Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer.

BACKGROUND: Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence. METHODS: In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life. RESULTS: Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan-Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group. CONCLUSIONS: Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.).

Patient reported outcomes for cisplatin and radiation followed by carboplatin/paclitaxel versus carboplatin/paclitaxel for locally advanced endometrial carcinoma: An NRG oncology study.

INTRODUCTION: Chemotherapy plus radiation (Cis-RT + CP) did not demonstrate superiority in prolonging relapse-free survival compared to chemotherapy alone in patients with stage III or IVA endometrial carcinoma. The impact of treatment on quality of life (QOL), neurotoxicity (NTX) and psychometric properties of the gastrointestinal (GI) symptoms subscale during treatment and up to 1 year are described herein. METHODS: QOL assessments were scheduled at baseline, 6 weeks (post completion of RT (Cis-RT + CP) or prior to cycle 3 (CP)), then 18 weeks (end of treatment) and 70 weeks (1 year after the end of treatment) after starting treatment. QOL instruments included the FACT-En TOI, FACT/GOG-neurotoxicity (Ntx) subscale (short), and the gastrointestinal (GI) symptoms subscale. RESULTS: At the end of treatment, patients receiving Cis-RT + CP reported a statistically significant decreased QOL when compared to CP. The decline in QOL was reflected in physical well-being, functional well-being, and endometrial cancer specific concerns, but the minimally important differences (MID) were not considered clinically meaningful. Patients in both groups reported increased chemotherapy-induced Ntx symptoms with the CP group having worse scores and reaching peak symptoms at the time of chemotherapy completion. Patients on Cis-RT + CP reported statistically significantly worse GI symptoms after radiation therapy compared to patients on CP, this occurred across assessment intervals, though the MID was not meaningful. Psychometric evaluations indicated that the GI symptom scale is reliable, valid, and responsive to change. CONCLUSIONS: PROs indicate that the chemoradiotherapy group experienced worse HRQoL and GI toxicity compared to patients randomized to chemotherapy alone for locally advanced endometrial cancer though based on the MID, these were not clinically meaningful differences. The GI symptom subscale was a reliable and valid scale that has value for future trials. TRIAL REGISTRATION: NCT00942357.

An Automated knowledge-based planning routine for stereotactic body radiotherapy of peripheral lung tumors via DCA-based volumetric modulated arc therapy.

PURPOSE: To develop a knowledge-based planning (KBP) routine for stereotactic body radiotherapy (SBRT) of peripherally located early-stage non-small-cell lung cancer (NSCLC) tumors via dynamic conformal arc (DCA)-based volumetric modulated arc therapy (VMAT) using the commercially available RapidPlanTM software. This proposed technique potentially improves plan quality, reduces complexity, and minimizes interplay effect and small-field dosimetry errors associated with treatment delivery. METHODS: KBP model was developed and validated using 70 clinically treated high quality non-coplanar VMAT lung SBRT plans for training and 20 independent plans for validation. All patients were treated with 54 Gy in three treatments. Additionally, a novel k-DCA planning routine was deployed to create plans incorporating historical three-dimensional-conformal SBRT planning practices via DCA-based approach prior to VMAT optimization in an automated planning engine. Conventional KBPs and k-DCA plans were compared with clinically treated plans per RTOG-0618 requirements for target conformity, tumor dose heterogeneity, intermediate dose fall-off and organs-at-risk (OAR) sparing. Treatment planning time, treatment delivery efficiency, and accuracy were recorded. RESULTS: KBPs and k-DCA plans were similar or better than clinical plans. Average planning target volume for validation was 22.4 ± 14.1 cc (7.1-62.3 cc). KBPs and k-DCA plans provided similar conformity to clinical plans with average absolute differences of 0.01 and 0.01, respectively. Maximal doses to OAR were lowered in both KBPs and k-DCA plans. KBPs increased monitor units (MU) on average 1316 (P < 0.001) while k-DCA reduced total MU on average by 1114 (P < 0.001). This routine can create k-DCA plan in less than 30 min. Independent Monte Carlo calculation demonstrated that k-DCA plans showed better agreement with planned dose distribution. CONCLUSION: A k-DCA planning routine was developed in concurrence with a knowledge-based approach for the treatment of peripherally located lung tumors. This method minimizes plan complexity associated with model-based KBP techniques and improve plan quality and treatment planning efficiency.

Predicting the effect of indirect cell kill in the treatment of multiple brain metastases via single-isocenter/multitarget volumetric modulated arc therapy stereotactic radiosurgery.

PURPOSE: Due to spatial uncertainty, patient setup errors are of major concern for radiosurgery of multiple brain metastases (m-bm) when using single-isocenter/multitarget (SIMT) volumetric modulated arc therapy (VMAT) techniques. However, recent clinical outcome studies show high rates of tumor local control for SIMT-VMAT. In addition to direct cell kill (DCK), another possible explanation includes the effects of indirect cell kill (ICK) via devascularization for a single dose of 15 Gy or more and by inducing a radiation immune intratumor response. This study quantifies the role of indirect cell death in dosimetric errors as a function of spatial patient setup uncertainty for stereotactic treatments of multiple lesions. MATERIAL AND METHODS: Nine complex patients with 61 total tumors (2-16 tumors/patient) were planned using SIMT-VMAT with geometry similar to HyperArc with a 10MV-FFF beam (2400 MU/min). Isocenter was placed at the geometric center of all tumors. Average gross tumor volume (GTV) and planning target volume (PTV) were 1.1 cc (0.02-11.5) and 1.9 cc (0.11-18.8) with an average distance to isocenter of 5.4 cm (2.2-8.9). The prescription was 20 Gy to each PTV. Plans were recalculated with induced clinically observable patient setup errors [±2 mm, ±2o ] in all six directions. Boolean structures were generated to calculate the effect of DCK via 20 Gy isodose volume (IDV) and ICK via 15 Gy IDV minus the 20 Gy IDV. Contributions of each IDV to the PTV coverage were analyzed along with normal brain toxicity due to the patient setup uncertainty. Induced uncertainty and minimum dose covering the entire PTV were analyzed to determine the maximum tolerable patient setup errors to utilize the ICK effect for radiosurgery of m-bm via SIMT-VMAT. RESULTS: Patient setup errors of 1.3 mm /1.3° in all six directions must be maintained to achieve PTV coverage of the 15 Gy IDV for ICK. Setup errors of ±2 mm/2° showed clinically unacceptable loss of PTV coverage of 29.4 ± 14.6% even accounting the ICK effect. However, no clinically significant effect on normal brain dosimetry was observed. CONCLUSIONS: Radiosurgery of m-bm using SIMT-VMAT treatments have shown positive clinical outcomes even with small residual patient setup errors. These clinical outcomes, while largely due to DCK, may also potentially be due to the ICK. Potential mechanisms, such as devascularization and/or radiation-induced intratumor immune enhancement, should be explored to provide a better understanding of the radiobiological response of stereotactic radiosurgery of m-bm using a SIMT-VMAT plan.

Development and clinical validation of a robust knowledge-based planning model for stereotactic body radiotherapy treatment of centrally located lung tumors.

PURPOSE: To develop a robust and adaptable knowledge-based planning (KBP) model with commercially available RapidPlanTM for early stage, centrally located non-small-cell lung tumors (NSCLC) treated with stereotactic body radiotherapy (SBRT) and improve a patient's"simulation to treatment" time. METHODS: The KBP model was trained using 86 clinically treated high-quality non-coplanar volumetric modulated arc therapy (n-VMAT) lung SBRT plans with delivered prescriptions of 50 or 55 Gy in 5 fractions. Another 20 independent clinical n-VMAT plans were used for validation of the model. KBP and n-VMAT plans were compared via Radiation Therapy Oncology Group (RTOG)-0813 protocol compliance criteria for conformity (CI), gradient index (GI), maximal dose 2 cm away from the target in any direction (D2cm), dose to organs-at-risk (OAR), treatment delivery efficiency, and accuracy. KBP plans were re-optimized with larger calculation grid size (CGS) of 2.5 mm to assess feasibility of rapid adaptive re-planning. RESULTS: Knowledge-based plans were similar or better than n-VMAT plans based on a range of target coverage and OAR metrics. Planning target volume (PTV) for validation cases was 30.5 ± 19.1 cc (range 7.0-71.7 cc). KBPs provided an average CI of 1.04 ± 0.04 (0.97-1.11) vs. n-VMAT plan'saverage CI of 1.01 ± 0.04 (0.97-1.17) (P < 0.05) with slightly improved GI with KBPs (P < 0.05). D2cm was similar between the KBPs and n-VMAT plans. KBPs provided lower lung V10Gy (P = 0.003), V20Gy (P = 0.007), and mean lung dose (P < 0.001). KBPs had overall better sparing of OAR at the minimal increased of average total monitor units and beam-on time by 460 (P < 0.05) and 19.2 s, respectively. Quality assurance phantom measurement showed similar treatment delivery accuracy. Utilizing a CGS of 2.5 mm in the final optimization improved planning time (mean, 5 min) with minimal or no cost to the plan quality. CONCLUSION: The RTOG-compliant adaptable RapidPlan model for early stage SBRT treatment of centrally located lung tumors was developed. All plans met RTOG dosimetric requirements in less than 30 min of planning time, potentially offering shorter "simulation to treatment" times. OAR sparing via KBPs may permit tumorcidal dose escalation with minimal penalties. Same day adaptive re-planning is plausible with a 2.5-mm CGS optimizer setting.

Risk of target coverage loss for stereotactic body radiotherapy treatment of synchronous lung lesions via single-isocenter volumetric modulated arc therapy.

Treating multiple lung lesions synchronously via single-isocenter volumetric modulated arc therapy (VMAT) stereotactic body radiation therapy (SBRT) improves treatment efficiency and patient compliance. However, aligning multiple lung tumors accurately on single pretreatment cone beam CTs (CBCTs) can be problematic. Tumors misaligned could lead to target coverage loss. To quantify this potential target coverage loss due to small, clinically realistic setup errors, a novel simulation method was developed. This method was used on 26 previously treated patients with two metastatic lung lesions. Patients were treated with 4D CT-based, highly conformal noncoplanar VMAT plans (clinical VMAT) with 6MV-flattening filter free (FFF) beam using AcurosXB dose calculation algorithm with heterogeneity corrections. A single isocenter was placed approximately between the lesions to improve patient convenience and clinic workflow. Average isocenter to tumor distance was 5.9 cm. Prescription dose was 54 Gy/50 Gy in 3/5 fractions. For comparison, a plan summation (simulated VMAT) was executed utilizing randomly simulated, clinically relevant setup errors, obtained from pretreatment setup, per treatment fraction, in Eclipse treatment planning system for each of the six degrees of freedom within ± 5.0 mm and ± 2°. Simulations yielded average deviations of 27.4% (up to 72% loss) (P < 0.001) from planned target coverage when treating multiple lung lesions using a single-isocenter plan. The largest deviations from planned coverage and desired biological effective dose (BED10, with α/ß = 10 Gy) were seen for the smallest targets (<10 cc), some of which received < 100 Gy BED10. Patient misalignment resulted in substantial decrease in conformity and increase in the gradient index, violating major characteristics of SBRT. Statistically insignificant differences were seen for normal tissue dose. Although, clinical follow-up of these patients is ongoing, the authors recommend an alternative treatment planning strategy to minimize the probability of a geometric miss when treating small lung lesions synchronously with single-isocenter VMAT SBRT plans.

Clinical validation of ring-mounted halcyon linac for lung SBRT: comparison to SBRT-dedicated C-arm linac treatments.

Stereotactic body radiotherapy (SBRT) of lung tumors via the ring-mounted Halcyon Linac, a fast kilovoltage cone beam CT-guided treatment with coplanar geometry, a single energy 6MV flattening filter free (FFF) beam and volumetric modulated arc therapy (VMAT) is a fast, safe, and feasible treatment modality for selected lung cancer patients. Four-dimensional (4D) CT-based treatment plans were generated using advanced AcurosXB algorithm with heterogeneity corrections using an SBRT board and Halcyon couch insert. Halcyon VMAT-SBRT plans with stacked and staggered multileaf collimators produced highly conformal radiosurgical dose distribution to the target, lower intermediate dose spillage, and similar dose to adjacent organs at risks (OARs) compared to SBRT-dedicated highly conformal clinical noncoplanar Truebeam VMAT plans following the RTOG-0813 requirements. Due to low monitor units per fraction and less multileaf collimator (MLC) modulation, the Halcyon VMAT plan can deliver lung SBRT fractions with an overall treatment time of less than 15 min (for 50 Gy in five fractions), significantly improving patient comfort and clinic workflow. Higher pass rates of quality assurance results demonstrate a more accurate treatment delivery on Halcyon. We have implemented Halcyon for lung SBRT treatment in our clinic. We suggest others use Halcyon for lung SBRT treatments using abdominal compression or 4D CT-based treatment planning, thus expanding the access of curative ultra-hypofractionated treatments to other centers with only a Halcyon Linac. Clinical follow-up results for patients treated on Halcyon Linac with lung SBRT is ongoing.

Automation and integration of a novel restricted single-isocenter stereotactic body radiotherapy (a-RESIST) method for synchronous two lung lesions.

Synchronous treatment of two lung lesions using a single-isocenter volumetric modulated arc therapy (VMAT) stereotactic body radiation therapy (SBRT) plan can decrease treatment time and reduce the impact of intrafraction motion. However, alignment of both lesions on a single cone beam CT (CBCT) can prove difficult and may lead to setup errors and unacceptable target coverage loss. A Restricted Single-Isocenter Stereotactic Body Radiotherapy (RESIST) method was created to minimize setup uncertainties and provide treatment delivery flexibility. RESIST utilizes a single-isocenter placed at patient's midline and allows both lesions to be planned separately but treated in the same session. Herein is described a process of automation of this novel RESIST method. Automation of RESIST significantly reduced treatment planning time while maintaining the benefits of RESIST. To demonstrate feasibility, ten patients with two lung lesions previously treated with a single-isocenter clinical VMAT plan were replanned manually with RESIST (m-RESIST) and with automated RESIST (a-RESIST). a-RESIST method automatically sets isocenter, creates beam geometry, chooses appropriate dose calculation algorithms, and performs VMAT optimization using an in-house trained knowledge-based planning model for lung SBRT. Both m-RESIST and a-RESIST showed lower dose to normal tissues compared to manually planned clinical VMAT although a-RESIST provided slightly inferior, but still clinically acceptable, dose conformity and gradient indices. However, a-RESIST significantly reduced the treatment planning time to less than 20 min and provided a higher dose to the lung tumors. The a-RESIST method provides guidance for inexperienced planners by standardizing beam geometry and plan optimization using DVH estimates. It produces clinically acceptable two lesions VMAT lung SBRT plans efficiently. We have further validated a-RESIST on phantom measurement and independent pretreatment dose verification of another four selected 2-lesions lung SBRT patients and implemented clinically. Further development of a-RESIST for more than two lung lesions and refining this approach for extracranial oligometastastic abdominal/pelvic SBRT, including development of automated simulated collision detection algorithm, merits future investigation.

Fast generation of lung SBRT plans with a knowledge-based planning model on ring-mounted Halcyon Linac.

PURPOSE: To demonstrate fast treatment planning feasibility of stereotactic body radiation therapy (SBRT) for centrally located lung tumors on Halcyon Linac via a previously validated knowledge-based planning (KBP) model to support offline adaptive radiotherapy. MATERIALS/METHODS: Twenty previously treated non-coplanar volumetric-modulated arc therapy (VMAT) lung SBRT plans (c-Truebeam) on SBRT-dedicated C-arm Truebeam Linac were selected. Patients received 50 Gy in five fractions. c-Truebeam plans were re-optimized for Halcyon manually (m-Halcyon) and with KBP model (k-Halcyon). Both m-Halcyon and k-Halcyon plans were normalized for identical or better target coverage than clinical c-Truebeam plans and compared for target conformity, dose heterogeneity, dose fall-off, and dose tolerances to the organs-at-risk (OAR). Treatment delivery parameters and planning times were evaluated. RESULTS: k-Halcyon plans were dosimetrically similar or better than m-Halcyon and c-Truebeam plans. k-Halcyon and m-Halcyon plan comparisons are presented with respect to c-Truebeam. Differences in conformity index were statistically insignificant in k-Halcyon and on average 0.02 higher (p = 0.04) in m-Halcyon plans. Gradient index was on average 0.43 (p = 0.006) lower and 0.27 (p = 0.02) higher for k-Halcyon and m-Halcyon, respectively. Maximal dose 2 cm away in any direction from target was statistically insignificant. k-Halcyon increased maximal target dose on average by 2.9 Gy (p < 0.001). Mean lung dose was on average reduced by 0.10 Gy (p = 0.004) in k-Halcyon and increased by 0.14 Gy (p < 0.001) in m-Halcyon plans. k-Halcyon plans lowered bronchial tree dose on average by 1.2 Gy. Beam-on-time (BOT) was increased by 2.85 and 1.67 min, on average for k-Halcyon and m-Halcyon, respectively. k-Halcyon plans were generated in under 30 min compared to estimated dedicated 180 ± 30 min for m-Halcyon or c-Truebeam plan. CONCLUSION: k-Halcyon plans were generated in under 30 min with excellent plan quality. This adaptable KBP model supports high-volume clinics in the expansion or transfer of lung SBRT patients to Halcyon.

Progress in endometrial cancer: Contributions of the former Gynecologic Oncology Group.

For over forty years, the Gynecologic Oncology Group drove progress in treating endometrial cancer. The first decades of investigation began with a meticulous prospective, surgicopathologic staging study that was the platform for development of all subsequent trials. The resultant statistical model of low risk, intermediate risk, and high-risk groups of patients led to trials where therapeutic modalities were best targeted at disease spread. A clear role for chemotherapy was established. It was realized that greater advances might be achieved with the advent of newer anti-neoplastic agents and these agents were subjected to extensive phase II testing. These agents later were integrated into comparison trials for advanced endometrial cancer. Multimodality therapy continues to show promise. Hormonal therapy was thoroughly investigated and led to combination hormonal therapy trials. Newer agents, including biologics are under active study, as well as the potential contribution of modern imaging techniques. Finally, GOG0210 established a repository of clinical specimens with detailed clinical and epidemiologic data from patients with surgically staged endometrial carcinoma. This should provide for a much greater understanding of molecular characteristics associated with risk of endometrial cancer recurrence, clinical and histological characteristics, and epidemiologic factors.

Flattening filter free VMAT for a stereotactic, single-dose of 30 Gy to lung lesion in a 15-min treatment slot.

Cone-beam CT-guided single dose of lung stereotactic body radiotherapy (SBRT) treatment with a flattening filter free (FFF) beam and volumetric modulated arc therapy (VMAT) is a safe and highly effective treatment modality for selective small lung lesions. Four-dimensional (4D) CT-based treatment plans were generated using advanced AcurosXB algorithm for heterogeneity corrections. 6X-FFF beam produced highly conformal radiosurgical dose distribution to the target and reduced lung SBRT fraction duration to less than 10 min for a single dose of 30 Gy, significantly improving patient comfort and clinic workflow. Early follow-up CT imaging results (mean, 8 months) show high local control rates (100%) with no acute lung or rib toxicity. Longer clinical follow-up in a larger patient cohort managed in this fashion is underway to further validate this treatment approach.

Evaluation of plan quality and treatment efficiency for single-isocenter/two-lesion lung stereotactic body radiation therapy.

PURPOSE/OBJECTIVES: To evaluate the plan quality and treatment delivery efficiency of single-isocenter/two-lesions volumetric modulated arc therapy (VMAT) lung stereotactic body radiation therapy (SBRT). MATERIALS/METHODS: Eight consecutive patients with two peripherally located early stage nonsmall-cell-lung cancer (NSCLC) lung lesions underwent single-isocenter highly conformal noncoplanar VMAT SBRT treatment in our institution. A single-isocenter was placed between the two lesions. Doses were 54 or 50 Gy in 3 and 5 fractions respectively. Patients were treated every other day. Plans were calculated in Eclipse with AcurosXB algorithm and normalized to at least 95% of the planning target volume (PTV) receiving 100% of the prescribed dose. For comparison, two-isocenter plans (isocenter placed centrally in each target) were retrospectively created. Conformity indices (CIs), heterogeneity index (HI), gradient index (GI), gradient distance (GD), and D2cm were calculated. The normal lung V5, V10, V20, mean lung dose (MLD) and other organs at risk (OARs) doses were evaluated. Total number of monitor units (MUs), beam-on time, and patient-specific quality assurance (QA) results were recorded. RESULTS: The mean isocenter to tumor distance was 6.7 ± 2.3 cm. The mean combined PTV was 44.0 ± 23.4 cc. There was no clinically significant difference in CI, HI, GD, GI, D2cm , and V20 including most of the OARs between single-isocenter and two-isocenter lung SBRT plans, evaluated per RTOG guidelines. However, for single-isocenter plans as the distance between the lesions increased, the V5, V10, and MLD increased, marginally. The total number of MUs and beam-on time was reduced by a factor of 1.5 for a single-isocenter plan compared to a two-isocenter plan. The single-isocenter/two-lesions VMAT lung SBRT QA plans demonstrated an accurate dose delivery of 98.1 ± 3.2% for clinical gamma passing rate of 3%/3 mm. CONCLUSION: The SBRT treatment of two peripherally located lung lesions with a centrally placed single-isocenter was dosimetrically equivalent to two-isocenter plans. Faster treatment delivery for single-isocenter treatment can improve patient compliance and reduce the amount of intrafraction motion errors for well-suited patients.

Receipt of adjuvant endometrial cancer treatment according to race: an NRG Oncology/Gynecologic Oncology Group 210 Study.

BACKGROUND: Black women with endometrial cancer are more likely to die of their disease compared with white women with endometrial cancer. These survival disparities persist even when disproportionately worse tumor characteristics among black women are accounted. Receipt of less complete adjuvant treatment among black patients with endometrial cancer could contribute to this disparity. OBJECTIVE: We assessed the hypothesis that black women with endometrial cancer are less likely than their white counterparts to receive adjuvant treatment within subgroups defined by tumor characteristics in the NRG Oncology/Gynecology Oncology Group 210 Study. STUDY DESIGN: Our analysis included 615 black and 4283 white women with endometrial cancer who underwent hysterectomy. Women completed a questionnaire that assessed race and endometrial cancer risk factors. Tumor characteristics were available from pathology reports and central review. We categorized women as low-, intermediate-, or high-risk based on the European Society for Medical Oncology definition. Adjuvant treatment was documented during postoperative visits and was categorized as no adjuvant treatment (54.3%), radiotherapy only (16.5%), chemotherapy only (15.2%), and radiotherapy plus chemotherapy (14.0%). We used polytomous logistic regression to estimate odds ratios and 95% confidence intervals for multivariable-adjusted associations between race and adjuvant treatment in the overall study population and stratified by tumor subtype, stage, or European Society for Medical Oncology risk category. RESULTS: Overall, black women were more likely to have received chemotherapy only (odds ratio, 1.40; 95% confidence interval, 1.04-1.86) or radiotherapy plus chemotherapy (odds ratio, 2.01; 95% confidence interval, 1.54-2.62) compared with white women in multivariable-adjusted models. No racial difference in the receipt of radiotherapy only was observed. In tumor subtype-stratified models, black women had higher odds of receiving radiotherapy plus chemotherapy than white women when diagnosed with low-grade endometrioid (odds ratio, 2.04; 95% confidence interval, 1.06-3.93) or serous tumors (odds ratio, 1.81; 95% confidence interval, 1.07-3.08). Race was not associated with adjuvant treatment among women who had been diagnosed with other tumor subtypes. In stage-stratified models, we observed no racial differences in the receipt of adjuvant treatment. In models that were stratified by European Society for Medical Oncology risk group, black women with high-risk cancer were more likely to receive radiotherapy plus chemotherapy compared with white women (odds ratio, 1.41; 95% confidence interval, 1.03-1.94). CONCLUSION: Contrary to our hypothesis, we observed higher odds of specific adjuvant treatment regimens among black women as compared with white women within specific subgroups of endometrial cancer characteristics.

Alcohol withdrawal in epileptic rats - Effects on postictal depression, respiration, and death.

Patients with epilepsy are at risk of sudden unexpected death in epilepsy (SUDEP). The most common series of events in witnessed cases of SUDEP is a generalized convulsive seizure followed by terminal apnea. Risk factors for SUDEP include prolonged postictal depression (PID), as well as alcohol abuse. The present study examined these issues in a genetic epilepsy model that exhibits generalized convulsive audiogenic seizures (AGSz) but rarely exhibits seizure-induced death, the genetically epilepsy-prone rats (GEPR-9s). We evaluated the effect of ethanol withdrawal (ETX) in GEPR-9s on respiration patterns, duration of PID, and the incidence of seizure-induced death. Audiogenic seizures were induced in GEPR-9s and in normal Sprague-Dawley rats, which were subjected to a 4-day binge ethanol protocol, 18-24h after the last ethanol dose. Following the tonic seizures, all GEPR-9s exhibited PID, characterized by loss of the righting reflex and respiratory distress (RD), which were absent during ETX seizures in the normal rats. During ETX, GEPR-9s exhibited significant increases in the duration of PID and RD, compared with vehicle-treated GEPR-9s. A significant increase in the incidence of death following seizure in GEPR-9s subjected to ETX was observed, compared with that in vehicle-treated GEPR-9s and normal rats subjected to ETX. Death in GEPR-9s was preceded by prolonged seizures because, in part, of the emergence of post-tonic generalized clonus. These results indicate that ETX induced significant increases in the duration of PID and RD, which contributed to the greater incidence of mortality in GEPR-9s compared with that in vehicle-treated GEPR-9s and normal rats. These experiments observed an elevated risk of sudden death associated with alcohol withdrawal in a genetic epilepsy model that had previously been identified as a risk factor in human SUDEP.

Serotonergic agents act on 5-HT3 receptors in the brain to block seizure-induced respiratory arrest in the DBA/1 mouse model of SUDEP.

Drugs that enhance the action of serotonin (5-hydroxytrypamine, 5-HT), including several selective serotonin reuptake inhibitors (SSRIs), reduce susceptibility to seizure-induced respiratory arrest (S-IRA) that leads to death in the DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP). However, it is not clear if specific 5-HT receptors are important in the action of these drugs and whether the brain is the major site of action of these agents in this SUDEP model. The current study examined the actions of agents that affect the 5-HT3 receptor subtype on S-IRA and whether intracerebroventricular (ICV) microinjection of an SSRI would reduce S-IRA susceptibility in DBA/1 mice. The data indicate that systemic administration of SR 57227, a 5-HT3 agonist, was effective in blocking S-IRA in doses that did not block seizures, and the S-IRA blocking effect of the SSRI, fluoxetine, was abolished by coadministration of a 5-HT3 antagonist, ondansetron. Intracerebroventricular administration of fluoxetine in the present study was also able to block S-IRA without blocking seizures. These findings suggest that 5-HT3 receptors play an important role in the block of S-IRA by serotonergic agents, such as SSRIs, which is consistent with the abnormal expression of 5-HT3 receptors in the brainstem of DBA mice observed previously. Taken together, these data indicate that systemically administered serotonergic agents act, at least, in part, in the brain, to reduce S-IRA susceptibility in DBA/1 mice and that 5-HT3 receptors may be important to this effect.

Implementation and early clinical results utilizing Cs-131 permanent interstitial implants for gynecologic malignancies.

OBJECTIVE: Permanent interstitial brachytherapy is an ideal yet underutilized treatment modality for accessible, small volume gynecological malignancies. We present early clinical results utilizing a new permanent isotope, Cs-131. METHODS: A retrospective review was performed evaluating patients treated with Cs-131 permanent interstitial radiation at our institution from July 2011 through June 2013. Doses were most commonly prescribed and calculated to a depth of 5mm using Paterson-Parker planar implant rules for Au-198. This activity was converted to air-kerma strength (U). A conversion factor of 1.1 was applied based on RBE calculations, clinical observation and experience. RESULTS: 14 patients were identified among whom 17 Cs-131 implants were performed. Seven patients were implanted as sole therapy, and a median dose of 50 Gy was delivered. Ten implants were performed as boost within a more extensive radiation treatment plan. In these patients, a median implant dose of 27.5 Gy was used and the median total dose delivered in combination was 78.25 Gy. After a median follow up of 12 months, the actuarial local control rate was 84.4%. A very low level of grade 1-3 reactions was observed with no fistula formations or other severe side effects. CONCLUSIONS: Permanent interstitial brachytherapy with Cs-131 was well tolerated with favorable early results compared to other series. Cs-131 has multiple favorable properties, including minimal radiation exposure to treating staff, and should be considered as a therapeutic option in appropriately selected patients. A methodology for dose prescription, calculation of radioactivity required and distribution of the isotope is also presented.

Impact of post-radiation biopsies on development of fistulae in patients with cervical cancer.

OBJECTIVE: In the post-radiation patient, late vascular sequelae and fibrosis predispose women to poor tissue healing, such that small tissue injuries could theoretically evolve into much larger ones such as fistulae. We sought to determine if a correlation exists between invasive procedures such as post-treatment biopsies and the subsequent development of gynecologic fistulae. METHODS: A retrospective review was performed evaluating all patients treated for cervical cancer at our institution between 1997 and 2010. Biopsies or pelvic surgeries were included if performed within the radiated field, and evaluated in a multivariate predictive model for development of gynecologic fistulae. RESULTS: Out of 325 total patients, 27 patients with fistulae were identified (8.2%). 14 fistulae (51.9%) were considered toxicity-related, 6 (22.2%) resulted from primary disease, and 7 (25.9%) were attributable to recurrent disease. Eighty-nine patients underwent an invasive procedure (55 biopsies and 34 pelvic surgeries). Recurrent and/or residual cancer was found in 28 (31.5%) specimens, and of the 61 patients who underwent an invasive procedure and were not found to have evidence of recurrent disease, 9 (14.8%) subsequently developed a fistula at a median 3.08 months. An elevated dose of radiation to the rectum (OR 1.001 for dose >72 Gy, p=0.0005), advancing tumor stage (OR 5.38 for stage III, OR 10.47 for stage IV, p=0.0288), and a post-radiation biopsy (OR 5.27, p=0.013) were significantly associated with fistula development. CONCLUSIONS: Performing a biopsy in an irradiated field is associated with a relatively low yield and significantly contributes to the risk for fistula development.

Serotonin and sudden death: differential effects of serotonergic drugs on seizure-induced respiratory arrest in DBA/1 mice.

In the DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP), administration of a selective serotonin (5-HT) reuptake inhibitor (SSRI), fluvoxamine, completely suppressed seizure-induced respiratory arrest (S-IRA) at 30 min after administration (i.p.) in a dose-related manner without blocking audiogenic seizures (AGSz), but another SSRI, paroxetine, reduced S-IRA but with a delayed (24 h) onset and significant toxicity. A serotonin-norepinephrine reuptake inhibitor, venlafaxine, reduced S-IRA incidence, but higher doses were ineffective. A selective 5-HT7 agonist, AS-19, was totally ineffective in reducing S-IRA. In developing DBA/1 mice that had not previously experienced AGSz, administration of a nonselective 5-HT antagonist, cyproheptadine, induced a significantly greater incidence of S-IRA than that of saline. This study confirms that certain drugs that enhance the activation of 5-HT receptors are able to prevent S-IRA, but not all serotonergic drugs are equally effective, which may be relevant to the potential use of these drugs for SUDEP prevention. Serotonergic antagonists may be problematic in patients with epilepsy.

Radiation Therapy With or Without Cisplatin for Local Recurrences of Endometrial Cancer: Results From an NRG Oncology/GOG Prospective Randomized Multicenter Clinical Trial.

PURPOSE: Pelvic recurrence is a frequent pattern of relapse for women with endometrial cancer. A randomized trial compared progression-free survival (PFS) after treatment with radiation therapy alone as compared with concurrent chemotherapy. MATERIALS AND METHODS: Between February 2008 and August 2020, 165 patients were randomly assigned 1:1 to receive either radiation treatment alone or a combination of chemotherapy and radiation treatment. The primary objective of this study was to determine whether chemoradiation therapy was more effective than radiation therapy alone at improving PFS. RESULTS: The majority of patients had low-grade (1 or 2) endometrioid histology (82%) and recurrences confined to the vagina (86%). External beam with either the three-dimensional or intensity modulated radiation treatment technique was followed by a boost delivered with brachytherapy or external beam. Patients randomly assigned to receive chemotherapy were treated with once weekly cisplatin (40 mg/m2). Rates of acute toxicity were higher in patients treated with chemoradiation as compared with radiation treatment alone. Median PFS was longer for patients treated with radiation therapy alone as compared with chemotherapy and radiation (median PFS was not reached for RT v 73 months for chemoradiation, hazard ratio of 1.25 (95% CI, 0.75 to 2.07). At 3 years, 73% of patients treated definitively with radiation and 62% of patients treated with chemoradiation were alive and free of disease progression. CONCLUSION: Excellent outcomes can be achieved for women with localized recurrences of endometrial cancer when treated with radiation therapy. The addition of chemotherapy does not improve PFS for patients treated with definitive radiation therapy for recurrent endometrial cancer and increases acute toxicity. Patients with low-grade and vaginal recurrences who constituted the majority of those enrolled are best treated with radiation therapy alone.