Patterns of Progression in Patients With Newly Diagnosed Glioblastoma Treated With 5-mm Margins in a Phase 1/2 Trial of 5-Fraction Stereotactic Radiosurgery With Concurrent and Adjuvant Temozolomide.

PURPOSE: In patients with newly diagnosed glioblastoma (GBM), tumor margins of at least 20 mm are the standard of care. We sought to determine the pattern of tumor progression in patients treated with 5-fraction stereotactic radiosurgery with 5-mm margins. METHODS AND MATERIALS: Thirty adult patients with newly diagnosed GBM were treated with 5-fraction stereotactic radiosurgery in escalated doses from 25 to 40 Gy with a 5-mm total treatment margin. Progression was scored as "in-field" if the recurrent tumor was within or contiguous with the 5-mm margin, "marginal" if between 5 and 20 mm, and "distant" if entirely occurring greater than 20 mm. As geometric patterns of progression do not reflect the biologic dose received, we calculated the minimum equi-effective dose in 2 Gy (EQD2) per day at the site of tumor recurrence. Progression was "dosimetrically in-field" if covered by a minimum EQD2 per day of 48 Gy10. RESULTS: From 2010 to 2016, 27 patients had progressed. Progression was in-field in 17 (63%), marginal in 3 (11%), and distant in 7 (26%) patients. In the 3 patients with marginal progression, the minimum EQD2 to recurrent tumor were 48 Gy10, 56 Gy10 (both considered dosimetrically in-field), and 7 Gy10 (ie, dosimetrically out-of-field). Median overall survival was 12.1 months for in-field (95% confidence interval [CI], 8.9-17.6), 15.1 months (95% CI, 10.1 to not achieved) for marginal, and 21.4 months (95% CI, 11.2-33.5) for distant progression. Patients with radiation necrosis were less likely to have in-field progression (1 of 7; 14%) compared with those without radiation necrosis (16 of 20; 80%; P = .003); those with necrosis had a median overall survival of 27.2 months (95% CI, 11.2-48.3) compared with 11.7 months (95% CI, 8.9-17.6) for patients with no necrosis (P = .077). CONCLUSIONS: In patients with newly diagnosed GBM treated with a 5-mm clinical target volume margin, 3 patients (11%) had marginal progression within 5 to 20 mm; only 1 patient (4%) may have dosimetrically benefitted from conventional 20-mm margins. Radiation necrosis was associated with in-field tumor control.

The Impact of Racial Disparities on Outcome in Patients With Stage IIIC Endometrial Carcinoma: A Pooled Data Analysis.

OBJECTIVE: To report the impact of race on clinical outcomes in patients with stage IIIC endometrial carcinoma. MATERIALS AND METHODS: A retrospective multi-institutional study included 90 black and 568 non-black patients with stage IIIC endometrial carcinoma who received adjuvant chemotherapy and radiation treatments. Overall survival (OS) and recurrence-free survival (RFS) were calculated by the Kaplan-Meier method. Propensity score matching (PSM) was conducted. Statistical analyses were conducted using SPSS version 27. RESULTS: The Median follow-up was 45.3 months. black patients were significantly older, had more nonendometrioid histology, grade 3 tumors, and were more likely to have >1 positive paraaortic lymph nodes compared with non-black patients (all P <0.0001). The 5-year estimated OS and RFS rates were 45% and 47% compared with 77% and 68% for black patients versus non-black patients, respectively ( P <0.001). After PSM, the 2 groups were well-balanced for all prognostic covariates. The estimated hazard ratios of black versus non-black patients were 1.613 ( P value=0.045) for OS and 1.487 ( P value=0.116) for RFS. After PSM, black patients were more likely to receive the "Sandwich" approach and concurrent chemoradiotherapy compared with non-black ( P =0.013) patients. CONCLUSIONS: Black patients have higher rates of nonendometrioid histology, grade 3 tumors, and number of involved paraaortic lymph nodes, worse OS, and RFS, and were more likely to receive the "Sandwich" approach compared with non-black patients. After PSM, black patients had worse OS with a nonsignificant trend in RFS. Access to care, equitable inclusion on randomized trials, and identification of genomic differences are warranted to help mitigate disparities.

Does Prophylactic Paraortic Lymph Node Irradiation Improve Outcomes in Women With Stage IIIC1 Endometrial Carcinoma?

PURPOSE: To evaluate the impact of prophylactic paraortic lymph node (PALN) radiation therapy (RT) on clinical outcomes in patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 endometrial cancer (EC). METHODS AND MATERIALS: A multi-institutional retrospective study included patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 EC lymph node assessment, status postsurgical staging, followed by adjuvant chemotherapy and RT using various sequencing regimens. Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. Univariable and multivariable analysis were performed by Cox proportional hazard models for RFS/OS. In addition, propensity score matching was used to estimate the effect of the radiation field extent on survival outcomes. RESULTS: A total of 378 patients were included, with a median follow-up of 45.8 months. Pelvic RT was delivered to 286 patients, and 92 patients received pelvic and PALN RT. The estimated OS and RFS rates at 5 years for the entire cohort were 80% and 69%, respectively. There was no difference in the 5-year OS (77% vs 87%, P = .47) and RFS rates (67% vs 70%, P = .78) between patients treated with pelvic RT and those treated with pelvic and prophylactic PALN RT, respectively. After propensity score matching, the estimated hazard ratios (HRs) of prophylactic PALN RT versus pelvic RT were 1.50 (95% confidence interval, 0.71-3.19; P = .28) for OS and 1.24 (95% confidence interval, 0.64-2.42; P = .51) for RFS, suggesting that prophylactic PALN RT does not improve survival outcomes. Distant recurrence was the most common site of first recurrence, and the extent of RT field was not associated with the site of first recurrence (P = .79). CONCLUSIONS: Prophylactic PALN RT was not significantly associated with improved survival outcomes in stage IIIC1 EC. Distant metastasis remains the most common site of failure despite routine use of systemic chemotherapy. New therapeutic approaches are necessary to optimize the outcomes for women with stage IIIC1 EC.

Financial Toxicity in Patients with Brain and Spine Metastases.

OBJECTIVE: Financial toxicity associated with cancer treatment has a deleterious impact on patient outcomes but has not been well characterized among patients with metastatic cancers. We characterize the extent of financial toxicity among this population and identify factors associated with financial toxicity. METHODS: We prospectively surveyed adult patients with brain and spine metastases who received radiosurgery at a large academic medical center between January 2018 and December 2019. Financial toxicity was measured with the Personal Financial Wellness (PFW) scale. RESULTS: In total, 93 patients were included, with a median survival of 17.7 months. Most patients had private insurance (47%) or Medicare with supplementary insurance (42%), whereas 11% of patients were uninsured or insured by Medicaid/Medicare/Veterans Affairs. Of patients, 60% were primary income earners, of whom 52% had dependents. The median PFW score was 7.0 (interquartile range, 5.1-9.1), with financial toxicity reported in 23 patients (25%). After adjusting for age and education level, private insurance (odds ratio [OR], 0.28; P = 0.080) was associated with a lower likelihood of financial toxicity. Having ≥1 emergency department visit (OR, 3.87; P = 0.024) and a cancer-related change in employment status (OR, 3.63; P = 0.036) were associated with greater likelihood of reporting financial toxicity. CONCLUSIONS: Most patients with cancer with brain and spine metastases with a poor prognosis treated at a tertiary center are primary income earners and experience financial toxicity. Further studies are warranted to assess the longitudinal impact of financial toxicity in patients with metastatic cancer, particularly those with ≥1 emergency department visit and a cancer-related change in employment status.

Prospective randomized trial of email and/or telephone reminders to enhance vaginal dilator compliance in patients undergoing brachytherapy for gynecologic malignancies.

PURPOSE: To evaluate whether email survey +/- telephone reminder versus no intervention would facilitate compliance with vaginal dilator use in women undergoing brachytherapy for gynecologic malignancies and to assess changes in vaginal canal (VC) length between the groups. METHODS AND MATERIALS: A 72 patients were enrolled onto a three-arm single-institution randomized prospective clinical trial and stratified by whether they received external beam radiation treatment in addition to brachytherapy and by total radiation dose to the VC. Patients were subsequently randomized to one of three groups: email survey alone, email survey + telephone reminder, or no intervention. Change in VC length over time was measured for each patient. RESULTS: The median follow-up time was 17.3 months. There were no differences in patient-reported compliance between the 3 groups. Vaginal dilator compliance fell over the course of the study period and was 33% at 24 months. Baseline VC length and radiation dose were found to be the most important predictors of VC shortening over time. When accounting for baseline length, radiation dose, and follow-up time, type of intervention did not impact changes in VC length from baseline (p = 0.20). CONCLUSIONS: Our study is the first to show the importance of baseline VC length as it relates to VC shortening following brachytherapy for gynecologic cancers and highlights the difficulties in improving VC compliance among this patient population. Further study is required to improve the incidence of late effects in this group.

A Multi-Institutional Analysis of Adjuvant Chemotherapy and Radiation Sequence in Women With Stage IIIC Endometrial Cancer.

PURPOSE: Our purpose was to evaluate the effect of sequence and type of adjuvant therapy for patients with stage IIIC endometrial carcinoma (EC) on outcomes. METHODS AND MATERIALS: In a multi-institutional retrospective cohort study, patients with stage IIIC EC who had surgical staging and received both adjuvant chemotherapy and radiation therapy (RT) were included. Adjuvant treatment regimens were classified as adjuvant chemotherapy followed by sequential RT (upfront chemo), which was predominant sequence; RT with concurrent chemotherapy followed by chemotherapy (concurrent); systemic chemotherapy before and after RT (sandwich); adjuvant RT followed by chemotherapy (upfront RT); or chemotherapy concurrent with vaginal cuff brachytherapy alone (chemo-brachy). Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. RESULTS: A total of 686 eligible patients were included with a median follow-up of 45.3 months. The estimated 5-year OS and RFS rates were 74% and 66%, respectively. The sequence and type of adjuvant therapy were not correlated with OS or RFS (adjusted P = .68 and .84, respectively). On multivariate analysis, black race, nonendometrioid histology, grade 3 tumor, stage IIIC2, and presence of adnexal and cervical involvement were associated with worse OS and RFS (all P < .05). Regardless of the sequence of treatment, the most common site of first recurrence was distant metastasis (20.1%). Vaginal only, pelvic only, and paraortic lymph node (PALN) recurrences occurred in 11 (1.6%),15 (2.2 %), and 43 (6.3 %) patients, respectively. Brachytherapy alone was associated with a higher rate of PALN recurrence (15%) compared with external beam radiation therapy (5%) P < .0001. CONCLUSIONS: The sequence and type of combined adjuvant therapy did not affect OS or RFS rates. Brachytherapy alone was associated with a higher rate of PALN recurrence, emphasizing the role of nodal radiation for stage IIIC EC. The vast proportion of recurrences were distant despite systemic chemotherapy, highlighting the need for novel regimens.

Phase II trial evaluating efficacy of a Fitbit program for improving the health of endometrial cancer survivors.

BACKGROUND: Despite the favorable prognosis of early stage endometrial cancer, mortality from cardiovascular disease is high. We aimed to evaluate the efficacy of a Fitbit program to improve physical activity in endometrial cancer survivors. METHODS: Eligible patients were diagnosed with stage IA-IIIA endometrial adenocarcinoma, ≥3 months out from treatment. Participants received a Fitbit Alta and were randomized to receive communication via telephone or electronic methods (email/text). Communication was every two weeks for two months, then once during months four and five. Average daily steps were assessed weekly for nine months. RESULTS: The 46 analyzable patients demonstrated a baseline of 5641 median daily average steps. Average steps increased by 22% at 6 months but decreased to baseline by nine months. Baseline activity level (daily steps and walks per week) was the greatest predictor of activity level. Only the telephone intervention participants demonstrated increased activity level at several timepoints, although not maintained by nine months. BMI was unchanged. There was mild improvement in physical and social well-being in those with low baseline well-being (p = 0.009 and 0.014, respectively), regardless of intervention group. Emotional well-being correlated with step count (p = 0.005). CONCLUSIONS: Activity level was low and mildly improved on the Fitbit program with the telephone intervention, but effects did not persist by study completion. The program had the greatest impact on a select group of telephone intervention patients with high baseline walking frequency and low baseline step count. Others may require more intense intervention to promote more robust/persistent lifestyle changes.

A phase I/II trial of 5-fraction stereotactic radiosurgery with 5-mm margins with concurrent temozolomide in newly diagnosed glioblastoma: primary outcomes.

BACKGROUND: We sought to determine the maximum tolerated dose (MTD) of 5-fraction stereotactic radiosurgery (SRS) with 5-mm margins delivered with concurrent temozolomide in newly diagnosed glioblastoma (GBM). METHODS: We enrolled adult patients with newly diagnosed glioblastoma to 5 days of SRS in a 3 + 3 design on 4 escalating dose levels: 25, 30, 35, and 40 Gy. Dose limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events grades 3-5 acute or late CNS toxicity, including adverse radiation effect (ARE), the imaging correlate of radiation necrosis. RESULTS: From 2010 to 2015, thirty patients were enrolled. The median age was 66 years (range, 51-86 y). The median target volume was 60 cm3 (range, 14.7-137.3 cm3). DLT occurred in 2 patients: one for posttreatment cerebral edema and progressive disease at 3 weeks (grade 4, dose 40 Gy); another patient died 1.5 weeks following SRS from postoperative complications (grade 5, dose 40 Gy). Late grades 1-2 ARE occurred in 8 patients at a median of 7.6 months (range 3.2-12.6 mo). No grades 3-5 ARE occurred. With a median follow-up of 13.8 months (range 1.7-64.4 mo), the median survival times were: progression-free survival, 8.2 months (95% CI: 4.6-10.5); overall survival, 14.8 months (95% CI: 10.9-19.9); O6-methylguanine-DNA methyltransferase hypermethylated, 19.9 months (95% CI: 10.5-33.5) versus 11.3 months (95% CI: 8.9-17.6) for no/unknown hypermethylation (P = 0.03), and 27.2 months (95% CI: 11.2-48.3) if late ARE occurred versus 11.7 months (95% CI: 8.9-17.6) for no ARE (P = 0.08). CONCLUSIONS: The per-protocol MTD of 5-fraction SRS with 5-mm margins with concurrent temozolomide was 40 Gy in 5 fractions. ARE was limited to grades 1-2 and did not statistically impact survival.

Improving gynecologic brachytherapy patient experience by optimizing MRI, anesthesia, and scheduling to decrease the length of time tandem and ovoid applicators are in place.

PURPOSE: Brachytherapy requires multiple different steps and plays a critical role in treatment for gynecological cancer. In an effort to improve gynecologic patient experience, we investigated how different aspects of the procedure influence how long the patient has the brachytherapy applicator in place. METHODS AND MATERIALS: We prospectively recorded 145 consecutive tandem and ovoid treatments for 33 patients and determined how anesthesia vs. conscious sedation, MRI or not, and the number of procedures in the day impact applicator in time. The data were analyzed in a mixed effects linear regression model to account for the within-patient correlation. RESULTS: We found average applicator in place time was 179 minutes (range: 87-311 minutes). Patients who received anesthesia had a significant increase in length of applicator in patient time by an average of 42 minutes compared with those who received conscious sedation. Undergoing an MRI increased length of applicator in time by an average of 66 minutes, although the actual MRI performed generally took less than 30 minutes. Having three or more procedures scheduled for 1 day increased the length of time the tandem and ovoid was inserted by an average of 35 minutes. CONCLUSION: The use of anesthesia vs. conscious sedation, MRI scans for treatment planning, and number of procedures scheduled per day have significant influence on the duration of brachytherapy treatments. This information can help us work to optimize scheduling and thereby improve patient brachytherapy experience.

Long-Term Update of Stereotactic Radiosurgery for Benign Spinal Tumors.

BACKGROUND: Stereotactic radiosurgery (SRS) for benign intracranial tumors is an established standard of care. The widespread implementation of SRS for benign spinal tumors has been limited by lack of long-term data. OBJECTIVE: To update our institutional experience of safety and efficacy outcomes after SRS for benign spinal tumors. METHODS: We performed a retrospective cohort study of 120 patients with 149 benign spinal tumors (39 meningiomas, 26 neurofibromas, and 84 schwannomas) treated with SRS between 1999 and 2016, with follow-up magnetic resonance imaging available for review. The primary endpoint was the cumulative incidence of local failure (LF), with death as a competing risk. Secondary endpoints included tumor shrinkage, symptom response, toxicity, and secondary malignancy. RESULTS: Median follow-up was 49 mo (interquartile range: 25-103 mo, range: 3-216 mo), including 61 courses with >5 yr and 24 courses with >10 yr of follow-up. We observed 9 LF for a cumulative incidence of LF of 2%, 5%, and 12% at 3, 5, and 10 yr, respectively. Excluding 10 tumors that were previously irradiated or that arose within a previously irradiated field, the 3-, 5-, and 10-yr cumulative incidence rates of LF were 1%, 2%, and 8%, respectively. At last follow-up, 35% of all lesions had decreased in size. With a total of 776 patient-years of follow-up, no SRS-related secondary malignancies were observed. CONCLUSION: Comparable to SRS for benign intracranial tumors, SRS provides longer term local control of benign spinal tumors and is a standard-of-care alternative to surgical resection.

Improving brachytherapy efficiency with dedicated dosimetrist planners.

PURPOSE: To investigate the different factors affecting the procedure duration for high-dose-rate brachytherapy for gynecologic malignancies. METHODS AND MATERIALS: We prospectively recorded 86 consecutive vaginal cylinder (VC) treatments and 82 tandem and ovoid treatments. Key time points in the brachytherapy process, identity of the planner and checker, number of treatments per day, and fraction number per patient were recorded. The data were analyzed in a mixed effects linear regression model to account for the within patient correlation. Post hoc pair-wise comparisons were performed using a Dunnett's adjustment for comparisons to a single control group and using a Tukey adjustment for all pair-wise comparisons. RESULTS: We focused on several key time intervals in the treatment: total, nursing/anesthesia preprocedure, procedure, contouring, and planning times. In analysis, multiple factors significantly influenced VC timing but not tandem and ovoid timing. The planners were separated and analyzed based on experience and profession. Inexperienced physicists planning times were on average 18 min (p = 0.0010) and 14 min (p = 0.0038) slower than dedicated brachytherapy dosimetrist and experienced physicists, respectively. An increase in the number of procedures for the day of treatment increased the VC total time (p = 0.0218). The VC procedure time changed depending on whether it was the patients' first, second, or third VC treatment (p < 0.0001). CONCLUSIONS: The use of dosimetrists as dedicated planners for brachytherapy is more cost and time efficient. There are multiple variables affecting brachytherapy treatment with actionable opportunities to improve procedure scheduling.