiation therapy are counseled against mesh incontinence surgery. We hypothesize that urethral radiation dose varies based on modality which may influence surgical risks. We aimed to demonstrate urethral radiation dose differences between vaginal brachytherapy (VBT) and external beam radiation therapy (EBRT). METHODS: This is a retrospective cohort study of women exposed to VBT for endometrial cancer and EBRT for rectal cancer. The urethra was contoured on CT imaging to calculate radiation doses in centigray (cGy). The primary outcome was the percent of treatment radiation dose estimated to be received by the urethra based on the volume dose to 0.2 cc of urethra. Secondary outcomes were point doses to the bladder neck, mid-urethra, and total mean urethral dose. Descriptive statistics described demographic characteristics. Bivariate analyses compared urethral radiation dose based on radiation modality. RESULTS: Between 2014-2017, 32 women treated were included: 18 with VBT and 14 with EBRT. Mean ± SD urethral volume doses were lower in VBT (1266 cGy ± 533, 42.2% of prescribed treatment dose) compared to EBRT (5051 cGy ± 192, 100.2% of prescribed treatment dose), p < 0.0001. VBT also had significantly lower mean total urethral dose and point doses to bladder neck and mid- urethra compared to EBRT (p < 0.0001). CONCLUSIONS: The female urethra is exposed to significantly less radiation in VBT compared to EBRT. These data highlight that modality of pelvic radiation should be considered in treatment counseling on urinary incontinence in women.

Pilot study to assess sexual function, quality of life (QOL) and change in vaginal dimensions following vaginal brachytherapy (VBT).

METHODS: 63 patients with early stage endometrial carcinoma treated with VBT 30 Gy in three fractions to the vaginal surface were invited to participate. 18 patients enrolled. Vaginal length and diameter were measured using original VBT cylinders to assess change. Patients completed sexual function, QOL, and toxicity questionnaires. The assessment of patients' sexual function relative to national mean was calculated and reported by the Health Measures Scoring Service, a third party. RESULTS: Median length of time from VBT start until research visit was 3.6 years. Mean original vaginal length of the 18 women was 13.7 cm (Range: 11-18 cm); mean original diameter was 3.0 cm (Range: 2.5-3.5 cm). There was a significant decrease in vaginal length of 1.2 cm (p = 0.0005). There was a mean vaginal diameter decrease of 0.03 cm that was not significant. Toxicities were grade 1-2 and infrequent. There were no grade two acute toxicities, and 1 patient (5.6%) who had a chronic toxicity, diarrhea. 7 patients had evaluable sexual function responses. Reported sexual function was above the national mean in global satisfaction, interest, and lubrication (52.9, 50.2, and 56.2 percentile). Patients performed beneath national mean in the categories of orgasm and discomfort (3.1, 46.7 percentile) which was not correlated with the decrease in vaginal length. DISCUSSION/CONCLUSION: VBT resulted in significant vaginal shortening. Patients underperformed in the categories of orgasm and vaginal discomfort relative to national mean. This report adds to the scarce literature of objective data on sexual satisfaction and vaginal sequelae of VBT for endometrial carcinoma.

Stereotactic body radiotherapy for synchronous early stage non-small cell lung cancer.

INTRODUCTION: In patients with non-small cell lung cancer (NSCLC) who present with multiple pulmonary nodules, it is often difficult to distinguish metastatic disease from synchronous primary lung cancers (SPLC). We sought to evaluate clinical outcomes after stereotactic body radiotherapy (SBRT) alone to synchronous primary lesions. MATERIAL AND METHODS: Patients with synchronous AJCC 8th Edition Stage IA-IIA NSCLC and treated with stereotactic body radiation therapy (SBRT) to all lesions between 2009-2018 were reviewed. SPLC was defined as patients having received two courses of SBRT within 180 days for treatment of separate early stage tumors. In total, 36 patients with 73 lesions were included. Overall survival (OS), progression-free survival (PFS), cumulative incidence of local failure (LF), and regional/distant failure (R/DF) were estimated and compared with a control cohort of solitary early stage NSCLC patients. RESULTS: Median PFS was 38.8 months (95% CI 14.3-not reached [NR]); 3-year PFS rates were 50.6% (35.6-72.1). Median OS was 45.9 months (95% CI: 35.9-NR); 3-year OS was 63.0% (47.4-83.8). Three-year cumulative incidence of LF and R/DF was 6.6% (3.7-13.9) and 35.7% (19.3-52.1), respectively. Patients with SPLC were compared to a control group (n = 272) of patients treated for a solitary early stage NSCLC. There was no statistically significant difference in PFS (p = .91) or OS (p = .43). Evaluation of the patterns of failure showed a trend for worse cumulative incidence of R/DF in SPLC patients as compared to solitary early stage NSCLC (p = .06). CONCLUSION: SBRT alone to multiple lung tumors with SPLC results in comparable PFS, OS, and LF rates to a cohort of patients treated for solitary early stage NSCLC. Those with SPLC had non-significantly higher R/DF. Patients with SPLC should be followed closely for failure and possible salvage therapy.

Adrenal SBRT: a multi-institutional review of treatment outcomes and toxicity.

The adrenal glands are a common site of metastatic disease. Definitive treatment for oligometastatic disease using ablative radiotherapy is becoming common in modern radiation oncology practice. However, most data on the treatment of adrenal metastases are limited to single institution reports. Furthermore, delivering ablative radiotherapy doses to intra-abdominal lesions can be challenging due to the proximity of the gastrointestinal tract. We report the outcomes of a multi-institutional cohort of patients treated with definitive radiotherapy for adrenal metastases, primarily using 10 fraction regimens. Retrospective review of institutional databases revealed 29 lesions in 27 patients were treated from 2005 to 2018 at two institutions. Outcome data, including local control, disease-free, and overall survival were abstracted from the medical record system. Toxicity was graded using CTCAE v5.0. Detailed radiotherapy data was abstracted from the treatment planning systems. The median dose was 50 Gy in 10 fractions. Actuarial 1 and 2 year local control was 86% and 76% respectively. The median overall and disease-free survival were 22.8 and 5.6 months respectively. There were no associations identified between local failure and GTV and PTV physical or biologic effective dose. Two patients developed late Grade 3 gastrointestinal toxicity. High dose radiotherapy to adrenal metastases is a feasible treatment with excellent local control and a reasonable safety profile. For lesions in close proximity to gastrointestinal structures, moderately hypofractionated 10 fraction regimens may be a reasonable compromise between local control and toxicity.

Bench to Bedside: Animal Models of Radiation Induced Musculoskeletal Toxicity.

Ionizing radiation is a critical aspect of current cancer therapy. While classically mature bone was thought to be relatively radio-resistant, more recent data have shown this to not be the case. Radiation therapy (RT)-induced bone loss leading to fracture is a source of substantial morbidity. The mechanisms of RT likely involve multiple pathways, including changes in angiogenesis and bone vasculature, osteoblast damage/suppression, and increased osteoclast activity. The majority of bone loss appears to occur rapidly after exposure to ionizing RT, with significant changes in cortical thickness being detectable on computed tomography (CT) within three to four months. Additionally, there is a dose-response relationship. Cortical thinning is especially notable in areas of bone that receive >40 gray (Gy). Methods to mitigate toxicity due to RT-induced bone loss is an area of active investigation. There is an accruing clinical trial investigating the use of risderonate, a bisphosphonate, to prevent rib bone loss in patients undergoing lung stereotactic body radiation therapy (SBRT). Additionally, several other promising therapeutic/preventative approaches are being explored in preclinical studies, including parathyroid hormone (PTH), amifostine, and mechanical loading of irradiated bones.

Does adjuvant concurrent or sequential chemotherapy increase the radiation-related toxicity of vaginal brachytherapy for endometrial cancer patients?

PURPOSE: To compare radiation toxicity in endometrial cancer patients treated with adjuvant vaginal brachytherapy (VBT) vs. VBT with concurrent chemotherapy (CCT) or sequential chemotherapy (SCT) METHODS: We retrospectively analyzed 131 patients with endometrial cancer treated with VBT without external beam radiation therapy. Toxicities were graded according to the Common Terminology Criteria for Adverse Events v4.03. CCT was defined as VBT delivered between the first and last cycle of chemotherapy (CT); SCT was defined as VBT delivered before or after CT. RESULTS: Median followup was 36 months, with a 3-year survival rate of 88%. Of the 131 patients, 92 were treated with VBT alone, 34 with VBT and CCT, and 5 with VBT and SCT. The most common toxicity was vaginal stricture, with 30 (22.9%) patients affected. The distribution of toxicities was vaginal 28%, urinary 12%, rectal 11%, and fatigue 5%; none greater than Grade 2. Compared with patients treated with VBT alone, the addition of CT did not increase the chance of vaginal stricture formation (p = 0.84). The difference in system-specific toxicities between treatment modalities was not statistically significant. CONCLUSION: The most common pelvic toxicity from VBT is vaginal stenosis with other toxicities being infrequent and generally Grade 1. The addition of CT in a sequential or concurrent fashion did not increase the rate of pelvic toxicity from VBT alone.

Multi-institutional Analysis of Vaginal Brachytherapy Alone for Women With Stage II Endometrial Carcinoma.

PURPOSE: To investigate the survival endpoints in women with International Federation of Gynecology and Obstetrics (FIGO) stage II endometrial cancer who received adjuvant vaginal brachytherapy (VBT) alone using multi-institutional pooled data. METHODS AND MATERIALS: We performed a multi-institutional analysis of surgically staged patients with FIGO stage II endometrioid-type endometrial cancer treated with VBT alone. Patient, tumor, and treatment characteristics were collected and analyzed. Univariable and multivariable frailty survival models were performed to assess clinicopathologic risk factors for recurrence and death. RESULTS: One hundred six patients were included (92 VBT alone and 14 VBT with chemotherapy) with median follow-up of 39.0 months. Pelvic node dissection was performed in 89.6% of patients. One hundred four patients (98.1%) and 2 patients (1.9%) had microscopic and macroscopic cervical stromal invasion, respectively. Grade 1 or 2 disease occurred in 88.6% of patients. For patients treated with VBT without chemotherapy, the 5-year estimates of vaginal failure, pelvic nodal failure, and distant metastases were 2.6%, 4.2%, and 7.2%, respectively. Five-year progression-free survival and overall survival were 74.0% and 76.2%, respectively. On univariable and multivariable models for progression-free survival, increasing age and lack of pelvic node resection were hazardous (P < .05). CONCLUSIONS: Vaginal and pelvic failure rates were low in this selected population of stage II patients receiving adjuvant VBT without external beam radiation therapy. It is reasonable to consider adjuvant VBT alone in selected patients with grade 1 or 2 disease and microscopic cervical stromal invasion who underwent pelvic lymphadenectomy.

Comparison of dosimetric and clinical outcomes between short- and long-channel cylinder applicators for vaginal brachytherapy in intermediate- and high-risk endometrial cancer.

PURPOSE: Vaginal brachytherapy (VBT) using a cylinder applicator is a standard treatment of intermediate- and high-risk endometrial cancer. We conducted a retrospective study of the dosimetric and clinical outcomes at our institution with 2 single-channel applicators in patients receiving VBT. METHODS AND MATERIALS: One hundred thirty-six patients with endometrial cancer treated from 2006 to 2016 receiving VBT after definitive surgery were evaluated. Two cylinders were used with the distal dwell position 7.1-12.8 mm from the apex varying by diameter (short channel), and 3.2 mm from the apex (long channel). We prescribed 18-26 Gy in 3-4 fractions at 0.5 cm depth. Measurements of the distance from the apex to the prescription isodose line were taken from CT imaging. Student's t test and the Wilcoxon rank-sum test were used with corrections for multiple comparisons. RESULTS: Patients had International Federation of Gynecology and Obstetrics 2009 Stage I-II disease (70 Stage IA, 58 Stage IB, 9 Stage II). Mean cylinder apex dose was 95.2% and 154.7% of prescription (p < 0.001), and mean distance from apex to the prescription isodose line was 0.54 mm and 3.5 mm (p < 0.001) for the short- and long-channel cylinders, respectively. There were no significant differences in any toxicity between cylinders. Four patients (2.9%) had vaginal recurrence, all of whom were treated with the short-channel cylinder. Cylinder type was not associated with vaginal recurrence (p = 0.27). CONCLUSIONS: A cylinder applicator with a distal dwell position closer to the apex results in higher doses to the vaginal cuff and increased D2cc to the bladder. All four recurrences were in the short-channel cylinder. Additional investigation into applicator design and impact on patient outcomes in larger cohorts with sufficient followup is warranted.

Adjuvant therapy in patients with clear cell endometrial carcinoma: An analysis of the National Cancer Database.

OBJECTIVE: To assess the impact of adjuvant treatment, sociodemographic and tumor factors on the survival of patients with non-metastatic clear cell endometrial carcinoma (CCC). METHODS: 4298 patients treated from 1998 to 2011 with Stage I-IVA CCC were identified within the National Cancer Database. FIGO 2009 staging system was used. Adjuvant groups included: hysterectomy (HYS); HYS+vaginal brachytherapy (VBT); HYS+chemotherapy (CT); HYS+external beam radiation therapy (EBRT); HYS+CT+EBRT; and HYS+CT+VBT. Univariable (UVA) and multivariable (MVA) frailty survival analyses were performed. RESULTS: On UVA, higher stage was associated with an increased risk of death. Compared to stage I-IA, the risk of death for stage IB was HR 1.75 (95% CI, 1.50-2.04; p<0.001), stage II was HR 1.77 (95% CI, 1.50-2.10; p<0.001), stage III-IIIB was HR 3.29 (95% CI, 2.86-3.80; p<0.001), stage IIIC-IIIC2 was HR 3.33 (95% CI: 2.94-3.77; p<0.001), and stage IVA was 8.59 (95% CI: 6.60-11.18; p<0.001). Other meaningful predictors of death included black race (p<0.001), public insurance (p<0.001), geographic education attainment (p=0.001), greater comorbidity score (p=0.001), increasing age (p<0.001), and increasing tumor size (p<0.001). After controlling for stage, insurance, race, education attainment, comorbidity score, age, and tumor size adjuvant treatment was not associated with decreased risk of mortality (p=0.26). CONCLUSION: Adjuvant therapy did not have a meaningful effect on survival in this sample from the National Cancer Center Database. Given the aggressive nature of the disease, clinical trials are required to determine the optimal adjuvant therapy in patients with non-metastatic CCC to improve clinical outcomes.

Attrition rates in neurosurgery residency: analysis of 1361 consecutive residents matched from 1990 to 1999.

OBJECT: The objective of this study is to determine neurosurgery residency attrition rates by sex of matched applicant and by type and rank of medical school attended. METHODS: The study follows a cohort of 1361 individuals who matched into a neurosurgery residency program through the SF Match Fellowship and Residency Matching Service from 1990 to 1999. The main outcome measure was achievement of board certification as documented in the American Board of Neurological Surgery Directory of Diplomats. A secondary outcome measure was documentation of practicing medicine as verified by the American Medical Association DoctorFinder and National Provider Identifier websites. Overall, 10.7% (n=146) of these individuals were women. Twenty percent (n=266) graduated from a top 10 medical school (24% of women [35/146] and 19% of men [232/1215], p=0.19). Forty-five percent (n=618) were graduates of a public medical school, 50% (n=680) of a private medical school, and 5% (n=63) of an international medical school. At the end of the study, 0.2% of subjects (n=3) were deceased and 0.3% (n=4) were lost to follow-up. RESULTS: The total residency completion rate was 86.0% (n=1171) overall, with 76.0% (n=111/146) of women and 87.2% (n=1059/1215) of men completing residency. Board certification was obtained by 79.4% (n=1081) of all individuals matching into residency between 1990 and 1999. Overall, 63.0% (92/146) of women and 81.3% (989/1215) of men were board certified. Women were found to be significantly more at risk (p<0.005) of not completing residency or becoming board certified than men. Public medical school alumni had significantly higher board certification rates than private and international alumni (82.2% for public [508/618]; 77.1% for private [524/680]; 77.8% for international [49/63]; p<0.05). There was no significant difference in attrition for graduates of top 10-ranked institutions versus other institutions. There was no difference in number of years to achieve neurosurgical board certification for men versus women. CONCLUSIONS: Overall, neurosurgery training attrition rates are low. Women have had greater attrition than men during and after neurosurgery residency training. International and private medical school alumni had higher attrition than public medical school alumni.

Microfiltración bacteriana, citotoxicidad y respuesta del periápice al MTA, al IRM, al super EBA y a la amalgama: una revisión / Bacterial microleakage, cytotoxicity and periapical response to MTA, IRM, super EBA and amalgam: a review

El propósito de esta revisión es establecer parámetros claros de cuáles métodos son los más adecuados para el estudio de la microfiltración, de la citotoxicidad y de la respuesta del periápice al MTA, la amalgama, el super EBA y el IRM como materiales de retroobturación, pues existen diversos métodos empleados en estas investigaciones, dentro de los cuales hay muchos que no ofrecen respuestas satisfactorias, ya sea porque son análogos con la clínica o por limitaciones intrínsecas de la prueba. La función principal de un material de obturación retrógrada es ofrecer sellado apical, para prevenir la colonización bacteriana y la difusión de sus productos desde el conducto a los tejidos periapicales. Las pruebas de microfiltración, citotoxicidad y los tests de implantación son las más empleadas en el estudio de estos materiales, pues a través de ellas se busca evaluar la compatibilidad con los tejidos y su capacidad de sellado. Las características de sellado, la adaptación marginal, las pruebas de citotoxicidad in vitro y las pruebas de uso e implantación en animales experimentales son altamente significativas para eliminar materiales con grados inaceptables de filtración y pobre biocompatibilidad. Estas pruebas son prerrequisitos y no sustitutos de estudios clínicos. La comparación clínica de los materiales de obturación retrógrada bajo condiciones similares quirúrgicas y postoperatorias debe ser el método más relevante para la evaluación del uso clínico y de su eficiencia a largo plazo