HyperArc VMAT stereotactic radiotherapy for locally recurrent previously-irradiated head and neck cancers: Plan quality, treatment delivery accuracy, and efficiency.

PURPOSE: This paper demonstrates the clinical feasibility and efficacy of HyperArc VMAT treatments for locally recurrent, locally advanced, or previously irradiated head and neck cancers treated with stereotactic radiotherapy (SRT). MATERIALS/METHODS: First, an anthropomorphic SRS head phantom from the MD Anderson's IROC credentialing laboratory containing a 1.9 cm diameter spherical target, including in vivo dosimetry system, was imaged, planned, and irradiated (25 Gy in 1 fraction) using HyperArc VMAT with a 6 MV flattening filter free (FFF) beam. Second, RANDO phantom was imaged, planned, and irradiated (35 Gy in 5 fractions) by generating eight HyperArc VMAT plans (4 right, 4 left neck tumors) at different anatomical locations (C1-C4). Average tumor volume was 21.7 cm3 up to 32.3 cm3 . Distance to isocenter from the central marker of the Encompass device down to neck was 25.8 cm up to 28.0 cm and 24.3 cm up to 27.1 cm for left- and right-sided neck tumors, respectively, and 9 cm from both lateral markers defined by the patient protection zone. Third, seven recurrent head and neck cancer patients with 80.3 cm3 tumors on average, and up to 159 cm3 , were imaged, planned, and treated with 30-40 Gy in 5 fractions with HyperArc SRT. Plan quality, treatment delivery accuracy, and efficiency are reported herein. RESULTS: Phantom irradiation results met all the compliance requirements set forth by the IROC for HyperArc SRS treatment. For end-to-end RANDO phantom tests, a highly conformal target dose distribution with 50% isodose fall-off within 5 mm from the surface of the target was obtained. Average beam modulation factor, beam-on-time, and overall treatment time were 2.9, 2.56 min, and 13.96 min with 99.1% pre-treatment quality assurance pass rate for the 2%/2 mm gamma criteria, respectively. Immediately adjacent critical structures, such as the spinal cord (maximum, 3.9 Gy and 0.35 cm3 of cord, 3.7 Gy) and skin (maximum, 10.3 Gy and 10 cm3 of skin, 5.7 Gy), were spared. Similar results were found on the patient's HyperArc VMAT plans including highly conformal target coverage, sharp dose fall-off, and low doses to the adjacent critical organs such as the spinal cord (< 5 Gy). Average perfect pitch couch correction was <1.5 mm and 2° in each direction. Average beam-on-time was approximately 3.21 min and treatments were completed within 15 min. CONCLUSION: For recurrent head and neck SRT treatments, HyperArc VMAT provided highly conformal dose distributions, rapid dose fall-off, excellent sparing of adjacent critical organs, and highly accurate treatments that could be delivered down to the C4 vertebral level. This could potentially allow for delivery of HyperArc SRT to patients with glomus tumors as well to those who may not tolerate frame-based SRS treatment. Clinical follow up of these patients is ongoing to confirm the therapeutic benefits of this novel treatment option.

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.

Human epidermal growth factor receptor 2 expression in women with uterine cervix adenocarcinoma from Appalachian Kentucky.

Introduction: High-risk human epidermal growth factor receptor 2 (HER2)-positive adenocarcinomas associate with early recurrence and death, prompting consideration of novel radiotherapeutic options like a trastuzumab-linked thorium-227 alpha-particle emitting radionuclide. Methods: We conducted a retrospective pilot biomarker study of uterine cervix cancers among patients in Appalachian Kentucky, to characterize an exploitable triage biomarker like HER2 expression before starting a prospective phase 0 trial. Results: Most (60%) adenocarcinomas showed HER2 cell-surface overexpression, whereas squamous cell carcinomas (4%) did not do so. Discussion: Further validation tests of HER2 expression as a triage biomarker for radiopharmaceutical selection are warranted.

Human gastrin- releasing peptide receptor expression in women with uterine cervix cancer.

Introduction: 212Pb-DOTAM-GRPR1 is a pharmaceutical radioimmunoconjugate consisiting of an α-particle-emitting radionuclide lead-212 (212Pb), a metal chelator DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), and a gastrin-releasing peptide receptor (GRPR)-targeted antagonist currently being evaluated as therapy in uterine cervix and other cancer types. Previous studies have revealed that a variable proportion of uterine cervix cancer tumors overexpress the radiopharmaceutical target GRPR when assessed by cell proportion and staining intensity immunoreactive scores (IRS). Tumor response to 212Pb-DOTAM-GRPR1 strongly associates with GRPR overexpression, and therefore, it seems reasonable to assess uterine cervix cancer GRPR immunoreactivity for greater insight into the feasibility of using 212Pb-DOTAM-GRPR1 as a radiopharmaceutical treatment. Methods: We examined a series of 33 uterine cervix cancer paraffin-embedded tumors in order to establish whether this tumor type overexpresses GRPR at an IRS score of 6 or higher, as 212Pb-DOTAM-GRPR1 is currently being evaluated in clinical trials against tumors showing such a level of expression. Results: The results show that five of five (100%) primary adenocarcinomas and 10 of 16 (63%) primary squamous cell tumors overexpress GRPR at an IRS score of 6 or higher. Discussion: The frequency of overexpression in this study suggests that 212Pb-DOTAM-GRPR1 radiopharmaceutical treatment may be useful in the management of persistent, recurrent, or metastatic uterine cervix cancer patients. A phase I clinical trial involving patients with metastatic uterine cervix cancer is currently underway (NCT05283330).

Hemoglobin level associates with survival in women from Appalachian Kentucky with uterine cervix cancer.

Introduction: The purpose of this retrospective study was to determine the relationship between pretherapy hemoglobin levels and progression-free survival among women with uterine cervix cancer undergoing concurrent weekly cisplatin and radiotherapy followed by brachytherapy. Methods: Patients with advanced-stage II-IVA uterine cervix cancer were grouped by hemoglobin level (Hgb ≥ 12.0, 11.9-10.0, or < 10.0 g/dL). Endpoints were progression-free survival, overall survival, and local control. Results: Between 01/2001 and 07/2022, 168 patients contributed demographic, tumor, pretherapy hemoglobin, and outcome data with a median follow-up of 31 months. Progression-free survival at three years was 73% (95% confidence interval: 58%-84%), 71% (95% confidence interval: 56%-82%), and 62% (95% confidence interval: 44%-75%) for the Hgb ≥ 12.0, 11.9-10.0, or < 10.0 g/dL groups, respectfully (P < 0.001). In addition, pretherapy hemoglobin levels were significant with treatment outcome when included in a multivariate analysis of prognostic variables. Discussion: In conclusion, the difference in pretherapy hemoglobin level was prognostic of progression-free survival.

Effects of Interfraction Dose Variations of Target and Organs at Risk on Clinical Outcomes in High Dose Rate Brachytherapy for Cervical Cancer.

Meeting dose prescription is critical to control tumors in radiation therapy. Interfraction dose variations (IDVs) from the prescribed dose in high dose rate brachytherapy (HDR) would cause the target dose to deviate from the prescription but their clinical effect has not been widely discussed in the literature. Our previous study found that IDVs followed a left-skewed distribution. The clinical effect of the IDVs in 100 cervical cancer HDR patients will be addressed in this paper. An in-house Monte Carlo (MC) program was used to simulate clinical outcomes by convolving published tumor dose response curves with IDV distributions. The optimal dose and probability of risk-free local control (RFLC) were calculated using the utility model. The IDVs were well-fitted by the left-skewed Beta distribution, which caused a 3.99% decrease in local control probability and a 1.80% increase in treatment failure. Utility with respect to IDV uncertainty increased the RFLC probability by 6.70% and predicted an optimal dose range of 83 Gy-91 Gy EQD2. It was also found that a 10 Gy dose escalation would not affect toxicity. In conclusion, HRCTV IDV uncertainty reduced LC probabilities and increased treatment failure rates. A dose escalation may help mitigate such effects.

Statistical Analysis of Interfraction Dose Variations of High-Risk Clinical Target Volume and Organs at Risk for Cervical Cancer High-Dose-Rate Brachytherapy.

Purpose: High-dose-rate (HDR) brachytherapy for cervical cancer treatment includes significant uncertainties. The aim of this study was to quantify the interfraction dosimetric variation (IDV) of the high-risk clinical target volume (HRCTV) from the prescribed dose and the corresponding effect on organ-at-risk (OAR) dose based on a comprehensive statistical analysis. Methods and Materials: Fifty patients with cervical cancer treated with high-dose-rate intracavity brachytherapy from October 2019 to December 2020 were retrospectively analyzed. The OARs of interest were the rectum, bladder, sigmoid, and bowel. The dosimetric parameters evaluated for all patients was the dose absorbed by 90% of the HRCTV ( D 90 ) and the dose absorbed by 0.1 ( D 0.1 c c ) and 2 cm3 ( D 2 c c ) of each respective OAR. The HRCTV variations were from the prescribed dose and the OAR variations were from the corresponding tolerance dose. Distribution fitting of the HRCTV variations was determined to quantify the IDV. Comparative statistics of the HRCTV variations with the OAR variations were conducted to determine correlations. Results: The mean HRCTV variation from the prescribed dose was -2.53% ± 8.74%. The HRCTV variations and OAR variations showed moderate to weak linear correlations despite the variations being relative to each other, with the bladder D 2 c c having the strongest correlation. There was a 30.0% (±2.62%, 95% confidence interval) probability of underdosing the HRCTV (-5% variation from prescription) and a 23.3% (±2.62%, 95% confidence interval) probability of overdosing the HRCTV (+5% variation from prescription). This tendency to underdose the HRCTV was a consequence of HRCTV IDV not being normally distributed. Conclusions: HRCTV dosimetric variations and OAR variations were complexly correlated with the bladder D 2 c c having the strongest correlation. HRCTV IDV was best described as a left-skewed distribution that indicates a tendency of underdosing the HRCTV. The clinical significance of such dose variations is expected and will be further investigated.

Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases.

INTRODUCTION: Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT. METHODS AND MATERIALS: Patients with brain metastases (BM) received daily trametinib for 28 days, starting 7 days prior to and continuing through WBRT (37.5 Gy/15 fractions). Dose levels (DL)1-3 were 1.0, 1.5, and 2.0 mg. The MTD of trametinib plus WBRT, the max dose where ≤1 of 6 patients experienced a dose limiting toxicity (DLT), was the primary endpoint. RESULTS: 10 patients were enrolled (median age-59 [47-64], BM-5 [1-10], 50% melanoma). Three and 7 patients were assigned to DL1 and 2. One DL2 patient withdrew. 89% of remaining patients completed therapy per protocol, but 1 DL2 patient with systemic progression discontinued therapy at 30 Gy. Thirteen grade (G)3-4 toxicities were observed, of which 12 occurred at DL2 (4/6 of patients). DLT was reached at DL2 (G4 thrombocytopenia and G3 diarrhea, 1 each). There were no G5 toxicities. Median overall survival was 2.2 months. During the study period, changing practice patterns favored utilization of stereotactic radiosurgery (SRS). Thus, the trial closed early prior to completion. CONCLUSIONS: In a patient population representative of modern candidates for WBRT, trametinib plus WBRT is highly toxic with a MTD <1.5 mg. The safety of trametinib with SRS remains an important question for future study.

Management of multiple brain metastases via dual-isocenter VMAT stereotactic radiosurgery.

Single-isocenter volumetric modulated arc therapy (VMAT) stereotactic radiosurgery (SRS) techniques to treat multiple brain metastases simultaneously can significantly improve treatment delivery efficiency, patient compliance, and clinic workflow. However, due to large number of brain metastases sharing the same MLC pair causing island blocking, there is higher low- and intermediate-dose spillage to the normal brain and higher dose to organs-at-risk (OAR). To minimize this problem and improve plan quality, this study proposes a dual-isocenter planning strategy that groups lesions based on hemisphere location (left vs right sided) in the brain parenchyma, providing less island blocking reducing the MLC travel distance. This technique offers simplified planning while also increasing patient comfort and compliance by allowing for large number of brain metastases to be treated in 2 groups. Seven complex patients with 5 to 16 metastases (64 total) were planned with a single-isocenter VMAT-SRS technique using a 10MV-FFF beam with a prescription of 20 Gy to each lesion. The isocenter was placed at the approximate geometric center of the targets. Each patient was replanned using the dual-isocenter approach, generating 2 plans and placing each isocenter at the approximate geometric center of the combined targets of each side with corresponding non-coplanar partial arcs. Compared to single-isocenter VMAT, dual-isocenter VMAT plans provided similar target coverage and dose conformity with less spread of intermediate dose to normal brain with reduction of dose to OAR. Reduction in total monitor units and beam on time was observed, but due to the second isocenter setup and verification, overall treatment time was increased. Dual-isocenter VMAT-SRS planning for multiple brain metastases is a simplified approach that provides superior treatment options for patient compliance who may not tolerate longer traditional treatment times as with individual isocenters to each target. This planning technique significantly reduces the amount of low- and intermediate-dose spillage, further sparing OAR and normal brain, potentially improving target accuracy though localization of left vs right-sided tumors for each isocenter set up.

Characterization of Uterine Cervix Cancers in Women from Appalachian Kentucky.

Uterine cervix cancer (UCCx) is clinically and socioeconomically diverse among women in the United States (US), which obscures the discovery of effective radiochemotherapy approaches for this disease. UCCx afflicts 7.5 per 100,000 American women nationally but 11.7 per 100,000 women in Appalachian Kentucky (AppKY), when age-adjusted to the 2000 US standard population. Epidemiological chart review was performed on 212 women with UCCx treated at the University of Kentucky (UKY) between January 2001 and July 2021. Demographics, tumor characteristics, and relative radiochemotherapy dose and schedule intensity were compared among AppKY and non-AppKY cohorts as well as Surveillance, Epidemiology, and End Results (SEER) data. One hundred thirty-eight (65%) of 212 women seeking radiochemotherapy treatment for UCCx resided in AppKY. Most (80%) sought external-beam radiochemotherapy close to their AppKY residence. Brachytherapy was then most frequently (96%) conducted at UKY. Cancer stage at diagnosis was significantly more advanced in AppKY residents. Women residing in AppKY had a median 10-week radiochemotherapy course, longer than an 8-week guideline. Estimated survival in women residing in AppKY was 8% lower than US national averages. In summary, this study identified an increased percentage of advanced-stage UCCx cancer at diagnosis arising in AppKY residents, with a confounding population-specific delay in radiochemotherapy schedule intensity lowering survival.

Treatment of locally advanced cervical cancer in a patient with a bicornuate uterus with MRI-guided intracavitary/interstitial brachytherapy.

PURPOSE: Definitive treatment for locally advanced cervical cancer (LACC) includes external beam radiation therapy (EBRT) with concurrent cisplatin and brachytherapy. Image-guided intracavitary brachytherapy utilizes CT and/or MRI for target and organ at risk delineation and has been shown to improve local control rates and decrease toxicity. Hybrid intracavitary/interstitial applicators can be used to improve tumor coverage in certain cases. We describe the use of combined intracavitary/interstitial brachytherapy to treat a cervical cancer patient with a bicornuate uterus. CASE PRESENTATION: A 30-year-old female with bicornuate uterus and FIGO IB2 adenocarcinoma of the cervix was treated with 45 Gy of EBRT to the pelvis with concurrent weekly cisplatin. An examination after EBRT demonstrated a persistent bulky tumor covering most of the cervix. Brachytherapy was delivered via a combined intracavitary/interstitial approach, using a tandem and ring applicator and an interstitial needle. The placement of the tandem was alternated between uterine cornua with each fraction, and the interstitial needle was placed on the side opposite the tandem. CT and MRI were obtained with each fraction. The patient completed the treatment without complications. Three-month restaging PET-CT showed significant interval improvement in the cervix, with a complete clinical response on physical examination. The patient is without evidence of disease 18 months after the treatment. CONCLUSIONS: We found that the use of the hybrid applicator allowed for adequate target coverage in a patient with unusual anatomy. The patient tolerated treatment well and demonstrated favorable response on follow-up exam and imaging. The long-term curative result needs to be further evaluated.

Waldenström's macroglobulinemia masquerading as ovarian cancer with peritoneal carcinomatosis, ascites, and elevated CA-125.

Waldenström's macroglobulinemia is a rare hematology malignancy which often presents with "B symptoms," anemia, and thrombocytopenia. A 46-year-old woman presented with 2 months of abdominal distension accompanied by an unintentional 20-lb weight loss. Her abdominal CT scan demonstrated diffuse carcinomatosis with bilateral ovarian lesions and screening labs revealed a markedly elevated CA-125, suggesting a diagnosis of ovarian cancer. Upon admission for workup, patient was found to have a significant protein gap, later attributed to a markedly elevated IgM. Omental and bone marrow biopsy confirmed the diagnosis of Waldenström's macroglobulinemia, with elevation in CA-125 thought to be secondary to peritoneal irritation. This patient has since been successfully treated with six cycles of bendamusine and rituximab with no evidence of disease on staging scans and normalization of both CA-125 and IgM. To our knowledge, this is the first documented case of Waldenström's macroglobulinemia presenting with symptoms classically associated with ovarian cancer and demonstrates the importance of maintaining a broad differential when evaluating patients with abdominal carcinomatosis.

Increasing Radiation Dose to the Thoracic Marrow Is Associated With Acute Hematologic Toxicities in Patients Receiving Chemoradiation for Esophageal Cancer.

Purpose: To test the hypothesis that increasing radiation dose to the thoracic marrow (TM) contributes to the development of hematologic toxicities (HT) in esophageal cancer (EC) patients receiving chemoradiation therapy (CRT). Methods: We identified EC cases treated with curative intent CRT at our institution from 2007 to 2016. The TM was contoured as the union of the vertebral bodies (VB) from T1-L1, the ribs from T1-L1, and the sternum. The TM-mean dose and the TM volume receiving at least 5-50 Gy (V5-V50) were collected. Grade ≥ 3 HT (HT3+) was the primary endpoint. Normal tissue complication probability (NTCP) was evaluated using the Lyman-Kutcher-Burman (LKB) model. Logistic regression was used to test associations between HT3+ and dosimetric parameters. Odds ratios (OR) and 95% confidence intervals (CI) are reported with p < 0.05 considered significant. Receiver operating characteristics analysis was used to determine optimal cut points. Results: We identified 137 EC cases, and most received concurrent carboplatin/paclitaxel (N = 83). Median radiation dose was 50.4 Gy (IQR = 50.4-50.4 Gy). The rate of HT3+ was 39.4%. Optimization of the LKB model yielded the results n = 0.70, m = 0.67, and TD50 = 20.1 Gy. The TM-V30 was most strongly associated with HT3+ and on multivariate analysis, patients with TM-V30 ≥ 14% had a 5.7-fold (95% CI 2.42-14.54, p < 0.001) increased odds of HT3+ in the entire cohort and a 4-fold (95% CI 1.54-11.11, p = 0.006) increased odds of HT3+ in the carboplatin/paclitaxel cohort compared to patients with TM-V30 < 14%. Radiation dose to the VB and rib sub-sites of the TM were also associated with HT3+, particularly VB-V40. Conclusion: We found that increasing TM radiation dose was associated with HT3+ in EC patients treated with CRT. Radiation dose to the VB and rib sub-sites were also associated with HT3+. These findings suggest that limiting radiation dose to the TM (or its sub-sites) may be sufficient to decrease HT3+, but further prospective evaluation of these results is needed.

Treatment of Glioblastoma (GBM) with the Addition of Tumor-Treating Fields (TTF): A Review.

Glioblastoma (GBM) is the most common primary brain tumor. Despite aggressive treatment, GBM almost always recurs. The current standard-of-care for treatment of newly diagnosed GBM has remained relatively unchanged since 2005: maximal safe resection followed by concomitant chemoradiation (CRT) with temozolomide (TMZ), and subsequent adjuvant TMZ. In 2011, the first-generation tumor treating fields (TTF) device, known at the time as the NovoTTF-100A System (renamed Optune), was approved by the Food and Drug Administration (FDA) for treatment of recurrent GBM. The TTF device was subsequently approved as an adjuvant therapy for newly-diagnosed GBM in 2015. The following is a review of the TTF device, including evidence supporting its use and limitations.

Association of MGMT Promoter Methylation Status With Survival Outcomes in Patients With High-Risk Glioma Treated With Radiotherapy and Temozolomide: An Analysis From the NRG Oncology/RTOG 0424 Trial.

Importance: The initial report of NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0424 demonstrated a 3-year overall survival benefit with the addition of temozolomide to radiotherapy compared with a historical control. However, an important end point of the trial-evaluation of the association between O6-methylgaunine-DNA-methyltransferase (MGMT) promoter methylation and survival outcomes-was not previously reported. Objective: To examine the proportion of patients in NRG Oncology/RTOG 0424 with MGMT promoter methylation and its association with survival outcomes. Design, Setting, and Participants: Specimens collected were analyzed after trial completion to determine MGMT promoter methylation and IDH1/2 status and the association between MGMT status and survival outcomes. A model derived from logistic regression (MGMT-STP27) was used to calculate MGMT promoter methylation status. Univariate and multivariable analyses were performed using the Cox proportional hazards regression model to determine the association of MGMT status with survival outcomes. Patient pretreatment characteristics were included as covariates in multivariable analyses. Main Outcomes and Measures: Progression-free survival (PFS) and overall survival (OS). Results: Of all 129 eligible patients in NRG Oncology/RTOG 0424, 75 (58.1%) had MGMT status available (median age, 48 years; age range, 20-76 years; 42 [56.0%] male): 57 (76.0%) methylated and 18 (24.0%) unmethylated. A total of 13 unmethylated patients (72.2%) had astrocytoma as opposed to oligoastrocytoma or oligodendroglioma, whereas 23 methylated patients (40.4%) had astrocytoma. On univariate analyses, an unmethylated MGMT promoter was significantly associated with worse OS (hazard ratio [HR], 3.52; 95% CI, 1.64-7.56; P < .001) and PFS (HR, 3.06; 95% CI, 1.55-6.04; P < .001). The statistical significances were maintained in multimarker multivariable analyses, including IDH1/2 status for both OS (HR, 2.70; 95% CI, 1.02-7.14; P = .045) and PFS (HR, 2.74; 95% CI, 1.19-6.33; P = .02). Conclusions and Relevance: In this study, MGMT promoter methylation was an independent prognostic biomarker of high-risk, low-grade glioma treated with temozolomide and radiotherapy. This is the first study, to our knowledge, to validate the prognostic importance of MGMT promoter methylation in patients with grade II glioma treated with combined radiotherapy and temozolomide and highlights its potential prognostic value beyond IDH1/2 mutation status. Trial Registration: ClinicalTrials.gov Identifier: NCT00114140.

A novel miRNA-based predictive model for biochemical failure following post-prostatectomy salvage radiation therapy.

PURPOSE: To develop a microRNA (miRNA)-based predictive model for prostate cancer patients of 1) time to biochemical recurrence after radical prostatectomy and 2) biochemical recurrence after salvage radiation therapy following documented biochemical disease progression post-radical prostatectomy. METHODS: Forty three patients who had undergone salvage radiation therapy following biochemical failure after radical prostatectomy with greater than 4 years of follow-up data were identified. Formalin-fixed, paraffin-embedded tissue blocks were collected for all patients and total RNA was isolated from 1mm cores enriched for tumor (>70%). Eight hundred miRNAs were analyzed simultaneously using the nCounter human miRNA v2 assay (NanoString Technologies; Seattle, WA). Univariate and multivariate Cox proportion hazards regression models as well as receiver operating characteristics were used to identify statistically significant miRNAs that were predictive of biochemical recurrence. RESULTS: Eighty eight miRNAs were identified to be significantly (p<0.05) associated with biochemical failure post-prostatectomy by multivariate analysis and clustered into two groups that correlated with early (≤ 36 months) versus late recurrence (>36 months). Nine miRNAs were identified to be significantly (p<0.05) associated by multivariate analysis with biochemical failure after salvage radiation therapy. A new predictive model for biochemical recurrence after salvage radiation therapy was developed; this model consisted of miR-4516 and miR-601 together with, Gleason score, and lymph node status. The area under the ROC curve (AUC) was improved to 0.83 compared to that of 0.66 for Gleason score and lymph node status alone. CONCLUSION: miRNA signatures can distinguish patients who fail soon after radical prostatectomy versus late failures, giving insight into which patients may need adjuvant therapy. Notably, two novel miRNAs (miR-4516 and miR-601) were identified that significantly improve prediction of biochemical failure post-salvage radiation therapy compared to clinico-histopathological factors, supporting the use of miRNAs within clinically used predictive models. Both findings warrant further validation studies.