Phase II Randomized Study of Salvage Radiation Therapy Plus Enzalutamide or Placebo for High-Risk Prostate-Specific Antigen Recurrent Prostate Cancer After Radical Prostatectomy: The SALV-ENZA Trial.

PURPOSE: We sought to investigate whether enzalutamide (ENZA), without concurrent androgen deprivation therapy, increases freedom from prostate-specific antigen (PSA) progression (FFPP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer after radical prostatectomy (RP). PATIENTS AND METHODS: Men with biochemically recurrent prostate cancer after RP were enrolled into a randomized, double-blind, phase II, placebo-controlled, multicenter study of SRT plus ENZA or placebo (ClinicalTrials.gov identifier: NCT02203695). Random assignment (1:1) was stratified by center, surgical margin status (R0 v R1), PSA before salvage treatment (PSA ≥ 0.5 v < 0.5 ng/mL), and pathologic Gleason sum (7 v 8-10). Patients were assigned to receive either ENZA 160 mg once daily or matching placebo for 6 months. After 2 months of study drug therapy, external-beam radiation (66.6-70.2 Gy) was administered to the prostate bed (no pelvic nodes). The primary end point was FFPP in the intention-to-treat population. Secondary end points were time to local recurrence within the radiation field, metastasis-free survival, and safety as determined by frequency and severity of adverse events. RESULTS: Eighty-six (86) patients were randomly assigned, with a median follow-up of 34 (range, 0-52) months. Trial arms were well balanced. The median pre-SRT PSA was 0.3 (range, 0.06-4.6) ng/mL, 56 of 86 patients (65%) had extraprostatic disease (pT3), 39 of 86 (45%) had a Gleason sum of 8-10, and 43 of 86 (50%) had positive surgical margins (R1). FFPP was significantly improved with ENZA versus placebo (hazard ratio [HR], 0.42; 95% CI, 0.19 to 0.92; P = .031), and 2-year FFPP was 84% versus 66%, respectively. Subgroup analyses demonstrated differential benefit of ENZA in men with pT3 (HR, 0.22; 95% CI, 0.07 to 0.69) versus pT2 disease (HR, 1.54; 95% CI, 0.43 to 5.47; Pinteraction = .019) and R1 (HR, 0.14; 95% CI, 0.03 to 0.64) versus R0 disease (HR, 1.00; 95% CI, 0.36 to 2.76; Pinteraction = .023). There were insufficient secondary end point events for analysis. The most common adverse events were grade 1-2 fatigue (65% ENZA v 53% placebo) and urinary frequency (40% ENZA v 49% placebo). CONCLUSION: SRT plus ENZA monotherapy for 6 months in men with PSA-recurrent high-risk prostate cancer after RP is safe and delays PSA progression relative to SRT alone. The impact of ENZA on distant metastasis or survival is unknown at this time.

TrueNTH Sexual Recovery Intervention for couples coping with prostate cancer: Randomized controlled trial results.

BACKGROUND: Despite significant sexual dysfunction and distress after localized prostate cancer treatment, patients typically receive only physiologic erectile dysfunction management. The authors performed a randomized controlled trial of an online intervention supporting couples' posttreatment recovery of sexual intimacy. METHODS: Patients treated with surgery, radiation, or combined radiation and androgen deprivation therapy who had partners were recruited and randomized to an online intervention or a control group. The intervention, tailored to treatment type and sexual orientation, comprised 6 modules addressing expectations for sexual and emotional sequelae of treatment, rehabilitation, and guidance toward sexual intimacy recovery. Couples, recruited from 6 sites nationally, completed validated measures at the baseline and 3 and 6 months after treatment. Primary outcome group differences were assessed with t tests for individual outcomes. RESULTS: Among 142 randomized couples, 105 patients (mostly surgery) and 87 partners completed the 6-month survey; this reflected challenges with recruitment and attrition. There were no differences between the intervention and control arms in Patient-Reported Outcomes Measurement Information System Global Satisfaction With Sex Life scores 6 months after treatment (the primary outcome). Three months after treatment, intervention patients and partners reported more engagement in penetrative and nonpenetrative sexual activities than controls. More than 73% of the intervention participants reported high or moderate satisfaction with module content; more than 85% would recommend the intervention to other couples. CONCLUSIONS: Online psychosexual support for couples can help couples to connect and experience sexual pleasure early after treatment despite patients' sexual dysfunction. Participants' high endorsement of the intervention reflects the importance of sexual health support to couples after prostate cancer treatment. LAY SUMMARY: This study tested a web-based program supporting couples' sexual recovery of sexual intimacy after prostate cancer treatment. One hundred forty-two couples were recruited and randomly assigned to the program (n = 60) or to a control group (n = 82). The program did not result in improvements in participants' satisfaction with their sex life 6 months after treatment, but couples in the intervention group engaged in sexual activity sooner after treatment than couples in the control group. Couples evaluated the program positively and would recommend it to others facing prostate cancer treatment.

Integrating Prostate-specific Antigen Kinetics into Contemporary Predictive Nomograms of Salvage Radiotherapy After Radical Prostatectomy.

BACKGROUND: Salvage radiotherapy (SRT) is an established treatment for men with biochemical recurrence following radical prostatectomy (RP). There are several risk factors associated with adverse outcomes; however, the value of postoperative prostate-specific antigen (PSA) kinetics is less clear in the ultrasensitive PSA era. OBJECTIVE: To characterize the impact of PSA kinetics on outcomes following SRT and generate nomograms to aid in identifying patients with an increased risk of adverse clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional analysis was conducted of 1005 patients with prostate cancer treated with SRT after RP, with a median follow-up of 5 years. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variables examined include immediate postoperative PSA, postoperative PSA doubling time (DT), and pre-SRT PSA, in addition to previously identified predictive factors. Multivariable survival analyses were completed using Fine-Gray competing risk regression. Rates of biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM) were estimated by the cumulative incidence method. Nomograms were generated from multivariable competing risk regression with bootstrap cross-validation. RESULTS AND LIMITATIONS: Factors associated with BF after SRT include PSA DT <6 mo, initial postoperative PSA ≥0.2 ng/ml, higher pre-SRT PSA, lack of androgen deprivation therapy, a higher Gleason score (GS), negative margins, seminal vesicle invasion, lack of pelvic nodal radiation, radiation total dose <66 Gy, a longer RP to SRT interval, and older age (p < 0.05 for each). Factors associated with DM include PSA DT <6 mo, pre-SRT PSA, a higher GS, and negative margins. Factors associated with PCSM include PSA DT not calculable or <6 mo and a higher GS. Nomograms were generated to estimate the risks of BF (concordance index [CI] 0.74), DM (CI 0.77), and PCSM (CI 0.77). Limitations include retrospective nature, broad treatment eras, institutional variations, and multiple methods available for the estimation of PSA DT. CONCLUSIONS: Postoperative PSA kinetics, particularly pre-SRT PSA and PSA DT, are strongly associated with adverse oncologic outcomes following SRT and should be considered in management decisions. PATIENT SUMMARY: In this report of men with prostate cancer who developed a prostate-specific antigen (PSA) recurrence after prostatectomy, we found that PSA levels after surgery and how quickly a PSA level doubles significantly impact the chance of prostate cancer recurrence after salvage radiation therapy. Based on this information, we created a tool to calculate a man's chance of cancer recurrence after salvage radiation therapy, and these estimations can be used to discuss whether additional treatment with radiation should be considered.

Development and Validation of a Clinical Prognostic Stage Group System for Nonmetastatic Prostate Cancer Using Disease-Specific Mortality Results From the International Staging Collaboration for Cancer of the Prostate.

Importance: In 2016, the American Joint Committee on Cancer (AJCC) established criteria to evaluate prediction models for staging. No localized prostate cancer models were endorsed by the Precision Medicine Core committee, and 8th edition staging was based on expert consensus. Objective: To develop and validate a pretreatment clinical prognostic stage group system for nonmetastatic prostate cancer. Design, Setting, and Participants: This multinational cohort study included 7 centers from the United States, Canada, and Europe, the Shared Equal Access Regional Cancer Hospital (SEARCH) Veterans Affairs Medical Centers collaborative (5 centers), and the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (43 centers) (the STAR-CAP cohort). Patients with cT1-4N0-1M0 prostate adenocarcinoma treated from January 1, 1992, to December 31, 2013 (follow-up completed December 31, 2017). The STAR-CAP cohort was randomly divided into training and validation data sets; statisticians were blinded to the validation data until the model was locked. A Surveillance, Epidemiology, and End Results (SEER) cohort was used as a second validation set. Analysis was performed from January 1, 2018, to November 30, 2019. Exposures: Curative intent radical prostatectomy (RP) or radiotherapy with or without androgen deprivation therapy. Main Outcomes and Measures: Prostate cancer-specific mortality (PCSM). Based on a competing-risk regression model, a points-based Score staging system was developed. Model discrimination (C index), calibration, and overall performance were assessed in the validation cohorts. Results: Of 19 684 patients included in the analysis (median age, 64.0 [interquartile range (IQR), 59.0-70.0] years), 12 421 were treated with RP and 7263 with radiotherapy. Median follow-up was 71.8 (IQR, 34.3-124.3) months; 4078 (20.7%) were followed up for at least 10 years. Age, T category, N category, Gleason grade, pretreatment serum prostate-specific antigen level, and the percentage of positive core biopsy results among biopsies performed were included as variables. In the validation set, predicted 10-year PCSM for the 9 Score groups ranged from 0.3% to 40.0%. The 10-year C index (0.796; 95% CI, 0.760-0.828) exceeded that of the AJCC 8th edition (0.757; 95% CI, 0.719-0.792), which was improved across age, race, and treatment modality and within the SEER validation cohort. The Score system performed similarly to individualized random survival forest and interaction models and outperformed National Comprehensive Cancer Network (NCCN) and Cancer of the Prostate Risk Assessment (CAPRA) risk grouping 3- and 4-tier classification systems (10-year C index for NCCN 3-tier, 0.729; for NCCN 4-tier, 0.746; for Score, 0.794) as well as CAPRA (10-year C index for CAPRA, 0.760; for Score, 0.782). Conclusions and Relevance: Using a large, diverse international cohort treated with standard curative treatment options, a proposed AJCC-compliant clinical prognostic stage group system for prostate cancer has been developed. This system may allow consistency of reporting and interpretation of results and clinical trial design.

Addition of Androgen-Deprivation Therapy or Brachytherapy Boost to External Beam Radiotherapy for Localized Prostate Cancer: A Network Meta-Analysis of Randomized Trials.

PURPOSE: In men with localized prostate cancer, the addition of androgen-deprivation therapy (ADT) or a brachytherapy boost (BT) to external beam radiotherapy (EBRT) have been shown to improve various oncologic end points. Practice patterns indicate that those who receive BT are significantly less likely to receive ADT, and thus we sought to perform a network meta-analysis to compare the predicted outcomes of a randomized trial of EBRT plus ADT versus EBRT plus BT. MATERIALS AND METHODS: A systematic review identified published randomized trials comparing EBRT with or without ADT, or EBRT (with or without ADT) with or without BT, that reported on overall survival (OS). Standard fixed-effects meta-analyses were performed for each comparison, and a meta-regression was conducted to adjust for use and duration of ADT. Network meta-analyses were performed to compare EBRT plus ADT versus EBRT plus BT. Bayesian analyses were also performed, and a rank was assigned to each treatment after Markov Chain Monte Carlo analyses to create a surface under the cumulative ranking curve. RESULTS: Six trials compared EBRT with or without ADT (n = 4,663), and 3 compared EBRT with or without BT (n = 718). The addition of ADT to EBRT improved OS (hazard ratio [HR], 0.71 [95% CI, 0.62 to 0.81]), whereas the addition of BT did not significantly improve OS (HR, 1.03 [95% CI, 0.78 to 1.36]). In a network meta-analysis, EBRT plus ADT had improved OS compared with EBRT plus BT (HR, 0.68 [95% CI, 0.52 to 0.89]). Bayesian modeling demonstrated an 88% probability that EBRT plus ADT resulted in superior OS compared with EBRT plus BT. CONCLUSION: Our findings suggest that current practice patterns of omitting ADT with EBRT plus BT may result in inferior OS compared with EBRT plus ADT in men with intermediate- and high-risk prostate cancer. ADT for these men should remain a critical component of treatment regardless of radiotherapy delivery method until randomized evidence demonstrates otherwise.

HSD3B1 Genotype and Clinical Outcomes in Metastatic Castration-Sensitive Prostate Cancer.

Importance: The adrenal-restrictive HSD3B1(1245A) allele limits extragonadal dihydrotestosterone synthesis, whereas the adrenal-permissive HSD3B1(1245C) allele augments extragonadal dihydrotestosterone synthesis. Retrospective studies have suggested an association between the adrenal-permissive allele, the frequency of which is highest in white men, and early development of castration-resistant prostate cancer (CRPC). Objective: To examine the association between the adrenal-permissive HSD3B1(1245C) allele and early development of CRPC using prospective data. Design, Setting, and Participants: The E3805 Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) was a large, multicenter, phase 3 trial of castration with or without docetaxel treatment in men with newly diagnosed metastatic prostate cancer. From July 28, 2006, through December 31, 2012, 790 patients underwent randomization, of whom 527 had available DNA samples. In this study, the HSD3B1 germline genotype was retrospectively determined in 475 white men treated in E3805 CHAARTED, and clinical outcomes were analyzed by genotype. Data analysis was performed from July 28, 2006, to October 17, 2018. Interventions: Men were randomized to castration plus docetaxel, 75 mg/m2, every 3 weeks for 6 cycles or castration alone. Main Outcomes and Measures: Two-year freedom from CRPC and 5-year overall survival, with results stratified by disease volume. Patients were combined across study arms according to genotype to assess the overall outcome associated with genotype. Secondary analyses by treatment arm evaluated whether the docetaxel outcome varied with genotype. Results: Of 475 white men with DNA samples, 270 patients (56.8%) inherited the adrenal-permissive genotype (≥1 HSD3B1[1245C] allele). Mean (SD) age was 63 (8.7) years. Freedom from CRPC at 2 years was diminished in men with low-volume disease with the adrenal-permissive vs adrenal-restrictive genotype: 51.0% (95% CI, 40.9%-61.2%) vs 70.5% (95% CI, 60.0%-80.9%) (P = .01). Overall survival at 5 years was also worse in men with low-volume disease with the adrenal-permissive genotype: 57.5% (95% CI, 47.4%-67.7%) vs 70.8% (95% CI, 60.3%-81.3%) (P = .03). Hazard ratios were 1.89 (95% CI, 1.13-3.14; P = .02) for CRPC and 1.74 (95% CI, 1.01-3.00; P = .045) for death. There was no association between genotype and outcomes in men with high-volume disease. There was no interaction between genotype and benefit from docetaxel. Conclusions and Relevance: Inheritance of the adrenal-permissive HSD3B1 genotype is associated with earlier castration resistance and shorter overall survival in men with low-volume metastatic prostate cancer and may help identify men more likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression.

Lung Cancer Surveillance After Definitive Curative-Intent Therapy: ASCO Guideline.

PURPOSE: To provide evidence-based recommendations to practicing clinicians on radiographic imaging and biomarker surveillance strategies after definitive curative-intent therapy in patients with stage I-III non-small-cell lung cancer (NSCLC) and SCLC. METHODS: ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, radiology, primary care, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2019. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 14 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS: Patients should undergo surveillance imaging for recurrence every 6 months for 2 years and then annually for detection of new primary lung cancers. Chest computed tomography imaging is the optimal imaging modality for surveillance. Fluorodeoxyglucose positron emission tomography/computed tomography imaging should not be used as a surveillance tool. Surveillance imaging may not be offered to patients who are clinically unsuitable for or unwilling to accept further treatment. Age should not preclude surveillance imaging. Circulating biomarkers should not be used as a surveillance strategy for detection of recurrence. Brain magnetic resonance imaging should not be used for routine surveillance in stage I-III NSCLC but may be used every 3 months for the first year and every 6 months for the second year in patients with stage I-III small-cell lung cancer who have undergone curative-intent treatment.

A phase II randomized placebo-controlled double-blind study of salvage radiation therapy plus placebo versus SRT plus enzalutamide with high-risk PSA-recurrent prostate cancer after radical prostatectomy (SALV-ENZA).

BACKGROUND: In men with a rising PSA following radical prostatectomy, salvage radiation therapy (SRT) offers a second chance for cure. Hormonal therapy can be combined with SRT in order to increase prostate tumor control, albeit with associated higher rates of treatment side effects. This trial studies the effectiveness of SRT combined with hormonal therapy using a more potent anti-androgen with a favorable side effect profile. Enzalutamide, a next generation selective androgen receptor antagonist, is approved by the Food and Drug Administration for the treatment of metastatic castrate-resistant prostate cancer (CRPC) where it has been shown to improve overall survival in combination with androgen deprivation therapy. The primary objective of this study is to evaluate the efficacy of combination SRT and enzalutamide for freedom-from-PSA-progression. Secondary objectives include time to local recurrence within the radiation field, metastasis-free survival and safety as determined by frequency and severity of adverse events. METHODS/DESIGN: This is a randomized, double-blind, phase II, prospective, multicenter study in adult males with biochemically recurrent prostate cancer following radical prostatectomy. Following registration, enzalutamide 160 mg or placebo by mouth (PO) once daily will be administered for 6 months. Following two months of study drug, external beam radiotherapy to 66.6-70.2 Gray (Gy) will be administered to the prostate bed over 7-8 weeks while continuing daily placebo/enzalutamide. This is followed by two additional months of placebo/enzalutamide. DISCUSSION: The SALV-ENZA trial is the first phase II placebo-controlled double-blinded randomized study to test SRT in combination with a next generation androgen receptor antagonist in men with high-risk recurrent prostate cancer after radical prostatectomy. The primary hypothesis of this study is that clinical outcomes will be improved by the addition of enzalutamide compared to standard-of-care SRT alone and pave the path for phase III evaluation of this combination. TRIAL REGISTRATIONS: ClinicaltTrials.gov Identifier: NCT02203695 Date of Registration: 06/16/2014. Date of First Participant Enrollment: 04/16/2015.

Stereotactic Body Radiation Therapy for Localized Prostate Cancer: A Systematic Review and Meta-Analysis of Over 6,000 Patients Treated On Prospective Studies.

PURPOSE: Utilization of stereotactic body radiation therapy (SBRT) for treatment of localized prostate cancer is increasing. Guidelines and payers variably support the use of prostate SBRT. We therefore sought to systematically analyze biochemical recurrence-free survival (bRFS), physician-reported toxicity, and patient-reported outcomes after prostate SBRT. METHODS AND MATERIALS: A systematic search leveraging Medline via PubMed and EMBASE for original articles published between January 1990 and January 2018 was performed. This was supplemented by abstracts with sufficient extractable data from January 2013 to March 2018. All prospective series assessing curative-intent prostate SBRT for localized prostate cancer reporting bRFS, physician-reported toxicity, and patient-reported quality of life with a minimum of 1-year follow-up were included. The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Meta-analyses were performed with random-effect modeling. Extent of heterogeneity between studies was determined by the I2 and Cochran's Q tests. Meta-regression was performed using Hartung-Knapp methods. RESULTS: Thirty-eight unique prospective series were identified comprising 6116 patients. Median follow-up was 39 months across all patients (range, 12-115 months). Ninety-two percent, 78%, and 38% of studies included low, intermediate, and high-risk patients. Overall, 5- and 7-year bRFS rates were 95.3% (95% confidence interval [CI], 91.3%-97.5%) and 93.7% (95% CI, 91.4%-95.5%), respectively. Estimated late grade ≥3 genitourinary and gastrointestinal toxicity rates were 2.0% (95% CI, 1.4%-2.8%) and 1.1% (95% CI, 0.6%-2.0%), respectively. By 2 years post-SBRT, Expanded Prostate Cancer Index Composite urinary and bowel domain scores returned to baseline. Increasing dose of SBRT was associated with improved biochemical control (P = .018) but worse late grade ≥3 GU toxicity (P = .014). CONCLUSIONS: Prostate SBRT has substantial prospective evidence supporting its use, with favorable tumor control, patient-reported quality of life, and levels of toxicity demonstrated. SBRT has sufficient evidence to be supported as a standard treatment option for localized prostate cancer while ongoing trials assess its potential superiority.

International Multicenter Validation of an Intermediate Risk Subclassification of Prostate Cancer Managed with Radical Treatment without Hormone Therapy.

PURPOSE: The NCCN Guidelines® recently endorsed a subclassification of intermediate risk prostate cancer into favorable and unfavorable subgroups. However, this subclassification was developed in a treatment heterogeneous cohort. Thus, to our knowledge the natural history of androgen deprivation treatment naïve favorable and unfavorable intermediate risk prostate cancer cases remains unknown. MATERIALS AND METHODS: Groups at 3 academic centers pooled data on patients with intermediate risk prostate cancer treated with radical monotherapy (dose escalated external beam radiotherapy, brachytherapy or radical prostatectomy) without combined androgen deprivation treatment. We used the cumulative incidence with competing risk analysis to estimate biochemical recurrence, distant metastasis and prostate cancer specific mortality. RESULTS: A total of 2,550 men at intermediate risk were included in study, of whom 1,063 and 1,487 were at favorable and unfavorable risk, respectively. Of the men 1,149 underwent radical prostatectomy, 1,143 underwent dose escalated external beam radiotherapy and 258 underwent brachytherapy. Median followup after the different treatments ranged from 60.4 to 107.4 months. The 10-year cumulative incidence of distant metastasis in the favorable vs unfavorable risk groups was 0.2% (95% CI 0.2-0.2) vs 11.6% (95% CI 7.7-15.5) for radical prostatectomy (p <0.001), 2.8% (95% CI 0.8-4.8) vs 13.5% (95% CI 9.6-17.4) for dose escalated external beam radiotherapy (p <0.001) and 3.5% (95% CI 0-7.4) vs 10.2% (95% CI 4.3-16.1) for brachytherapy (p = 0.063). The 10-year rate of prostate cancer specific mortality in the favorable vs unfavorable risk groups was 0% (95% CI 0-0) vs 3.7% (95% CI 1.7-5.7) for radical prostatectomy (p = 0.016), 0.5% (95% CI 0.5-0.5) vs 5.6% (95% CI 3.6-7.6) for dose escalated external beam radiotherapy (p = 0.015) and 0% (95% CI 0-0) vs 2.5% (95% CI 0.5-4.5) for brachytherapy (p = 0.028). CONCLUSIONS: This multicenter international effort independently validates the prognostic value of the intermediate risk prostate cancer subclassification in androgen deprivation treatment naïve cases across all radical treatment modalities. It is unlikely that treatment intensification would meaningfully improve oncologic outcomes in men at favorable intermediate risk.

Adverse events in radiation oncology: A case series from wake up safe, the pediatric anesthesia quality improvement initiative.

BACKGROUND: Radiation therapy in pediatric patients often requires anesthesia and poses environmental challenges. Monitoring must be done remotely to limit radiation exposure to the provider. Airway access can be limited by masks or frames. Care is often delivered in relatively inaccessible locations in the hospital. While individual institutions have reported their outcomes, this case series aims to review a multicenter registry of significant adverse events and make recommendations for improved care. METHODS: Wake Up Safe: The Pediatric Quality Improvement Initiative maintains a multisite, voluntary registry of pediatric perianesthetic significant adverse events. This was queried for reports from radiation oncology from January 1, 2010 to May 10, 2018. The database contained 3,379 significant adverse events from approximately 3.3 million anesthetics. All 33 institutions submitted data on a standardized form to a central data repository (Axio Research, Seattle Washington). Prior to each significant adverse events case submission, three anesthesiologists who were not involved in the event analyzed the event using a standardized root cause analysis method to identify the causal or contributing factor(s). RESULTS: Six significant adverse events were identified. In three, incorrect programming of a propofol infusion resulted in overdose. In case one, the 3-year-old female became hypotensive, requiring vasopressors and volume resuscitation. In the second, the 2-year-old female experienced airway obstruction and apnea requiring chin lift. In case three, the child suffered no consequences despite a noted overdose of propofol infusion. In case four, a 2-year-old female with recent respiratory infection suffered laryngospasm during an unmonitored transport to the recovery area. She developed profound oxygen desaturation with bradycardia treated with succinylcholine and chest compressions. In case five, a 6-year-old former premature child suffered laryngospasm at the conclusion of mask creation under general anesthesia with a laryngeal mask airway. The radiation mask delayed recognition of copious secretions. Finally, in case six, a 6-year-old undergoing stereotactic radiosurgery in a head halo suffered bronchospasm and unintended extubation during therapy which required multiple attempts at reintubation by multiple providers ultimately requiring cancellation of the treatment and transport to the intensive care unit. CONCLUSION: There were few radiation oncology significant adverse events, but analysis has led to the identification of several specific opportunities for improvement in pediatric anesthesia for radiation oncology.

Changes in prostate orientation due to removal of a Foley catheter.

PURPOSE: Investigate the impact on prostate orientation caused by use and removal of a Foley catheter, and the dosimetric impact on men prospectively treated with prostate stereotactic body radiotherapy (SBRT). METHODS: Twenty-two men underwent a CT simulation with a Foley in place (FCT), followed immediately by a second treatment planning simulation without the Foley (TPCT). The change in prostate orientation was determined by rigid registration of three implanted transponders between FCT and TPCT and compared to measured orientation changes during treatment. The impact on treatment planning and delivery was investigated by analyzing the measured rotations during treatment relative to both CT scans, and introducing rotations of ±15° in the treatment plan to determine the maximum impact of allowed rotations. RESULTS: Removing the Foley caused a statistically significant prostate rotation (P < 0.0028) compared to normal biological motion in 60% of patients. The largest change in rotation due to removing a Foley occurs about the left-right axis (tilt) which has a standard deviation two to five times larger than changes in rotation about the Sup-Inf (roll) and Ant-Post (yaw) axes. The change in tilt due to removing a Foley for prone and supine patients was -1.1° ± 6.0° and 0.3° ± 7.4°, showing no strong directional bias. The average tilt during treatment was -1.6° ± 7.1° compared to the TPCT and would have been -2.0° ± 7.1° had the FCT been used as the reference. The TPCT was a better or equivalent representation of prostate tilt in 82% of patients, vs 50% had the FCT been used for treatment planning. However, 92.7% of fractions would still have been within the ±15° rotation limit if only the FCT were used for treatment planning. When rotated ±15°, urethra V105% = 38.85Gy  < 20% was exceeded in 27% of the instances, and prostate (CTV) coverage was maintained above D95%  > 37 Gy in all but one instance. CONCLUSIONS: Removing a Foley catheter can cause large prostate rotations. There does not appear to be a clear dosimetric benefit to obtaining the CT scan with a Foley catheter to define the urethra given the changes in urethral position from removing the Foley catheter. If urethral sparing is desired without the use of a Foley, utilization of an MRI to define the urethra may be necessary, or a pseudo-urethral planning organ at risk volume (PRV) may be used to limit dosimetric hot spots.

Intermediate Endpoints After Postprostatectomy Radiotherapy: 5-Year Distant Metastasis to Predict Overall Survival.

BACKGROUND: Intermediate clinical endpoints (ICEs) prognostic for overall survival (OS) are needed for men receiving postprostatectomy radiation therapy (PORT) to improve clinical trial design. OBJECTIVE: To identify a potential ICE for men receiving PORT. DESIGN, SETTING, AND PARTICIPANTS: We performed an institutional review board-approved multi-institutional retrospective study of 566 men consecutively treated with PORT at tertiary care centers from 1986 to 2013. The median follow-up was 8.2 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical failure (BF), distant metastases (DM), and castrate-resistant prostate cancer (CRPC) were evaluated for correlation with OS and assessed as time-dependent variables in a multivariable Cox proportional hazards model and in landmark analyses at 1, 3, 5, and 7 yr after PORT. Cross-validated concordance (c) indices were used to assess model discrimination. RESULTS AND LIMITATIONS: OS at 1, 3, 5, and 7 yr after PORT was 98%, 95%, 90%, and 82%, respectively. In a time-varying model controlling for clinical and pathologic variables, BF (hazard ratio [HR] 2.32, 95% confidence interval [CI] 1.45-3.71; p<0.001), DM (HR 6.52, 95% CI 4.20-10.1; p<0.001), and CRPC (HR 2.47, 95% CI 1.56-3.92; p<0.001) were associated with OS. In landmark analyses, 5-yr DM had the highest c index when adjusting for baseline covariates (0.78), with 5-yr DM also providing the greatest increase in discriminatory power over a model only including baseline covariates. These findings require validation in prospective randomized data. CONCLUSIONS: While limited by the retrospective nature of the data, 5-yr DM is associated with lower OS following PORT, outperforming the prognostic capability of BF and CRPC at 1, 3, 5, or 7 yr after treatment. Confirmation of this ICE as a surrogate for OS is needed from randomized trial data so that it can be incorporated into future clinical trial design. PATIENT SUMMARY: We assessed potential intermediate clinical endpoints prognostic for overall survival in a cohort of men receiving radiotherapy after prostatectomy. We identified the development of metastatic disease within 5 yr after treatment as the strongest predictor of overall survival.

Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer With Adverse Pathological Features.

Importance: Prostate cancer with adverse pathological features (ie, pT3 and/or positive margins) after prostatectomy may be managed with adjuvant radiotherapy (ART) or surveillance followed by early-salvage radiotherapy (ESRT) for biochemical recurrence. The optimal timing of postoperative radiotherapy is unclear. Objective: To compare the clinical outcomes of postoperative ART and ESRT administered to patients with prostate cancer with adverse pathological features. Design, Setting, and Participants: This multi-institutional, propensity score-matched cohort study involved 1566 consecutive patients who underwent postprostatectomy ART or ESRT at 10 US academic medical centers between January 1, 1987, and December 31, 2013. Propensity score 1-to-1 matching was used to account for covariates potentially associated with treatment selection. Data were collected from January 1 to September 30, 2016. Data analysis was conducted from October 1, 2016, to October 21, 2017. Main Outcomes and Measures: Freedom from postirradiation biochemical failure, freedom from distant metastases, and overall survival. All outcomes were measured from date of surgery to address lead-time bias. Results: Of 1566 patients, 1195 with prostate-specific antigen levels of 0.1 to 0.5 ng/mL received ESRT and 371 patients with prostate-specific antigen levels lower than 0.1 ng/mL received ART. The median age (interquartile range) was 60 (55-65) years. After propensity score matching, the median (interquartile range) follow-up after surgery was similar between the ESRT and ART groups (73.3 [44.9-106.6] months vs 65.8 [40-107] months; P = .22). Adjuvant RT, compared with ESRT, was associated with higher freedom from biochemical failure (12-year actuarial rates: 69% [95% CI, 60%-76%] vs 43% [95% CI, 35%-51%]; effect size, 26%), freedom from distant metastases (95% [95% CI, 90%-97%] vs 85% [95% CI, 76%-90%]; effect size, 10%), and overall survival (91% [95% CI, 84%-95%] vs 79% [95% CI, 69%-86%]; effect size, 12%). Adjuvant RT, lower Gleason score and T stage, nodal irradiation, and postoperative androgen deprivation therapy were favorable prognostic features on multivariate analysis for biochemical failure. Sensitivity analysis demonstrated that the decreased risk of biochemical failure associated with ART remained significant unless more than 56% of patients in the ART group were cured by surgery alone. This threshold is greater than the estimated 12-year freedom from biochemical failure rate of 33% to 52% after radical prostatectomy alone, as determined by a contemporary dynamic nomogram. Conclusions and Relevance: Adjuvant RT, compared with ESRT, was associated with reduced biochemical recurrence, distant metastases, and death for high-risk patients, pending prospective validation. These findings suggest that a greater proportion of patients with prostate cancer who have adverse pathological features may benefit from postprostatectomy ART rather than surveillance followed by ESRT.

Impact of Biochemical Failure After Salvage Radiation Therapy on Prostate Cancer-specific Mortality: Competition Between Age and Time to Biochemical Failure.

BACKGROUND: Disease progression following salvage radiotherapy (SRT) for prostate cancer (PC) is common, and the time to biochemical recurrence (BCR) is heterogeneous. OBJECTIVE: To describe the temporal distribution and clinical impact of BCR following SRT and model outcomes using patient age and time to BCR from SRT. DESIGN, SETTING, AND PARTICIPANTS: A retrospective multi-institutional study included 547 consecutive men with lymph node-negative PC receiving SRT from 1985 to 2013. The median follow-up after SRT was 8.4 yr. Intervention All men received SRT with three-dimensional or intensity-modulated RT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: BCR was defined as a rise in prostate-specific antigen (PSA) ≥0.2ng/ml above the PSA nadir followed by a sequentially equal or higher value. Additional outcomes included distant metastasis (DM), PC-specific mortality (PCSM), and overall mortality (OM). Cox proportional hazards models, a landmark analysis, and comparison of c-indices were used. Cumulative incidence curves were estimated from a Fine and Gray regression model. RESULTS AND LIMITATIONS: The estimated 10-yr cumulative incidence of BCR was 60%. Of the 274 men experiencing BCR, 149 (54%) had BCR within 18 mo of SRT. BCR ≤18 mo after SRT was associated with a higher risk of DM (hazard ratio [HR] 7.44, 95% confidence interval [CI] 4.91-11.3; p<0.001), PCSM (HR 12.3, 95% CI 5.95-25.2; p<0.001), and OM (HR 2.85, 95% CI 1.94-4.17; p<0.001). We provide a model to estimate the cumulative incidence of DM and PCSM using age and time to BCR. The retrospective nature of our analysis limits our findings. CONCLUSIONS: A strikingly large proportion of men experience early BCR following SRT and are at higher risk of DM and PCSM. Novel predictive biomarkers are needed to identify men harboring micrometastatic disease to avoid potentially futile local therapies or allow for intensification of systemic therapies. PATIENT SUMMARY: Many men will develop biochemical recurrence of prostate cancer after salvage radiotherapy. Men with biochemical recurrence within 18 mo of salvage radiotherapy constitute a cohort at higher risk of distant metastasis and prostate cancer-specific mortality.

Multi-institutional Evaluation of Elective Nodal Irradiation and/or Androgen Deprivation Therapy with Postprostatectomy Salvage Radiotherapy for Prostate Cancer.

BACKGROUND: Outcomes with postprostatectomy salvage radiation therapy (SRT) are not ideal. Little evidence exists regarding potential benefits of adding whole pelvic radiation therapy (WPRT) alone or in combination with androgen deprivation therapy (ADT). OBJECTIVE: To explore whether WPRT and/or ADT added to prostate bed radiation therapy (PBRT) improves freedom from biochemical failure (FFBF) or distant metastases (DM). DESIGN, SETTING, AND PARTICIPANTS: A database was compiled from 10 academic institutions of patients with postprostatectomy prostate-specific antigen (PSA) >0.01 ng/ml; pT1-4, Nx/0, cM0; and Gleason score (GS) ≥7 treated between 1987 and 2013. Median follow-up was 51 mo. INTERVENTIONS: WPRT and/or ADT in addition to PBRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: FFBF and DM were calculated using cumulative incidence estimation. Multivariable analysis (MVA) utilized cumulative incidence regression. RESULTS AND LIMITATION: Median pre-SRT PSA was 0.5 ng/ml for 1861 patients. Median follow-up for patients not experiencing biochemical failure (BF) was 55 mo. MVA showed increased BF for PBRT versus WPRT (hazard ratio [HR] 1.82, p<0.001) and no ADT versus ADT (HR 1.70, p<0.001). WPRT was associated with a 5-yr FFBF of 62% versus 49% (p<0.001) for PBRT. ADT use was associated with improved 5-yr FFBF (55% vs 50%, p=0.012). No significant differences in DM cumulative incidence were found. CONCLUSIONS: For patients with GS ≥7 receiving SRT, clinicians should weigh FFBF benefits of WPRT and ADT against toxicities. Future studies should explore the impact of WPRT on quality of life, clinical progression, and overall survival. PATIENT SUMMARY: We evaluated patients with prostate cancer treated with radiation after surgery to remove the prostate. Both radiation to the pelvic lymph nodes and suppression of testosterone lowered the chance of increasing prostate-specific antigen (a marker for cancer returning).

Serum MicroRNA Signature Predicts Response to High-Dose Radiation Therapy in Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE: To assess the utility of circulating serum microRNAs (c-miRNAs) to predict response to high-dose radiation therapy for locally advanced non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Data from 80 patients treated from 2004 to 2013 with definitive standard- or high-dose radiation therapy for stages II-III NSCLC as part of 4 prospective institutional clinical trials were evaluated. Pretreatment serum levels of 62 miRNAs were measured by quantitative reverse transcription-polymerase chain reaction array. We combined miRNA data and clinical factors to generate a dose-response score (DRS) for predicting overall survival (OS) after high-dose versus standard-dose radiation therapy. Elastic net Cox regression was used for variable selection and parameter estimation. Model assessment and tuning parameter selection were performed through full cross-validation. The DRS was also correlated with local progression, distant metastasis, and grade 3 or higher cardiac toxicity using Cox regression, and grade 2 or higher esophageal and pulmonary toxicity using logistic regression. RESULTS: Eleven predictive miRNAs were combined with clinical factors to generate a DRS for each patient. In patients with low DRS, high-dose radiation therapy was associated with significantly improved OS compared to treatment with standard-dose radiation therapy (hazard ratio 0.22). In these patients, high-dose radiation also conferred lower risk of distant metastasis and local progression, although the latter association was not statistically significant. Patients with high DRS exhibited similar rates of OS regardless of dose (hazard ratio 0.78). The DRS did not correlate with treatment-related toxicity. CONCLUSIONS: Using c-miRNA signature and clinical factors, we developed a DRS that identified a subset of patients with locally advanced NSCLC who derive an OS benefit from high-dose radiation therapy. This DRS may guide dose escalation in a patient-specific manner.

Association of HSD3B1 Genotype With Response to Androgen-Deprivation Therapy for Biochemical Recurrence After Radiotherapy for Localized Prostate Cancer.

IMPORTANCE: The variant HSD3B1 (1245C) allele enhances dihydrotestosterone synthesis and predicts resistance to androgen-deprivation therapy (ADT) for biochemically recurrent prostate cancer after prostatectomy and for metastatic disease. Whether this is true after radiotherapy is unknown. OBJECTIVE: To determine whether the HSD3B1 (1245C) allele predicts worse clinical outcomes from ADT for biochemical recurrence after radiotherapy. DESIGN, SETTING, AND PARTICIPANTS: The Prostate Clinical Research Information System at Dana-Farber Cancer Institute was used to identify the study cohort, which included men treated with ADT for biochemical recurrence after primary radiotherapy between 1996 and 2013. We retrospectively determined HSD3B1 genotype. MAIN OUTCOMES AND MEASURES: Time to progression, time to metastasis, and overall survival according to genotype. Demographic and treatment characteristics were evaluated for confounders. Multivariable analyses were performed to adjust for known prognostic factors. RESULTS: A total of 218 eligible men were identified, of whom 213 (98%) were successfully genotyped. Of these, 97 of 213 (46%), 96 of 213 (45%) and 20 of 213 (9%) carried 0, 1, and 2 variant alleles. Overall variant allele frequency was 136 of 426 alleles (32%). Median patient age (interquartile range) was 69 (63-74), 72 (65-78), and 69 (65-77) years for 0, 1, and 2 variant alleles (P = .03). Demographic and treatment factors were otherwise similar. During a median follow-up of 7.9 years, median time to progression was 2.3 years (95% CI, 1.6-3.1 years) with 0 variant alleles, 2.3 years (95% CI, 1.5-3.3 years) with 1 variant allele, and 1.4 years (95% CI, 0.7-3.3 years) with 2 variant alleles (P = .68). Median time to metastasis diminished with the number of variant alleles inherited: 7.4 (95% CI, 6.7-9.7), 5.8 (95% CI, 4.9-6.5), and 4.4 (95% CI, 3.0-5.7) years, with inheritance of 0, 1, and 2 variant alleles, respectively (P = .03). Median OS was 7.7 (95% CI, 6.7-10.3), 6.9 (95% CI, 5.8-8.4), and 7.2 (95% CI, 3.8-7.9) years with inheritance of 0, 1, and 2 variant alleles, respectively (P = .31). On multivariable analysis with 0 variant alleles as the reference, the adjusted hazard ratio for metastasis was 1.19 (95% CI, 0.74-1.92) (P = .48) for 1 variant allele and 2.01 (95% CI, 1.02-3.97) (P = .045) for 2 variant alleles. Multivariable analysis did not demonstrate significant differences in TTP or OS. CONCLUSIONS AND RELEVANCE: In this study, the HSD3B1 (1245C) allele was associated with more rapid development of metastases in men treated with ADT for biochemical recurrence after primary radiation therapy for prostate cancer. Notably, 105 of 213 men (49%) had received prior ADT, and 119 of 213 (56%) received an androgen receptor antagonist during salvage treatment, both of which may attenuate the effect of the variant allele.

Radiation-induced lung toxicity in non-small-cell lung cancer: Understanding the interactions of clinical factors and cytokines with the dose-toxicity relationship.

BACKGROUND AND PURPOSE: Current methods to estimate risk of radiation-induced lung toxicity (RILT) rely on dosimetric parameters. We aimed to improve prognostication by incorporating clinical and cytokine data, and to investigate how these factors may interact with the effect of mean lung dose (MLD) on RILT. MATERIALS AND METHODS: Data from 125 patients treated from 2004 to 2013 with definitive radiotherapy for stages I-III NSCLC on four prospective clinical trials were analyzed. Plasma levels of 30 cytokines were measured pretreatment, and at 2 and 4weeks midtreatment. Penalized logistic regression models based on combinations of MLD, clinical factors, and cytokine levels were developed. Cross-validated estimates of log-likelihood and area under the receiver operating characteristic curve (AUC) were used to assess accuracy. RESULTS: In prognosticating grade 3 or greater RILT by MLD alone, cross-validated log-likelihood and AUC were -28.2 and 0.637, respectively. Incorporating clinical features and baseline cytokine levels increased log-likelihood to -27.6 and AUC to 0.669. Midtreatment cytokine data did not further increase log-likelihood or AUC. Of the 30 cytokines measured, higher levels of 13 decreased the effect of MLD on RILT, corresponding to a lower odds ratio for RILT per Gy MLD, while higher levels of 4 increased the association. CONCLUSIONS: Although the added prognostic benefit from cytokine data in our model was modest, understanding how clinical and biologic factors interact with the MLD-RILT relationship represents a novel framework for understanding and investigating the multiple factors contributing to radiation-induced toxicity.

Cardiac Events After Radiation Therapy: Combined Analysis of Prospective Multicenter Trials for Locally Advanced Non-Small-Cell Lung Cancer.

Purpose Radiation therapy is a critical component in the care of patients with non-small-cell lung cancer (NSCLC), yet cardiac injury after treatment is a significant concern. Therefore, we wished to elucidate the incidence of cardiac events and their relationship to radiation dose to the heart. Patients and Materials Study eligibility criteria included patients with stage II to III NSCLC treated on one of four prospective radiation therapy trials at two centers from 2004 to 2013. All cardiac events were reviewed and graded per Common Terminology Criteria for Adverse Events (v4.03). The primary end point was the development of a grade ≥ 3 cardiac event. Results In all, 125 patients met eligibility criteria; median follow-up was 51 months for surviving patients. Median prescription dose was 70 Gy, 84% received concurrent chemotherapy, and 27% had pre-existing cardiac disease. Nineteen patients had a grade ≥ 3 cardiac event at a median of 11 months (interquartile range, 6 to 24 months), and 24-month cumulative incidence was 11% (95% CI, 5% to 16%). On multivariable analysis (MVA), pre-existing cardiac disease (hazard ratio [HR], 2.96; 95% CI, 1.07 to 8.21; P = .04) and mean heart dose (HR, 1.07/Gy; 95% CI, 1.02 to 1.13/Gy; P = .01) were significantly associated with grade ≥ 3 cardiac events. Analyzed as time-dependent variables on MVA analysis, both disease progression (HR, 2.15; 95% CI, 1.54 to 3.00) and grade ≥ 3 cardiac events (HR, 1.76; 95% CI, 1.04 to 2.99) were associated with decreased overall survival. However, disease progression (n = 71) was more common than grade ≥ 3 cardiac events (n = 19). Conclusion The 24-month cumulative incidence of grade ≥ 3 cardiac events exceeded 10% among patients with locally advanced NSCLC treated with definitive radiation. Pre-existing cardiac disease and higher mean heart dose were significantly associated with higher cardiac event rates. Caution should be used with cardiac dose to minimize risk of radiation-associated injury. However, cardiac risks should be balanced against tumor control, given the unfavorable prognosis associated with disease progression.