Genomic biomarkers to guide precision radiotherapy in prostate cancer.

Our ability to prognosticate the clinical course of patients with cancer has historically been limited to clinical, histopathological, and radiographic features. It has long been clear however, that these data alone do not adequately capture the heterogeneity and breadth of disease trajectories experienced by patients. The advent of efficient genomic sequencing has led to a revolution in cancer care as we try to understand and personalize treatment specific to patient clinico-genomic phenotypes. Within prostate cancer, emerging evidence suggests that tumor genomics (e.g., DNA, RNA, and epigenetics) can be utilized to inform clinical decision making. In addition to providing discriminatory information about prognosis, it is likely tumor genomics also hold a key in predicting response to oncologic therapies which could be used to further tailor treatment recommendations. Herein we review select literature surrounding the use of tumor genomics within the management of prostate cancer, specifically leaning toward analytically validated and clinically tested genomic biomarkers utilized in radiotherapy and/or adjunctive therapies given with radiotherapy.

High-risk, recurrent and oligometastatic prostate cancer: recent developments on the role of radiation.

PURPOSE OF REVIEW: Although a standard of care in the treatment of organ-confined prostate cancer, use of radiation for treatment in the high-risk, metastatic and salvage settings is evolving rapidly. RECENT FINDINGS: Recent clinical trials have explored the role of increased treatment for high-risk disease with the addition of adjuvant chemotherapy and expanded the role of radiation in settings previously reserved for systemic therapy. Addition of adjuvant chemotherapy for high-risk prostate cancer is controversial and recent evidence is discussed that continues to refine the patient population for further evaluation. Evidence recently published demonstrates that for patients with low burden metastatic disease and those with oligometastatic disease may have a survival benefit with radiation treatment to all sites of known disease. Finally, reirradiation after prior radiotherapy-based treatment offers a potential salvage option for patients with locally recurrent prostate cancer. SUMMARY: As treatment paradigms evolve for prostate cancer, recent evidence continues to demonstrate benefit for the use of local therapy, both in patients with organ-confined disease and, more increasingly, in those with limited metastatic or locally recurrent disease. Further work is needed to identify subgroups of patients who may benefit from available treatment escalation approaches.

Major complications from radiotherapy following treatment for atypical meningiomas.

OBJECTIVEComplications from radiotherapy (RT), in a primary or adjuvant setting, have overall been described as uncommon, with few detailed descriptions of major complications. The authors present two cases involving significant complications and their management in their review of patients undergoing RT for treatment of atypical meningioma.METHODSThe authors conducted a retrospective review of all patients with pathologically confirmed atypical meningioma (WHO grade II) treated with primary or adjuvant RT from February 2011 through February 2019. They identified two patients with long-term, grade 3 toxicity. The cases of these patients are described in detail.RESULTSTwo patients had major complications associated with postoperative RT. Patients 1 and 2 both were treated with postoperative RT for pathologically confirmed atypical meningioma. Patient 1 experienced worsening behavioral changes, cognitive decline, and hydrocephalus following treatment. This required cerebrospinal fluid diversion. Patient 2 developed radiation necrosis with mass effect and cognitive decline. Neither patient returned to his/her initial post-RT status after steroid therapy, and each remained in need of supportive care. Both patients remained free of tumor progression at 52 and 38 months following treatment.CONCLUSIONSThe postoperative management of patients with atypical meningioma continues to be defined, with questions remaining regarding timing of RT, dose, target delineation, and fractionation. Both of the patients in this study received fractionated RT, which included a greater volume of normal brain than more focal treatment options such as would be required by stereotactic radiosurgery (SRS). Further research is needed to compare SRS and fractionated RT for the management of patients with grade II meningiomas. The more focused nature of SRS may make this a preferred option in certain cases of focal recurrence.

Conditional Risk and Predictive Factors Associated with Late Toxicity for Prostate Cancer Patients Treated with External Beam Radiotherapy Alone on Randomized Trial RTOG 0126.

PURPOSE: The objective of this study was to characterize the conditional risk of developing a grade 2+ urinary or gastrointestinal toxicity for patients treated with external beam radiotherapy on RTOG 0126. A secondary objective was to analyze baseline patient and treatment characteristics and determine their relevance in predicting toxicity both at the time of trial enrollment and later points of follow up. METHODS AND MATERIALS: 1,532 patients with localized prostate cancer were enrolled between March 2002 and August 2008, of whom 1,499 were eligible and included in data analysis with a median follow up of 8.4 years (range 0.02-13). Patients were treated with either 3DCRT or IMRT according to institutional practice without the addition of androgen deprivation and randomized to receive either standard dose radiotherapy of 70.2 Gy or dose escalated radiotherapy of 79.2 Gy of radiotherapy to the prostate only with standard fractionation. UVA and MVA analyses were determine if initial factors were predictive of late toxicity at time of treatment and at later timepoints. RESULTS: As patients proceed further from completion of radiotherapy without the development of toxicity, the subsequent risk of both grade 2+ GU and GI toxicity decreased with time. At time of enrollment the risk of developing a grade 2+ toxicity over the next 5 years was 9.57 and 17.89% respectively. After five years of toxicity free survival, the risk of developing a grade 2+ GU or GI toxicity in the subsequent five years was 3.02% and 1.54% respectively. Baseline treatment and patient related factors predicted late toxicity both at trial enrollment and after two years of toxicity free survivorship. Baseline urinary dysfunction and dose escalated radiotherapy were associated with increased late GU toxicity. Acute GI toxicity and dose escalated radiotherapy were associated with increased risk of late GI toxicity. Treatment with IMRT was associated with reduced risk of either toxicity. CONCLUSIONS: The conditional risk of grade 2+ toxicities decrease as patients proceed further from treatment with most toxicities occurring in the first few years after treatment completion. Baseline patient and treatment characteristics remain relevant at both enrollment and later time points.

Identification of a Predictive Genomic Biomarker for Prostate-directed Therapy in Synchronous Low-volume Metastatic Castration-sensitive Prostate Cancer.

BACKGROUND: Standard of care management for synchronous metastatic castration-sensitive prostate cancer (mCSPC) includes androgen deprivation therapy with a second-generation antiandrogen therapy and/or docetaxel. Recently, randomized data have demonstrated that prostate-directed therapy (PDT) is associated with an improvement in overall survival (OS) among patients with low-volume metastatic disease. Tumor genomics represents an additional dimension to define the clinical trajectory of patients with mCSPC. OBJECTIVE: To evaluate a high-risk (HiRi) genomic signature to predict the benefit from PDT. DESIGN, SETTING, AND PARTICIPANTS: We performed a single-institution retrospective review of men with synchronous low-volume mCSPC who underwent DNA panel sequencing of their tumor. Patients were classified according to the presence of HiRi mutation including pathogenic mutations in TP53, ATM, BRCA1, BRCA2, or Rb1. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was to determine the effect of PDT on OS in patients with and without a HiRi mutation. A survival analysis was performed with the Kaplan-Meier method compared with log-rank test and multivariable Cox regression. The interaction between HiRi mutation and PDT was evaluated. RESULTS AND LIMITATIONS: A total of 101 patients with synchronous low-volume CSPC were included with a median follow-up of 44 mo. Approximately half of patients were found to have a HiRi pathogenic mutation (49%). Patients with HiRi mutations demonstrated median OS of 73 versus 66.8 mo (p = 0.3) for no PDT versus PDT. Conversely, patients without a HiRi mutation demonstrated a significant improvement in OS of 60 versus 105.3 mo (p < 0.001) for no PDT versus PDT. The p value for interaction for OS between PDT and HiRi mutation was statistically significant (p < 0.001). Limitations include the retrospective nature of the study. CONCLUSIONS: Here, we have identified a HiRi genomic biomarker that appears predictive for the lack of benefit from PDT in men with synchronous low-volume mCSPC. Further work validating these results is warranted. PATIENT SUMMARY: In this report, we evaluated a high-risk genomic biomarker to predict the benefit from prostate-directed therapy for men with synchronous low-volume metastatic castration-sensitive prostate cancer. We found that men without a high-risk mutation appear to experience a greater clinical benefit from prostate-directed therapy than those with a high-risk mutation.

Genomic Determinants Associated with Modes of Progression and Patterns of Failure in Metachronous Oligometastatic Castration-sensitive Prostate Cancer.

BACKGROUND AND OBJECTIVE: Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state in the progression of metastatic disease for which patients experience better outcomes in comparison to those with higher disease burden. Despite the generally more indolent nature, there is still much heterogeneity, with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Our aim was to investigate correlation of tumor genomics with the mode of progression (MOP) and pattern of failure (POF) following first treatment (metastasis-directed and/or systemic therapy) for omCSPC. METHODS: We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC who underwent tumor next-generation sequencing with at least 1 yr of follow-up after their first treatment. Descriptive MOP and POF results are reported with respect to the presence of genomic alterations in pathways of interest. MOP was defined as class I, long-term control (LTC; no radiographic progression at last follow-up), class II, oligoprogression (1-3 lesions), or class III, polyprogression (≥4 lesions). POF included the location of lesions at first failure. Genomic pathways of interest included TP53, ATM, RB1, BRCA1/2, SPOP, and WNT (APC, CTNNB1, RNF43). Genomic associations with MOP/POF were compared using χ2 tests. Exploratory analyses revealed that the COSMIC mutational signature and differential gene expression were also correlated with MOP/POF. Overall survival (OS) was calculated via the Kaplan-Meier method from the time of first failure. KEY FINDINGS AND CLINICAL IMPLICATIONS: We included 267 patients in our analysis; the majority had either one (47%) or two (30%) metastatic lesions at oligometastasis. The 3-yr OS rate was significantly associated with MOP (71% for polyprogression vs 91% for oligoprogression; p = 0.005). TP53 mutation was associated with a significantly lower LTC rate (27.6% vs 42.3%; p = 0.04) and RB1 mutation was associated with a high rate of polyprogression (50% vs 19.9%; p = 0.022). Regarding POF, bone failure was significantly more common with tumors harboring TP53 mutations (44.8% vs25.9%; p = 0.005) and less common with SPOP mutations (7.1% vs 31.4%; p = 0.007). Visceral failure was more common with tumors harboring either WNT pathway mutations (17.2% vs 6.8%, p = 0.05) or SPOP mutations (17.9% vs 6.3%; p = 0.04). Finally, visceral and bone failures were associated with distinct gene-expression profiles. CONCLUSIONS AND CLINICAL IMPLICATIONS: Tumor genomics provides novel insight into MOP and POF following treatment for metachronous omCSPC. Patients with TP53 and RB1 mutations have a higher likelihood of progression, and TP53, SPOP, and WNT pathway mutations may have a role in metastatic organotropism. PATIENT SUMMARY: We evaluated cancer progression after a first treatment for metastatic prostate cancer with up to five metastases. We found that mutations in certain genes were associated with the location and extent of further metastasis in these patients.

Prognostic Significance of Immune Cell Infiltration in Muscle-invasive Bladder Cancer Treated with Definitive Chemoradiation: A Secondary Analysis of RTOG 0524 and RTOG 0712.

Chemoradiation therapy (CRT) is a treatment for muscle-invasive bladder cancer (MIBC). Using a novel transcriptomic profiling panel, we validated prognostic immune biomarkers to CRT using 70 pretreatment tumor samples from prospective trials of MIBC (NRG/RTOG 0524 and 0712). Disease-free survival (DFS) and overall survival (OS) were estimated via the Kaplan-Meier method and stratified by genes correlated with immune cell activation. Cox proportional-hazards models were used to assess group differences. Clustering of gene expression profiles revealed that the cluster with high immune cell content was associated with longer DFS (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.26-1.10; p = 0.071) and OS (HR 0.48, 95% CI 0.24-0.97; p = 0.040) than the cluster with low immune cell content. Higher expression of T-cell infiltration genes (CD8A and ICOS) was associated with longer DFS (HR 0.40, 95% CI 0.21-0.75; p = 0.005) and OS (HR 0.49, 95% CI 0.25-0.94; p = 0.033). Higher IDO1 expression (IFNγ signature) was also associated with longer DFS (HR 0.44, 95% CI 0.24-0.88; p = 0.021) and OS (HR 0.49, 95% CI 0.24-0.99; p = 0.048). These findings should be validated in prospective CRT trials that include biomarkers, particularly for trials incorporating immunotherapy for MIBC. PATIENT SUMMARY: We analyzed patient samples from two clinical trials (NRG/RTOG 0524 and 0712) of chemoradiation for muscle-invasive bladder cancer using a novel method to assess immune cells in the tumor microenvironment. Higher expression of genes associated with immune activation and high overall immune-cell content were associated with better disease-free survival and overall survival for patients treated with chemoradiation.

Conditional Risks of Biochemical Failure and Prostate Cancer-Specific Death in Patients Undergoing External Beam Radiotherapy: A Secondary Analysis of 2 Randomized Clinical Trials.

Importance: As patients achieve years of survival after treatment for prostate cancer, the risk of biochemical failure (BF) or prostate cancer-specific death (PCSD) may evolve over time, with clinical relevance to both patients and clinicians. Objective: To determine conditional BF-free survival, PSCD, and overall survival estimates for patients with low- or intermediate-risk prostate cancer enrolled in the Radiation Therapy Oncology Group (RTOG) 0126 and RTOG 0415 clinical trials. A secondary objective was to determine whether prognostic factors at diagnosis remain relevant at later points in follow-up. Design, Setting, and Participants: A pooled secondary analysis of patients treated with external-beam radiotherapy alone and enrolled in the prospective randomized clinical trials RTOG 0126 and RTOG 0415 was performed. Patients included for analysis were enrolled between March 2002 and December 2009 with a median follow-up of 6.9 years. Overall survival was calculated using the Kaplan-Meier method at various survivorship time points. Cumulative incidence was used to calculate BF rates using the Phoenix definition, as well as PCSD. Risk factors such as Gleason score, tumor (T) stage, prostate-specific antigen level, and the equivalent dose in 2 Gy fractions of prescribed dose were analyzed at different time points using multivariable Cox proportional hazards modeling. Data were analyzed from November 2021 to February 2023. Main Outcomes and Measures: Conditional risks of BF and PCSD after completion of external-beam radiotherapy. Results: A total of 2591 patients (median [IQR] age, 69 [63-73] years) were included in the study with a mean (range) PSA level of 7.1 (4.7-8.9) ng/mL, 1334 patients (51.5%) with a Gleason score 6 disease, and 1706 patients (65.8%) with T1 disease. Rates of BF from time of treatment were 1.63% (95% CI, 1.20%-2.18%) at 1 year, 7.04% (95% CI, 6.09%-8.08%) at 3 years, 12.54% (95% CI, 11.28%-13.88%) at 5 years, and 22.32% (95% CI, 20.46%-24.24%) at 8 years. For patients surviving 1, 3, and 5 years without BF, the rates of BF in the next 5 years were 14.20% (95% CI, 12.80%-15.66%), 17.19% (95% CI, 15.34%-19.14%), and 18.85% (95% CI, 16.21%-21.64%), respectively. At the initial time point, the rate of PCSD in the next 5 years was 0.66% (95% CI, 0.39%-1.04%). For patients who achieved 1, 3, 5, and 8 years of survivorship, the rates of PCSD in the next 5 years were 1.16% (95% CI, 0.77-1.67) at 1 year, 2.42% (95% CI, 1.74%-3.27%) at 3 years, 2.88% (95% CI, 2.01%-3.99%) at 5 years, and 3.49% (95% CI, 0.98%-8.73%) at 8 years. Conclusions and Relevance: In this secondary analysis of 2 randomized clinical trials of patients undergoing external beam radiotherapy for prostate cancer, the conditional risks of BF and death from prostate cancer increased with time for patients with low- and intermediate-risk prostate cancer treated with radiotherapy alone. These results could inform optimal trial design and may be helpful information for patients evaluated in follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT00033631; NCT00331773.

Racial Analysis of Clinical and Biochemical Outcomes in Patients With Prostate Cancer Treated With Low-Dose-Rate Brachytherapy.

PURPOSE: Black men in the United States experience significantly higher incidence of and mortality from prostate cancer (PCa) than non-Black men. The cause of this disparity is multifactorial, though inequitable access to curative radiation modalities, including low-dose-rate (LDR) brachytherapy, may contribute. Despite this, there are few analyses evaluating the potential of different radiation therapies to mitigate outcome disparities. Therefore, we examined the clinical outcomes of Black and non-Black patients treated with definitive LDR brachytherapy for PCa. METHODS: Data were collected for all patients treated with definitive LDR brachytherapy between 2005 and 2018 on a retrospective institutional review board approved protocol. Pearson χ2 analysis was used to assess demographic and cancer differences between Black and non-Black cohorts. Freedom from biochemical failure (FFBF) was calculated using Kaplan-Meier analysis. Univariate and multivariate analyses were used to identify factors predictive of biochemical failure. RESULTS: One hundred and sixty-seven patients were included in the analysis (Black: n = 81; 48.5%) with a median follow-up of 88.4 months. Black patients were from lower income communities (P < .01), had greater social vulnerability (P < .01), and had a longer interval between diagnosis and treatment (P = .011). Overall cumulative FFBF was 92.3% (95% confidence interval [CI], 87.8%-96.8%) at 5 years and 87.7% (95% CI, 82.0%-93.4%) at 7 years. There was no significant difference in FFBF in Black and non-Black patients (P = .114) and Black race was not independently predictive of failure (hazard ratio, 1.51; 95% CI, 0.56-4.01; P = .42). Overall survival was comparable between racial groups (P = .972). Only nadir prostate-specific antigen was significantly associated with biochemical failure on multivariate (hazard ratio, 3.57; 95% CI, 02.44-5.22; P < .001). CONCLUSIONS: Black men treated with LDR brachytherapy achieved similar FFBF to their non-Black counterparts despite poorer socioeconomic status. This suggests that PCa treatment with brachytherapy may eliminate some disparities in clinical outcomes.

Clinical and Genomic Differences Between Advanced Molecular Imaging-detected and Conventional Imaging-detected Metachronous Oligometastatic Castration-sensitive Prostate Cancer.

In metastatic castration-sensitive prostate cancer (mCSPC), disease volume plays an integral role in guiding treatment recommendations, including selection of docetaxel therapy, metastasis-directed therapy, and radiation to the prostate. Although there are multiple definitions of disease volume, they have commonly been studied in the context of metastases detected via conventional imaging (CIM). One such numeric definition of disease volume, termed oligometastasis, is heavily dependent on the sensitivity of the imaging modality. We performed an international multi-institutional retrospective review of men with metachronous oligometastatic CSPC (omCSPC), detected via either advanced molecular imaging alone (AMIM) or CIM. Patients were compared with respect to clinical and genomic features using the Mann-Whitney U test, Pearson's χ2 test, and Kaplan-Meier overall survival (OS) analyses with a log-rank test. A total of 295 patients were included for analysis. Patients with CIM-omCSPC had significantly higher Gleason grade group (p = 0.032), higher prostate-specific antigen at omCSPC diagnosis (8.0 vs 1.7 ng/ml; p < 0.001), more frequent pathogenic TP53 mutations (28% vs 17%; p = 0.030), and worse 10-yr OS (85% vs 100%; p < 0.001). This is the first report of clinical and biological differences between AMIM-detected and CIM-detected omCSPC. Our findings are particularly important for ongoing and planned clinical trials in omCSPC. PATIENT SUMMARY: Metastatic prostate cancer with just a few metastases only detected via newer scanning methods (called molecular imaging) is associated with fewer high-risk DNA mutations and better survival in comparison to metastatic cancer detected via conventional scan methods.

WNT Pathway Mutations in Metachronous Oligometastatic Castration-Sensitive Prostate Cancer.

PURPOSE: WNT signaling is a cellular pathway that has been implicated in the development and progression of prostate cancer. Oligometastatic castration-sensitive prostate cancer (omCSPC) represents a unique state of disease in which metastasis-directed therapy (MDT) has demonstrated improvement in progression-free survival. Herein, we investigate the clinical implications of genomic alterations in the WNT signaling cascade in men with omCSPC. METHODS AND MATERIALS: We performed an international multi-institutional retrospective study of 277 men with metachronous omCSPC who underwent targeted DNA sequencing of their primary/metastatic tumor. Patients were classified by presence or absence of pathogenic WNT pathway mutations (in the genes APC, RNF43, and CTNNB1). Pearson χ2 and Mann-Whitney U tests were used to determine differences in clinical factors between genomic strata. Kaplan-Meier survival curves were generated for radiographic progression-free survival and overall survival, stratified according to WNT pathway mutation status. RESULTS: A pathogenic WNT pathway mutation was detected in 11.2% of patients. Patients with WNT pathway mutations were more likely to have visceral metastases (22.6% vs 2.8%; P < .01) and less likely to have regional lymph node metastases (29.0% vs 50.4%; P = .02). At time of oligometastasis, these patients were treated with MDT alone (33.9%), MDT + limited course of systemic therapy (20.6%), systemic therapy alone (22.4%), or observation (defined as no treatment for ≥6 months after metastatic diagnosis). Multivariable cox regression demonstrated WNT pathway mutations associated with significantly worse overall survival (hazard ratio, 3.87; 95% confidence interval, 1.25-12.00). CONCLUSIONS: Somatic WNT pathway alterations are present in approximately 11% of patients with omCSPC and are associated with an increased likelihood of visceral metastases. Although these patients have a worse natural history, they may benefit from MDT.

Burnout in Radiation Oncology Physician Workforce: The Effect of Mindfulness and Fulfillment.

Purpose: Mindfulness, defined as awareness of the moment while acknowledging and accepting one's feelings, thoughts, and sensations, is the aim of mindfulness meditation. Our objective was to investigate the relationship between burnout, mindfulness, fulfillment, and other personal characteristics in radiation oncology (RO) residents/attendings compared with other specialties. Methods and Materials: From December 2019 to February 2020, residents and attendings in multiple specialties at a single tertiary care academic institution were sent surveys, including the mindfulness attention awareness scale, Stanford professional fulfillment index, and a personal questionnaire. A Pearson correlation was conducted on the relationship between mindfulness, fulfillment, disengagement, and exhaustion. To determine risk factors for burnout (overall burnout ≥ 1.33), a univariate analysis was conducted to yield odds ratios (ORs) on debt, specialty, income, sleep, exercise, marital status, number of children, work hours, mindfulness (mindfulness attention awareness scale ≥ 4), fulfillment (professional fulfillment ≥ 3), and time with family/friends. Significant factors on univariate analysis were entered into multivariate analysis. Results: There were 180 surveys completed by 60 residents and attendings across 17 specialties. Eighteen (30%) respondents were in RO. Mindfulness positively correlated with fulfillment (P < .001, r = 0.534), negatively correlated with exhaustion (P < .001, r = -0.578), and negatively correlated with disengagement (P < .001, r = -0.483). Univariate analysis for factors associated with burnout was significant for mindfulness (OR = 0.065, P < .001), RO versus other specialty (OR = 0.024, P = .044), working >60 h/wk (OR = 5.091, P = .018), spending >10 h/wk with family or friends (OR = 0.120, P = .001), and fulfillment (OR = 0.103, P < .001). Multivariate analysis showed mindfulness and fulfillment to significantly decrease odds of burnout. Conclusions: RO physicians experienced less burnout than physicians in other specialties at our institution. Mindfulness, professional fulfillment, moderate work hours, and spending time with loved ones protected against burnout. Further study of interventions to promote mindfulness and fulfillment may help us understand how best to improve the mental and emotional health of RO physicians.

Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.

Computed tomography-based flap brachytherapy for non-melanoma skin cancers of the face.

PURPOSE: Non-melanoma skin cancers of the face are at high-risk for local recurrence and metastatic spread. While surgical interventions such as Mohs microsurgery are considered the standard of care, this modality has the potential for high rates of toxicity in sensitive areas of the face. Catheter flap high-dose-rate (HDR) brachytherapy has shown promising results, with high rates of local control and acceptable cosmetic outcomes. MATERIAL AND METHODS: Patients with non-melanoma skin cancers (NMSC) located on the face were treated with 40 Gy in 8 fractions, given twice weekly via catheter flap HDR brachytherapy. Clinical target volume (CTV) included the visible tumor plus a margin of 5 mm in all directions, with no additional planning target volume (PTV) margin. RESULTS: Fifty patients with 53 lesions on the face were included, with a median follow-up of 15 months. All were considered high-risk based on NCCN guidelines. Median tumor size and thickness were 18 mm and 5 mm, respectively. Median PTV volume and D90 were 1.7 cc and 92%, respectively. Estimated rate of local control at twelve months was 92%. Three patients (5%) experienced acute grade 2 toxicity. Two patients (4%) continued to suffer from chronic grade 1 skin toxicity at 12 months post-radiotherapy (RT), with an additional two patients (4%) experiencing chronic grade 2 skin toxicity. Forty-nine lesions (92%) were found to have a good or excellent cosmetic outcome with complete tumor remission. CONCLUSIONS: CT-based flap applicator brachytherapy is a valid treatment option for patients with NMSC of the face. This modality offers high rates of local control with acceptable cosmetic outcomes and low rates of toxicity.

Biochemical Control and Toxicity Outcomes of Stereotactic Body Radiation Therapy Versus Low-Dose-Rate Brachytherapy in the Treatment of Low- and Intermediate-Risk Prostate Cancer.

PURPOSE: Low-dose-rate (LDR) brachytherapy and stereotactic body radiation therapy (SBRT) have both shown acceptable outcomes in the treatment of low- and intermediate-risk prostate cancer. Minimal data have been published directly comparing rates of biochemical control and toxicity with these 2 modalities. We hypothesize that LDR and SBRT will provide similar rates of biochemical control. METHODS AND MATERIALS: All low- and intermediate-risk patients with prostate cancer treated definitively with SBRT or LDR between 2010 and 2018 were captured. Phoenix definition was used for biochemical failure. Independent t tests were used to compare baseline characteristics, and repeated measure analysis of variance test was used to compare American Urologic Association (AUA) and the Expanded Prostate Cancer Index Composite (EPIC) scores between treatment arms over time. Biochemical control was estimated using the Kaplan-Meier method. Differences in acute and late toxicity were assessed via Pearson χ2. RESULTS: In the study, 219 and 118 patients were treated with LDR and SBRT. Median follow-up was 4.3 years (interquartile range, 3.1-6.1). All patients treated with LDR received 125.0 Gy in a single fraction. SBRT consisted of 42.5 Gy in 5 fractions. Five-year biochemical control for LDR versus SBRT was 91.6% versus 97.6% (P = .108). LDR patients had a larger increase in mean AUA scores at 1 month (17.2 vs 10.3, P < .001) and 3 months posttreatment (14.0 vs 9.7, P < .001), and in mean EPIC scores at 1 month (15.7 vs 13.8, P < .001). There was no significant difference between LDR and SBRT in late grade 3 genitourinary toxicity (0.9% vs 2.5%, P = .238); however, LDR had lower rates of late grade 3 gastrointestinal toxicity (0.0% vs 2.5%, P = .018). CONCLUSIONS: Our data show similar biochemical control and genitourinary toxicity rates at 5 years for both SBRT and LDR, with slightly higher gastrointestinal toxicity with SBRT and higher AUA and EPIC scores with LDR.

Impact of stereotactic body radiation therapy on geriatric assessment and management for older patients with head and neck cancer using G8.

PURPOSE: Management of head and neck cancers (HNC) in older adults is a common but challenging clinical scenario. We assess the impact of Stereotactic Body Radiation Therapy (SBRT) on survival utilizing the Geriatric-8 (G8) questionnaire. MATERIALS AND METHODS: 171 HNC patients, deemed medically unfit for definitive treatment, were treated with SBRT ± systemic therapy. G8 questionnaires were collected at baseline, at 4-6 weeks, and at 2-3 months post-treatment. Patients were stratified according to their baseline G8 score: <11 as 'vulnerable', 11-14 as 'intermediate', and >14 as 'fit'. Overall survival (OS) was assessed through univariate Kaplan Meier analysis. Repeated measures ANOVA was used to determine if baseline characteristics affected G8 score changes. RESULTS: Median follow-up was seventeen months. 60% of patients presented with recurrent HNC, 30% with untreated HNC primaries, and 10% with metastatic non-HNC primaries. Median age was 75 years. Median Charlson Comorbidity Index score was 2. 51% of patients were 'vulnerable', 37% were 'intermediate', and 12% were 'fit' at baseline, with median survival of 13.2, 24.3, and 41.0 months, respectively (p = .004). Patients who saw a decrease in their follow-up G8 score (n = 69) had significantly lower survival than patients who had stable or increased follow-up G8 scores (n = 102), with median survival of 8.6 vs 36.0 months (p < .001). CONCLUSION: The G8 questionnaire may be a useful tool in upfront treatment decision-making to predict prognosis and prevent older patients from receiving inappropriate anti-cancer treatment. Decline in follow-up G8 scores may also predict worse survival and aid in goals of care following treatment.

Stereotactic body radiotherapy as primary treatment for elderly and medically inoperable patients with head and neck cancer.

BACKGROUND: Patients with head and neck cancer (HNC) who are not candidates for definitive treatment represent an increasing challenge, with limited data to guide management. Conventional local therapies such as surgery and chemoradiation can significantly impact quality of life (QoL). There has been limited data published using stereotactic body radiotherapy (SBRT) as primary treatment in previously unirradiated patients. We hypothesize that SBRT provides high rates of control while limiting toxicity. METHODS: A total of 66 medically unfit previously unirradiated patients with HNC were treated with SBRT, consisting of 35-40 Gy to gross tumor volume and 30 Gy to clinical target volume in five fractions. RESULTS: Median age was 80 years. Local control (LC) and overall survival (OS) at 1 year were 73% and 64%. Two patients experienced grade 3 toxicity. CONCLUSION: SBRT shows acceptable outcomes with relatively low toxicity in previously unirradiated patients with HNC who are medically unfit for conventional treatment. SBRT may provide an aggressive local therapy with high rates of LC and OS while maintaining QoL.

Phase I trial of dose-escalated stereotactic radiosurgery (SRS) boost for unfavorable locally advanced oropharyngeal cancer.

BACKGROUND AND PURPOSE: Patients with locally advanced oropharynx squamous cell carcinoma have suboptimal outcomes with standard chemoradiation. Here, we evaluated toxicity and oncologic outcomes of dose escalation using radiosurgical boost for patients with unfavorable oropharynx squamous cell carcinoma. MATERIALS AND METHODS: Between 2010-2017, Thirty four patients with intermediate- or high-risk oropharynx squamous cell carcinoma were enrolled onto this prospective phase I trial. Each patient received concurrent cisplatin and fractionated radiotherapy totaling 60 Gy or 66 Gy followed by radiosurgery boost to areas of residual gross tumor: single fraction of 8 Gy or 10 Gy, or two fractions of 5 Gy each. Primary endpoint was treatment toxicity. Secondary endpoints were local, regional, and distant disease control. RESULTS: Eleven, sixteen and seven patients received radiosurgery boost with 8 Gy in 1 fraction, 10 Gy in 1 fraction, and 10 Gy in 2 fractions respectively. Acute toxicities include 4 patients with tumor necrosis causing grade 3 dysphagia, of which 3 developed grade 4 pharyngeal hemorrhage requiring surgical intervention. At 24 months after treatment, 7%, 9%, and 15% had grade 2 dysgeusia, xerostomia, and dysphagia, respectively, and two patients remained feeding tube dependent. No grade 5 toxicities occurred secondary to treatment. Local, regional, and distant control at a median follow up of 4.2 years were 85.3%, 85.3% and 88.2%, respectively. Five patients died resulting in overall survival of 85.3%. CONCLUSIONS: This study is the first to report the use of radiosurgery boost dose escalation in patients with unfavorable oropharynx squamous cell carcinoma. Longer follow-up, larger cohorts, and further refinement of boost methodology are needed prior to implementation in routine clinical practice. TRIAL REGISTRATION: Northwell Health Protocol #09-309A (NCT02703493) ( https://clinicaltrials.gov/ct2/show/NCT02703493 ).

Outcomes of a Dose-Escalated Stereotactic Body Radiation Phase 1 Trial for Patients With Low- and Intermediate-Risk Prostate Cancer.

PURPOSE: This study presents a prospective phase 1, institutional review board-approved dose-escalated stereotactic body radiation therapy trial for prostate cancer (CaP) to assess the impact of dose level on quality of life, toxicity, and clinical outcomes. METHODS AND MATERIALS: From 2011 to 2016, 26 patients with low- and intermediate-risk CaP received 40, 45, and 50 Gy in 5 fractions to the prostate in cohorts of 9, 10, and 7 patients. Self-reported quality of life was prospectively measured from the Expanded Prostate Cancer Index Composite and American Urological Association. Common Terminology Criteria for Adverse Events (version 4.03) data were collected to observe acute and late toxicities. The Phoenix definition was used to calculate outcome. No patients received androgen deprivation therapy. RESULTS: Median follow-up was 67.2 months (range, 71-230 months). There was an increase in Expanded Prostate Cancer Index Composite and American Urological Association scores followed by a return to baseline over 2 years for all cohorts. There were no grade 3 or higher toxicities or significant differences in toxicity between treatment arms. The prostate-specific antigen (PSA) nadir was significantly lower in the 45-Gy and 50-Gy cohorts when compared with the 40-Gy cohort (P < .05). Two biochemical failures were observed in the 40-Gy arm after 43 and 62 months, resulting in a freedom from biochemical failure rate of 92%. PSA survival was 100%, and actuarial overall survival was 96%. PSA nadir was 0.6, 0.1, and 0.1 ng/mL, in the 40-Gy, 45-Gy, and 50-Gy cohorts, respectively. CONCLUSIONS: This prospective, phase 1 dose-escalation study of stereotactic body radiation therapy for CaP identified acceptable genitourinary and gastrointestinal toxicity for each dose level of 40, 45, and 50 Gy. Although there was no difference in biochemical failure between the groups, we showed that higher doses of 45 and 50 Gy are associated with improved PSA nadir. The results of this study will be used to develop a larger prospective study to confirm the findings.

Quality of Life Outcomes Following Organ-Sparing SBRT in Previously Irradiated Recurrent Head and Neck Cancer.

Purpose: To present a retrospective analysis of the efficacy, toxicity, and quality of life (QoL) of patients treated with OAR Extreme -sparing stereotactic body radiotherapy (SBRT) in previously-irradiated head and neck cancer. Materials/Methods: From 11/2012 to 7/2015, 60 patients with in-field recurrence of head and neck cancer underwent re-irradiation with SBRT. Retreatment sites included the aerodigestive tract (43%), lateral neck (22%), and skull base (35%). The median prior RT dose was 63.6 Gy with a median time from prior irradiation of 16.5 months. The median volume treated was 61.0 cc. Patients were treated with 40 Gy in the definitive setting or 35 Gy in the post-operative setting in five fractions. Dose constraints to the OAR Extreme were calculated with a BED calculator using an alpha/beta ratio of 3 to reduce the risk of late toxicities. QoL data was collected from patients at the time of consultation and at subsequent follow up appointments using the MD Anderson Dysphagia Inventory (MDADI) and Symptom Inventory (MDASI). Results: The 1- and 2- year rates of local, regional, and distant control and overall survival were 79/79, 74/70, 74/71, and 59/45%, respectively. Late grade 3 toxicities were seen in 3% in the group treated to the aerodigestive tract and 1% in the group treated to the skull base. No grade 4 or 5 toxicities were observed. Patients with skull base re-irradiation maintained a stable QoL score after radiation treatment, while patients treated to the aerodigestive tract demonstrated a slight impairment associated with worsening dysphagia, compared to their pretreatment baseline. All groups experienced an increase in xerostomia. Conclusions: OAR Extreme -sparing SBRT is able to achieve excellent tumor coverage while protecting the organs at highest risk of re-irradiation-related complications. The potential for lower toxicities and maintained QoL with this treatment makes it a promising option for salvage of recurrent head and neck cancer. SUMMARY: Local control and overall survival rates for recurrent head and neck cancer remain poor, despite the use of local therapy. In addition, re-irradiation with conventional radiation therapy confers a high rate of grade 3 and higher late toxicities. SBRT appears to improve the therapeutic ratio in this patient population, and treatment planning with a focus on sparing OAR Extreme may further decrease the rates of morbidity in these patients.