Introduction: Sotorasib has emerged as a treatment option for patients with KRAS-mutated non-small cell lung cancer (NSCLC); however, its effect in patients with brain metastases is not well described. We assessed the intracranial response of sotorasib in a retrospective case series of patients with brain metastases (BMs) at a single institution. Methods: Patients with KRAS-mutated NSCLC with BMs who received sotorasib at Mass General Brigham Hos-pitals were included. Patients were stratified into three groups: patients with active BM without local therapy within one month of sotorasib initiation (group 1), patients with active BM with local therapy (surgery or ra-diation) within one month of sotorasib initiation (group 2), and patients with stable BM (group 3). Intracranial progression-free survival (ICPFS) and overall survival (OS) were explored using Kaplan Meier curves that were compared through log-rank test. Results: Thirty patients were included (five in group 1; seven in group 2; 18 in group 3). Mean age at sotorasib initiation was 60 years. Most (67 %) patients had between one and four BMs at sotorasib initiation. Median ICPFS was three months (95 % CI: 0- 7.7) from start of sotorasib for group 1, two months (0-5.7) for group 2, and 15 months (6.0-24.0) for group 3 (p-value = 0.02). Median OS was four months (1.9-6.1) for group 1, six months (0-13.7) for group 2, and 12 months (3.5-20.5) for group 3 (p-value = 0.13). 57 % of patients experienced intracranial progression, including 44 % of patients who had stable BM at sotorasib initiation. Conclusion: While sotorasib may have some intracranial activity, a multidisciplinary approach to BM therapy is still warranted, as are future studies with larger patient samples, controls, and extended follow-up.

OBJECTIVE:The incidence of leptomeningeal disease (LMD) has increased as treatments for brain metastases (BMs) have improved and patients with metastatic disease are living longer. Sample sizes of individual studies investigating LMD after surgery for BMs and its risk factors have been limited, ranging from 200 to 400 patients at risk for LMD, which only allows the use of conventional biostatistics. Here, the authors used machine learning techniques to enhance LMD prediction in a cohort of surgically treated BMs.METHODS:A conditional survival forest, a Cox proportional hazards model, an extreme gradient boosting (XGBoost) classifier, an extra trees classifier, and logistic regression were trained. A synthetic minority oversampling technique (SMOTE) was used to train the models and handle the inherent class imbalance. Patients were divided into an 80:20 training and test set. Fivefold cross-validation was used on the training set for hyperparameter optimization. Patients eligible for study inclusion were adults who had consecutively undergone neurosurgical BM treatment, had been admitted to Brigham and Women's Hospital from January 2007 through December 2019, and had a minimum of 1 month of follow-up after neurosurgical treatment.RESULTS:A total of 1054 surgically treated BM patients were included in this analysis. LMD occurred in 168 patients (15.9%) at a median of 7.05 months after BM diagnosis. The discrimination of LMD occurrence was optimal using an XGboost algorithm (area under the curve = 0.83), and the time to LMD was prognosticated evenly by the random forest algorithm and the Cox proportional hazards model (C-index = 0.76). The most important feature for both LMD classification and regression was the BM proximity to the CSF space, followed by a cerebellar BM location. Lymph node metastasis of the primary tumor at BM diagnosis and a cerebellar BM location were the strongest risk factors for both LMD occurrence and time to LMD.CONCLUSIONS:The outcomes of LMD patients in the BM population are predictable using SMOTE and machine learning. Lymph node metastasis of the primary tumor at BM diagnosis and a cerebellar BM location were the strongest LMD risk factors.

Background Laser interstitial thermal therapy (LITT) in the setting of post-SRS radiation necrosis (RN) for patients with brain metastases has growing evidence for efficacy. However, questions remain regarding hospitalization, local control, symptom control, and concurrent use of therapies. Methods Demographics, intraprocedural data, safety, Karnofsky performance status (KPS), and survival data were prospectively collected and then analyzed on patients who consented between 2016-2020 and who were undergoing LITT for biopsy-proven RN at one of 14 US centers. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable Fine and Gray analysis, and Kaplan-Meier estimated survival. Results Ninety patients met the inclusion criteria. Four patients underwent 2 ablations on the same day. Median hospitalization time was 32.5 hours. The median time to corticosteroid cessation after LITT was 13.0 days (0.0, 1229.0) and cumulative incidence of lesional progression was 19% at 1 year. Median post-procedure overall survival was 2.55 years [1.66, infinity] and 77.1% at one year as estimated by KaplanMeier. Median KPS remained at 80 through 2-year follow-up. Seizure prevalence was 12% within 1-month post-LITT and 7.9% at 3 months; down from 34.4% within 60-day prior to procedure. Conclusions LITT for RN was not only again found to be safe with low patient morbidity but was also a highly effective treatment for RN for both local control and symptom management (including seizures). In addition to averting expected neurological death, LITT facilitates ongoing systemic therapy (in particular immunotherapy) by enabling the rapid cessation of steroids, thereby facilitating maximal possible survival for these patients.

BACKGROUND: Current prognostic models for brain metastases (BMs) have been constructed and validated almost entirely with data from patients receiving up-front radiotherapy, leaving uncertainty about surgical patients. OBJECTIVE: To build and validate a model predicting 6-month survival after BM resection using different machine learning algorithms. METHODS: An institutional database of 1062 patients who underwent resection for BM was split into an 80:20 training and testing set. Seven different machine learning algorithms were trained and assessed for performance; an established prognostic model for patients with BM undergoing radiotherapy, the diagnosis-specific graded prognostic assessment, was also evaluated. Model performance was assessed using area under the curve (AUC) and calibration. RESULTS: The logistic regression showed the best performance with an AUC of 0.71 in the hold-out test set, a calibration slope of 0.76, and a calibration intercept of 0.03. The diagnosis-specific graded prognostic assessment had an AUC of 0.66. Patients were stratified into regular-risk, high-risk and very high-risk groups for death at 6 months; these strata strongly predicted both 6-month and longitudinal overall survival ( P < .0005). The model was implemented into a web application that can be accessed through http://brainmets.morethanml.com. CONCLUSION: We developed and internally validated a prediction model that accurately predicts 6-month survival after neurosurgical resection for BM and allows for meaningful risk stratification. Future efforts should focus on external validation of our model.

BACKGROUND:In patients with locally recurrent brain metastases (LRBMs), the role of (repeat) craniotomy is controversial. This study aimed to analyze long-term oncological outcomes in this heterogeneous population. METHODS:Craniotomies for LRBM were identified from a tertiary neuro-oncological institution. First, we assessed overall survival (OS) and intracranial control (ICC) stratified by molecular profile, prognostic indices, and multimodality treatment. Second, we compared LRBMs to propensity score-matched patients who underwent craniotomy for newly diagnosed brain metastases (NDBM). RESULTS:Across 180 patients, median survival after LRBM resection was 13.8 months and varied by molecular profile, with >24 months survival in ALK/EGFR+ lung adenocarcinoma and HER2+ breast cancer. Furthermore, 102 patients (56.7%) experienced intracranial recurrence; median time to recurrence was 5.6 months. Compared to NDBMs (n = 898), LRBM patients were younger, more likely to harbor a targetable mutation and less likely to receive adjuvant radiation (P < 0.05). After 1:3 propensity matching stratified by molecular profile, LRBM patients generally experienced shorter OS (hazard ratio 1.67 and 1.36 for patients with or without a mutation, P < 0.05) but similar ICC (hazard ratio 1.11 in both groups, P > 0.20) compared to NDBM patients with similar baseline. Results across specific molecular subgroups suggested comparable effect directions of varying sizes. CONCLUSIONS:In our data, patients with LRBMs undergoing craniotomy comprised a subgroup of brain metastasis patients with relatively favorable clinical characteristics and good survival outcomes. Recurrent status predicted shorter OS but did not impact ICC. Craniotomy could be considered in selected, prognostically favorable patients.

PURPOSE:Patients with triple-negative breast cancer (TNBC) experience higher local-regional recurrence rates than those with luminal or HER2-positive tumors. This prospective, phase 1B trial was designed to assess the safety and to establish the maximum tolerated dose (MTD) of cisplatin with radiation therapy for women with early-stage TNBC.METHODS AND MATERIALS:Eligible patients had stage II or III TNBC. Cisplatin was initiated at 10 mg/m2 intravenously once weekly during radiation and then escalated in a 3 + 3 design by 10 mg/m2 at each dose level until 40 mg/m2, or the MTD, was reached. Patients undergoing breast-conserving therapy (BCT) or mastectomy were accrued in separate parallel cohorts during dose escalation, followed by a 10-patient expansion at the MTD.RESULTS:During 2013 to 2018, 55 patients were accrued. Four patients developed dose-limiting toxicity. In the BCT cohort, 1 patient receiving 40 mg/m2 developed tinnitus resulting in a cisplatin delay; therefore, this was the BCT cohort MTD. In the mastectomy cohort, 1 patient receiving 20 mg/m2 developed a grade 3 urinary infection, and 2 additional patients had dose-limiting toxicities at 40 mg/m2 (grade 3 neutropenia and grade 2 tinnitus), both resulting in cisplatin delay. Thus, 30 mg/m2 was the mastectomy cohort MTD. Median follow-up was 48.5 months. Three-year disease-free survival was 74.7% for the BCT cohort and 64.4% for the mastectomy cohort.CONCLUSIONS:Adjuvant radiation therapy with concurrent cisplatin is feasible with a recommended phase 2 dose of 30 mg/m2 and 40 mg/m2 intravenously weekly in mastectomy and BCT cohorts, respectively.

Abstract INTRODUCTION Small cell lung cancer (SCLC) is known for rapid growth, and about 40-50% of SCLC patients will develop brain metastases (BM). The addition of immune checkpoint inhibitors (ICI) to the standard chemotherapy, which is the current backbone of first-line therapy, has resulted in more prolonged survival than chemotherapy alone in SCLC patients. PURPOSE This study aimed to assess the effect of ICI before BM development in SCLC patients on time to BM development and survival. METHODS A single-institutional retrospective review of SCLC patients that underwent cranial radiation therapy between January 2014 and June 2020 was performed to assess the impact of ICI therapy on time to BM development, overall survival (OS), and time to failure of BM treatment (defined as local or distant BM recurrence) using a multivariable Cox Proportional Hazards model. RESULTS Among 197 included patients, 23 patients (11.7%) received ICI before BM development. Extensive stage of SCLC at diagnosis was observed in eighteen patients (78.2%) in the ICI group and 133 (76.4%) in the non-ICI group. In total, seventeen patients (8.6%) received prophylactic cranial irradiation, of which seven patients (30.4%) also received ICI. ICI were associated with prolonged time to BM in comparison with the non-ICI group (HR = 0.29, 95% CI: 0.18-0.47). ICI were also associated with an increased OS (HR = 0.56, 95% CI: 0.32-0.97) and prolonged time to BM treatment failure (HR = 0.32, 95% CI: 0.15-0.71) in comparison with patients who did not receive ICI. CONCLUSION The use of ICI before BM development was associated with a longer time to BM. Additionally, ICI therapy was associated with an increased OS and prolonged BM treatment failure. These results are a proof of concept of the potential benefit of ICI therapy in SCLC patients, and the presented results should be further validated in larger cohorts.

In several cancers treated with immune checkpoint inhibitors (ICIs), a remarkable association between the occurrence of immune-related adverse events (irAEs) and superior oncological outcomes has been reported. This effect has hitherto not been reported in the brain. This study aimed to investigate the relation between irAEs and outcomes in brain metastases (BM) patients treated with both local treatment to the brain (LT; i.e. surgery and/or radiation) and ICIs. This study is a retrospective cohort analysis of patients treated for non-small cell lung cancer (NSCLC) BMs in a tertiary institution in Boston, MA. Outcomes of interest were overall survival (OS) and intracranial progression-free survival (IC-PFS), measured from the time of LT. Sensitivity analyses were performed to account for immortal time bias (i.e., patients who live longer receive more cycles of ICIs and thus have more opportunity to develop an irAE). A total of 184 patients were included; 62 (33.7%) were treated with neurosurgical resection and 122 (66.3%) with upfront brain radiation. irAEs occurred in 62 patients (33.7%). After adjusting for lung-Graded Prognostic Assessment, type of LT, type of ICI, newly diagnosed vs. recurrent BM, BM size and number, targetable mutations, and smoking status, irAEs were strongly associated with better OS (HR 0.33, 95% CI 0.19 – 0.58, p < 0.0001) and IC-PFS (HR 0.41; 95% CI 0.26 – 0.65; p = 0.0001). Landmark analysis including only patients who received more than 3 cycles of ICI (n = 133) demonstrated similar results for OS and IC-PFS, as did sensitivity analysis adjusting for the number of cycles administered (HR range 0.36 – 0.51, all p-values < 0.02). After adjusting for known prognostic factors, irAEs strongly predict superior outcomes after LT in NSCLC BM patients. Sensitivity analysis suggests that this is unlikely due to immortal time bias.

PURPOSE:Among patients with brain metastases, hippocampal avoidance whole brain radiation (HA-WBRT) preserves neurocognitive function relative to conventional WBRT but the feasibility of hippocampal sparing in patients with metastases in/near the hippocampus is unknown. We identified the incidence of hippocampal/perihippocampal metastases and evaluated the feasibility of HA-WBRT in such patients.MATERIALS/METHODS:Dosimetric data from 34 patients randomized to HA-WBRT (30 Gy/10 fractions) in a phase III trial (NCT03075072) comparing HA-WBRT to stereotactic radiation in patients with 5 to 20 brain metastases were analyzed. Patients with metastases in/near the hippocampi received HA-WBRT with prioritization of tumor coverage over hippocampal avoidance. Target coverage and hippocampal sparing metrics were compared between patients with targets in/near the hippocampus versus not.RESULTS:In total, 9 of 34 (26%) patients had targets in the hippocampus and an additional 5 of 34 (15%) patients had targets in the hippocampal avoidance zone (HAZ, hippocampus plus 5 mm expansion) but outside the hippocampus. Patients with targets within the hippocampus and those with targets in the HAZ but outside the hippocampus were spared 34% and 73% of the ipsilateral mean biologically equivalent prescription dose, respectively. Of the latter cohort, 88% and 25% met conventional hippocampal sparing metrics of Dmin ≤ 9 Gy and Dmax ≤ 16 Gy, respectively. Among 11 patients with unilateral hippocampal/perihippocampal involvement, the uninvolved/contralateral hippocampus was limited to Dmin ≤ 9 Gy and Dmax ≤ 17 Gy in all cases.CONCLUSIONS:In this study, a substantial percentage of patients with 5 to 20 brain metastases harbored metastases in/near the hippocampus. In such cases, minimizing hippocampal dose while providing tumor coverage was feasible and may translate to neurocognitive protection.

Abstract BACKGROUND Programmed death receptor ligand one (PD-L1) expression is known to predict response to PD-1/PD-L1 inhibitors in non-small cell lung cancer (NSCLC). However, the predictive role of this biomarker in brain metastases (BMs) is unknown. The aim of this study was to assess whether PD-L1 expression predicts survival in patients with NSCLC BMs treated with PD-1/PD-L1 inhibitors, after adjusting for established prognostic models. METHODS In this multi-institutional retrospective cohort study, we identified NSCLC-BM patients treated with PD-1/PD-L1 inhibitors after local BM treatment (radiotherapy or neurosurgery) but before intracranial progression. Cox proportional hazards models were used to assess predictive value PD-L1 expression for overall survival (OS) and intracranial progression free survival (IC-PFS). RESULTS Forty-eight BM patients with available PD-L1 expression were identified. PD-L1 expression was positive in 33 patients (69%). Median survival was 26 months. In univariable analysis, PD-L1 predicted favorable OS (HR = 0.44; 95% CI 0.19 – 1.02; p = 0.055). This effect persisted after correcting for lung-graded prognostic assessment (lung-GPA) and other identified potential confounders (HR = 0.24; 95% CI = 0.10 – 0.61; p = 0.002). Moreover, when modeled as a continuous variable, there appeared to be a proportional relationship between percentage of PD-L1 expression and survival (HR = 0.86 per 10% expression, 95% CI 0.77 – 0.98, p = 0.02). In contrast, PD-L1 expression did not predict IC-PFS in uni- or multivariable analysis (adjusted HR = 0.54, 95% CI 0.26 – 1.14, p = 0.11). CONCLUSIONS In patients with NSCLC-BMs treated with PD-1/PD-L1 checkpoint inhibitors and local treatment, PD-L1 expression may predict OS independent of lung-GPA. IC-PFS did not show association with PD-L1 expression, although the present analysis may lack power to assess this. Larger studies are required to validate these findings.

Brain metastases can be radiographically cystic or solid. Cystic metastases are associated with a greater intracranial disease burden and poorer oncologic outcomes, but the impact of cystic versus solid appearance on local control after radiation remains unknown. We investigated whether cystic versus solid nature is predictive of local control after management with stereotactic or whole brain radiation (WBRT) and whether the radiation modality utilized is an effect modifier.

301 Background: Modern cancer care faces increasing complexity and the challenge of delivering consistent, high-quality care across growing networks. Dana-Farber Pathways address these concerns by translating expert content into treatment algorithms delivered through a web-based platform and implemented across the network. We had previously built 31 Medical Oncology (MO) pathways. Our goal was to build and implement Radiation Oncology (RO) pathways for common cancer conditions in 18 months. Methods: Partnering with lead clinicians from each disease group, we chose the most appropriate framework for each pathway: expand previously established RO pathway; use corresponding MO pathway; or if no framework was available, develop RO pathway in its entirety. We worked with each disease group to gain consensus about the recommended on-pathway selections that reflect the latest research and institutional standard of care. Implementation consisted of pre- and post-launch department communications about metric goals and individual provider training on the system. Because the program was launched without provider incentivization, the usage rate goal was navigations for at least 25% of patients receiving radiation treatment. The on-pathway rate goal range was 70-80%. Results: We exceeded our goal: we built and implemented 25 pathways in 12 months and constructed all 27 pathways in 18 months. We have met both key rate goals across all disease pathways since time of launch: usage rate is 63%; on-pathway rate is 85% (39 providers across 3 sites). Conclusions: A preliminary analysis of RO Pathway data demonstrates collective adoption across all sites. Qualitative surveys show it to be a useful resource in radiation treatment decision-making and in palliative care service. We will continue to analyze the use of RO Pathways and develop strategies to collaborate with MO to further guide multi-disciplinary decision-making.[Table: see text]

BACKGROUND:Brain metastases commonly manifest in patients with cancer, with ∼20%-50% presenting with 1 intracranial lesion. Among patients with 1, small brain metastasis and controlled or absent extracranial disease, it remains unclear whether aggressive intracranial management using neurosurgical resection plus cavity stereotactic radiosurgery/stereotactic radiotherapy (SRS/SRT) rather than SRS/SRT alone is beneficial. In patients with controlled or absent extracranial disease and 1 brain metastasis ≤2 cm in size, we evaluated the effect of surgery plus SRS/SRT compared with SRS/SRT on oncologic outcomes, including overall survival. METHODS:We retrospectively identified 86 patients with controlled or absent extracranial disease and 1 brain metastasis ≤2 cm in size who had been treated from 2000 to 2015 at our institution. We examined differences in the rates of local and distant failure, use of salvage treatment, and other oncologic outcomes, including all-cause mortality. RESULTS:The baseline characteristics were similar between the 2 cohorts. The median follow-up period for the surviving patients was 38 months. On multivariable analysis, surgical resection plus cavity SRS/SRT was associated with a lower risk of all-cause mortality (hazard ratio, 0.44; 95% confidence interval, 0.19-1.00; P = 0.05) compared with SRS/SRT alone. The 1- and 2-year rates of overall survival were 100% and 88% versus 74% and 52% for surgery plus cavity SRS/SRT versus SRS/SRT alone, respectively. CONCLUSIONS:Aggressive, local therapy, including neurosurgical resection, might benefit patients with 1 brain metastasis in the context of controlled or absent systemic disease, even if the lesion in question is small. Further studies are needed to evaluate these associations.

Purpose: Acute gastrointestinal (GI) toxicity has been studied inGI and gynecological (GYN) cancers, with volume receiving 15 Gy (V15) <830 mL, V25 <650 mL, and V45 <195 mL identified as dose constraints for the peritoneal space (bowel bag [BB]). There are no reported constraints derived from retroperitoneal sarcoma (RPS), and prospective trials for RPS have adopted some of the GI and GYN constraints. This study quantified GI toxicity during preoperative radiation therapy (RT) for RPS, assessed toxicity using published constraints, and evaluated predictors for toxicity.Methods and materials: From 2003 to 2013, 56 patients with RPS underwent preoperative RT at 2 institutions. Toxicity was scored using Radiation Therapy Oncology Group criteria for upper and lower acute GI toxicity. BB was contoured on planning computed tomography scans per Radiation Therapy Oncology Group atlas guidelines with review by a radiologist. Relationships among toxicity, clinical factors, and BB dose were analyzed.Results: Three patients (5%) developed grade >= 3 acute GI toxicity: 2 grade 3 toxicities (anorexia and nausea) and 1 grade 5 toxicity (tumor-bowel fistula). Thirty-six patients (64%) had grade 2 toxicity (nausea, 55%; diarrhea, 23%; pain, 20%). Tumor size was the only significant clinical predictor of grade >= 2 acute GI toxicity. Larger mean BB volumes predicted for grade >= 2 toxicity (P = .001). On receiver operating characteristics analysis, V30 was the best discriminator for toxicity (P = .0001). Median BB V15 was 1375 mL; 75% of patients had V15 >= 830 mL. Median V25 was 1083 mL; 68% had V25 >= 650 mL. Median V45 was 575 mL; 82% had V45 >= 195 mL. V25 >= 650 mL was significantly associated with grade >= 2 toxicity (P = .01).Conclusions: Among patients treated with preoperative RT for RPS, significant acute GI toxicity was very low despite BB dose exceeding established constraints for most cases. Acceptable dose constraints for RPS may be higher than those for GI or GYN cancers. Further assessment of dose-volume constraints for RPS is needed. (C) 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Purpose: To investigate the dosimetric variability associated with interobserver organat- risk delineation differences on computed tomography in patients undergoing gynecologic interstitial brachytherapy.Methods and Materials: The rectum, bladder, and sigmoid of 14 patients treated with gynecologic interstitial brachytherapy were retrospectively contoured by 13 physicians. Geometric variability was calculated using k statistics, conformity index (CIgen), and coefficient of variation (CV) of volumes contoured across physicians. Dosimetric variability of the single-fraction D-0.1cc and D-2cc was assessed through CV across physicians, and the standard deviation of the total EQD2 (equivalent dose in 2 Gy per fraction) brachytherapy dose (SD TOT) was calculated.Results: The population mean +/- 1 standard deviation of k, CIgen, and volume CV were, respectively: 0.77 +/- 0.06, 0.70 +/- 0.08, and 20% +/- 6% for bladder; 0.74 +/- 06, 0.67 +/- 0.08, and 20% +/- 5% for rectum; and 0.33 +/- 0.20, 0.26 +/- 0.17, and 82% +/- 42% for sigmoid. Dosimetric variability was as follows: for bladder, CV = 31% +/- 19% (SD TOT = 72 +/- 64 Gy) for D-0.1cc and CV = 16% +/- 10% ( SDTOT = 9 +/- 6 Gy) for D-2cc; for rectum, CV=11% +/- 5%( SD TOT=16 +/- 17 Gy) forD(0.1cc) and CV=7% +/- 2% (SD TOT = 4 +/- 3 Gy) for D-2cc; for sigmoid, CV = 39% +/- 28% (SD TOT = 12 +/- 18 Gy) for D-0.1cc and CV = 34% +/- 19% ( SD TOT = 4 +/- 4 Gy) for D-2cc.Conclusions: Delineation of bladder and rectum by 13 physicians demonstrated substantial geometric agreement and resulted in good dosimetric agreement for all dose- volume histogram parameters except bladder D-0.1cc. Small delineation differences in high- dose regions by the posterior bladder wall may explain these results. The delineation of sigmoid showed fair geometric agreement. The higher dosimetric variability for sigmoid compared with rectum and bladder did not correlate with higher variability in the total brachytherapy dose but rather may be due to the sigmoid being positioned in low-dose regions in the cases analyzed in this study. (c) 2014 Elsevier Inc.

The addition of androgen deprivation therapy (ADT) to external beam radiotherapy (RT) decreases prostate cancer-specific mortality (PCSM) in patients with intermediate- and high-risk prostate cancer (PCa); however, whether this is true across the spectrum of percent positive biopsy (PPB) values is unknown and was evaluated in the current study.

We provide evidence that differing Gleason scores (GSs) at biopsy (ComboGS) is associated with an approximately 80% decrease in the odds of upgrading and a 60% decrease in the risk of prostate cancer-specific mortality (PCSM) after definitive treatment. If validated, future randomized noninferiority studies evaluating deescalated treatment approaches in men with ComboGS could be considered. Introduction/Background: The GS is an established prostate cancer prognostic factor. Whether the presence of differing GSs at biopsy (eg, 4+3 and 3+3), which we term ComboGS, improves the prognosis that would be predicted based on the highest GS (eg, 4+3) because of decreased upgrading is unknown. Therefore, we evaluated the odds of upgrading at time of radical prostatectomy (RP) and the risk of PCSM when ComboGS was present versus absent. Patients and Methods: Logistic and competing risks regression were performed to assess the effect that ComboGS had on the odds of upgrading at time of RP in the index (n = 134) and validation cohorts (n = 356) and the risk of PCSM after definitive therapy in a long-term cohort (n = 666), adjusting for known predictors of these end points. We calculated and compared the area under the curve using a receiver operating characteristic analysis when ComboGS was included versus excluded from the upgrading models. Results: ComboGS was associated with decreased odds of upgrading (index: adjusted odds ratio [AOR], 0.14; 95% confidence interval [CI], 0.04-0.50; P = .003; validation: AOR, 0.24; 95% CI, 0.11-0.51; P < .001) and added significantly to the predictive value of upgrading for the in-sample index (P = .02), validation (P = .003), and out-of-sample prediction models (P = .002). ComboGS was also associated with a decreased risk of PCSM (adjusted hazard ratio, 0.40; 95% CI, 0.19-0.85; P = .02). Conclusion: Differing biopsy GSs are associated with a lower odds of upgrading and risk of PCSM. If validated, future randomized noninferiority studies evaluating deescalated treatment approaches in men with ComboGS could be considered. (C) 2014 Elsevier Inc. All rights reserved.

INTRODUCTION/BACKGROUND:Men with highest GS ≥ 7 and a differing, lower GS core (ComboGS) have decreased PC-specific mortality (PCSM) risk after RT or RT and androgen deprivation therapy (ADT). Whether the greatest percentage of involved core length (GPC) modulates this risk is unknown. PATIENTS AND METHODS:Men with GS ≥ 7 PC (n = 333) consecutively treated between December 1989 and July 2000 using RT (n = 268; 80%) or RT and 6 months of ADT (n = 65; 20%) comprised the study cohort. The GPC was calculated using biopsy core and tumor lengths. We used competing risks regression to assess whether increasing GPC was associated with increased PCSM risk in men with or without ComboGS adjusting for risk group, age, and treatment. RESULTS:After a median follow-up of 5.36 years (interquartile range, 3.22-7.61 years), 92 (28%) men died, 28 (30%) of PC. Increasing GPC was significantly associated with increased risk of PCSM (adjusted hazard ratio, 1.02; 95% confidence interval, 1.01-1.03; P = .005). Men with GPC ≥ 50% versus < 50% had significantly greater PCSM estimates when ComboGS was present (P < .001) versus absent (P = .55). Of the 127 men with ComboGS and GPC < 50%, 83% were treated with RT alone and 2 PC deaths were observed; neither in men with GS 7 and favorable intermediate-risk PC. CONCLUSION:Men treated with RT for ComboGS, GPC < 50%, GS 7, and favorable intermediate-risk PC have a very low risk of early PCSM. The RTOG 0815 trial will establish whether ADT is necessary to optimize curability in these men.

e16026 Background: We evaluated the odds of upgrading at radical prostatectomy when a biopsy core with a lower Gleason score (GS) compared to the core with the highest GS was present (ComboGS) versus not at diagnosis and in a concurrent submission, test ComboGS in a validation data set on the endpoint of prostate cancer-specific mortality. Methods: The study cohort consisted of 134 men with clinically localized PC diagnosed between 4/08 and 9/11 using a 12-core prostate needle biopsy. GS at biopsy and RP were assigned by an expert genitourinary pathologist. Logistic regression multivariable analysis (Table) was performed to assess the impact that ComboGShad on the odds of upgrading at RP adjusting for known predictors of upgrading. Results: Of 134 patients, 46 (34%) were upgraded. Both increasing percent positive biopsies (ppb) (p < 0.001) and PSA level (p=0.001) were associated with an increased odds of upgrading, whereas ComboGSwas associated with a decreased odds of upgrading (0.18 [95% CI: 0.04-0.76); p = 0.02). Men whose ppb was ≥ 33% (median) were upgraded in 47% (28 of 60) versus 14% (3 of 21) of cases (p = 0.009) when ComboGSwas absent versus present. These respective estimates in men with a PSA ≥ 5.2 ng/ml (median) were 43% and 12% (p = 0.019). Conclusions: In men with clinical factors associated with upgrading namely, increasing ppb and PSA, ComboGSis a favorable prognostic factor associated with a high rate of downgrading (> 40%) and a low rate (< 15%) of upgrading. Adjusted odds ratios and associated 95% confidence intervals and p values representing the impact of clinical factors at diagnosis on upgrading at radical prostatectomy. [Table: see text]