Association of Radiation Therapy With Risk of Adverse Events in Patients Receiving Immunotherapy: A Pooled Analysis of Trials in the US Food and Drug Administration Database.

Importance: Immune checkpoint inhibitors (ICIs) and radiation therapy (RT) are widely used to treat various cancers, but little data are available to guide clinicians on ICI use sequentially with RT. Objective: To assess whether there is an increased risk of serious adverse events (AEs) associated with RT given within 90 days prior to an ICI. Design, Setting, and Participants: Individual patient data were pooled from 68 prospective trials of ICIs submitted in initial or supplemental licensing applications in the US Food and Drug Administration (FDA) databases through December 2019. Two cohorts were generated: (1) patients who received RT within the 90 days prior to beginning ICI therapy and (2) those who did not receive RT within the 90 days prior to beginning ICI therapy, and AE frequencies were determined. A 1:1 propensity score-matched analysis was performed. Interventions: All patients received an ICI (atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab, or pembrolizumab); 1733 received RT within the 90 days prior to starting ICI therapy, and 13 956 did not. Main Outcomes and Measures: The primary outcome was frequency and severity of AEs. Incidence of AEs was compared descriptively between participants who did vs did not receive RT in the propensity score-matched set. Because all analyses are exploratory (ie, not preplanned and no alpha allocated), assessment for statistical significance of the differences between groups was not considered appropriate. Results: A total of 25 469 patients were identified; 8634 were excluded because they lacked comparators who had received RT (n = 976), did not receive an ICI (n = 4949), received RT outside of the target window (n = 2338), or had missing data in 1 or more variables used in the propensity analysis (n = 371), leaving 16 835 patients included in the analysis. The majority were younger than 65 years (9447 [56.1%]), male (10 459 [62.1%]), and White (13 422 [79.7%]). Patients receiving RT had generally similar rates of AEs overall to those patients who did not receive RT. The average absolute difference in rates across the AEs was 1.2%, and the difference ranged from 0% for neurologic AEs to 8% for fatigue. No difference in grade 3 to 4 AEs was observed between the 2 groups (absolute difference ranged from 0.01% to 2%). These findings persisted after propensity score matching. Conclusions and Relevance: In this pooled analysis, administration of an ICI within 90 days following RT did not appear to be associated with an increased risk of serious AEs. Thus, it would appear to be safe to administer an ICI within 90 days of receiving RT. These findings should be confirmed in future prospective trials.

Radiation biology workforce in the United States.

In recent decades, the principal goals of participants in the field of radiation biologists have included defining dose thresholds for cancer and non-cancer endpoints to be used by regulators, clinicians and industry, as well as informing on best practice radiation utilization and protection applications. Importantly, much of this work has required an intimate relationship between "bench" radiation biology scientists and their target audiences (such as physicists, medical practitioners and epidemiologists) in order to ensure that the requisite gaps in knowledge are adequately addressed. However, despite the growing risk for public exposure to higher-than-background levels of radiation, e.g. from long-distance travel, the increasing use of ionizing radiation during medical procedures, the threat from geopolitical instability, and so forth, there has been a dramatic decline in the number of qualified radiation biologists in the U.S. Contributing factors are thought to include the loss of applicable training programs, loss of jobs, and declining opportunities for advancement. This report was undertaken in order to begin addressing this situation since inaction may threaten the viability of radiation biology as a scientific discipline.

Survival outcomes in older men with non-metastatic castration-resistant prostate cancer treated with androgen receptor inhibitors: a US Food and Drug Administration pooled analysis of patient-level data from three randomised trials.

BACKGROUND: Little is known about the benefit-risk profile of second-generation androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. We aimed to examine the efficacy and safety of second-generation androgen receptor inhibitors in men aged 80 years or older with non-metastatic castration-resistant prostate cancer. METHODS: We searched for all randomised controlled clinical trials evaluating second-generation androgen receptor inhibitors in patients with non-metastatic castration-resistant prostate cancer submitted to the US Food and Drug Administration before Aug 15, 2020, and pooled data from three trials that met the selection criteria. All three trials enrolled patients who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, castration-resistant prostate cancer, prostate-specific antigen (PSA) 2·0 µg/L or greater, PSA doubling time of 10 months or less, and no evidence of distant metastatic disease on conventional imaging per the investigator's assessment at the time of screening. All patients had histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small-cell features. All patients who were randomly assigned to androgen receptor inhibitor or placebo groups in these trials were considered assessable and were included in this pooled analysis. We evaluated the effect of age on metastasis-free survival and overall survival across age groups (<80 years vs ≥80 years) in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study treatment. FINDINGS: Between Oct 14, 2013, and March 9, 2018, 4117 patients were assigned to androgen receptor inhibitor (apalutamide, enzalutamide, or daralutamide; n=2694) or placebo (n=1423) across three randomised trials. The median follow-up duration for metastasis-free survival was 18 months (IQR 11-26) and for overall survival was 44 months (32-55). In patients aged 80 years or older (n=1023), the estimated median metastasis-free survival was 40 months (95% CI 36-41) in the androgen receptor inhibitor groups and 22 months (18-29) in the placebo groups (adjusted hazard ratio [HR] 0·37 [95% CI 0·28-0·47]), and the median overall survival was 54 months (50-61) versus 49 months (43-58), respectively (adjusted HR 0·79 [0·64-0·98]). In patients younger than 80 years of age (n=3094), the estimated median metastasis-free survival was 41 months (95% CI 36-not estimable [NE]) in the androgen receptor inhibitor groups and 16 months (15-18) in the placebo groups (adjusted HR 0·31 [95% CI 0·27-0·35]), and the median overall survival was 74 months (74-NE) versus 61 months (56-NE), respectively (adjusted HR 0·69 [0·60-0·80]). In patients aged 80 years or older, grade 3 or worse adverse events were reported in 371 (55%) of 672 patients in the androgen receptor inhibitor groups and 140 (41%) of 344 patients in the placebo groups, compared with 878 (44%) of 2015 patients in the androgen receptor inhibitor groups and 321 (30%) of 1073 patients in the placebo groups among patients younger than 80 years. The most common grade 3-4 adverse events were hypertension (168 [8%] of 2015 patients aged <80 years and 51 [8%] of 672 patients aged ≥80 years in the androgen receptor inhibitor groups vs 53 [5%] of 1073 patients aged <80 years and 22 [6%] of 344 patients aged ≥80 years in the placebo groups) and fracture (61 [3%] and 36 [5%] in the androgen receptor inhibitor groups vs 15 [1%] and 11 [3%] in the placebo groups). INTERPRETATION: The findings of this pooled analysis support the use of androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. Incorporating geriatric assessment tools in the care of older adults with non-metastatic castration-resistant prostate cancer might help clinicians to offer individualised treatment to each patient. FUNDING: None.

Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy.

Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of "one-two punch" cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.

Hypofractionated Postprostatectomy Radiation Therapy for Prostate Cancer to Reduce Toxicity and Improve Patient Convenience: A Phase 1/2 Trial.

PURPOSE: The phase 1 portion of this multicenter, phase 1/2 study of hypofractionated (HypoFx) prostate bed radiation therapy (RT) as salvage or adjuvant therapy aimed to identify the shortest dose-fractionation schedule with acceptable toxicity. The phase 2 portion aimed to assess the health-related quality of life (QoL) of using this HypoFx regimen. METHODS AND MATERIALS: Eligibility included standard adjuvant or salvage prostate bed RT indications. Patients were assigned to receive 1 of 3 daily RT schedules: 56.6 Gy in 20 Fx, 50.4 Gy in 15 Fx, or 42.6 Gy in 10 Fx. Regional nodal irradiation and androgen deprivation therapy were not allowed. Participants were followed for 2 years after treatment with outcome measures based on prostate-specific antigen levels, toxicity assessments (Common Terminology Criteria for Adverse Events, v4.0), QoL measures (the Expanded Prostate Cancer Index Composite [EPIC] and EuroQol EQ-5D instruments), and out-of-pocket costs. RESULTS: There were 32 evaluable participants, and median follow-up was 3.53 years. The shortest dose-fractionation schedule with acceptable toxicity was determined to be 42.6 Gy in 10 Fx, with most patients (23) treated with this schedule. Grade 3 genitourinary (GU) and gastrointestinal (GI) toxicities occurred in 3 patients and 1 patient, respectively. There was 1 grade 4 sepsis event. Higher dose to the hottest 25% of the rectum was associated with increased risk of grade 2+ GI toxicity; no dosimetric factors were found to predict for GU toxicity. There was a significant decrease in the mean bowel, but not bladder, QoL score at 1 year compared with baseline. Prostate-specific antigen failure occurred in 34.3% of participants, using a definition of nadir plus 2 ng/mL. Metastases were more likely to occur in regional lymph nodes (5 of 7) than in bones (2 of 7). The mean out-of-pocket cost for patients during treatment was $223.90. CONCLUSIONS: We identified 42.6 Gy in 10 fractions as the shortest dose-fractionation schedule with acceptable toxicity in this phase 1/2 study. There was a higher than expected rate of grade 2 to 3 GU and GI toxicity and a decreased EPIC bowel QoL domain with this regimen. Future studies are needed to explore alternative adjuvant/salvage HypoFx RT schedules after radical prostatectomy.

FDA Approval Summary: Rucaparib for the Treatment of Patients with Deleterious BRCA-Mutated Metastatic Castrate-Resistant Prostate Cancer.

The U.S. Food and Drug Administration (FDA) granted accelerated approval to rucaparib in May 2020 for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane. This approval was based on data from the ongoing multicenter, open-label single-arm trial TRITON2. The primary endpoint, confirmed objective response rate, in the 62 patients who met the above criteria, was 44% (95% confidence interval [CI]: 31%-57%). The median duration of response was not estimable (95% CI: 6.4 to not estimable). Fifty-six percent of patients had a response duration of >6 months and 15% >12 months. The safety profile of rucaparib was generally consistent with that of the class of poly-(ADP-ribose) polymerase enzyme inhibitors and other trials of rucaparib in the treatment of ovarian cancer. Deaths due to adverse events (AEs) occurred in 1.7% of patients, and 8% discontinued rucaparib because of an AE. Grade 3-4 AEs occurred in 59% of patients. No patients with prostate cancer developed myelodysplastic syndrome or acute myeloid leukemia. The trial TRITON3 in patients with mCRPC is ongoing and is planned to verify the clinical benefit of rucaparib in mCRPC. This article summarizes the FDA thought process and data supporting this accelerated approval. IMPLICATIONS FOR PRACTICE: The accelerated approval of rucaparib for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer who have been treated with androgen receptor-directed therapy and a taxane represents the first approved therapy for this selected patient population. This approval was based on a single-arm trial demonstrating a confirmed objective response rate greater than that of available therapy with a favorable duration of response and an acceptable toxicity profile. The ongoing trial TRITON3 is verifying the clinical benefit of this drug.

Moderately Hypofractionated Intensity Modulated Radiation Therapy With Simultaneous Integrated Boost for Prostate Cancer: Five-Year Toxicity Results From a Prospective Phase I/II Trial.

BACKGROUND: In this phase I/II trial, 5-year physician-assessed toxicity and patient reported quality of life data is reported for patients undergoing moderately hypofractionated intensity modulated radiation therapy (IMRT) for prostate cancer using a simultaneous integrated boost (SIB) and pelvic lymph node (LN) coverage. MATERIALS AND METHODS: Patients with T1-T2 localized prostate cancer were prospectively enrolled, receiving risk group based coverage of prostate ± seminal vesicles (SVs) ± pelvic lymph nodes (LNs). Low risk (LR) received 69.6 Gy/29 fractions to the prostate, while intermediate risk (IR) and high risk (HR) patients received 72 Gy/30fx to the prostate and 54Gy/30fx to the SVs. If predicted risk of LN involvement >15%, 50.4 Gy/30fx was delivered to pelvic LNs. Androgen deprivation therapy was given to IR and HR patients. RESULTS: There were 55 patients enrolled and 49 patients evaluable at a median follow up of 60 months. Included were 11 (20%) LR, 23 (41.8%) IR, and 21 (38.2%) HR patients. Pelvic LN treatment was given in 25 patients (51%). Prevalence rates of late grade 2 GI toxicity at 1, 3, and 5 years was 5.8, 3.9, and 5.8%, respectively, with no permanent grade 3 events. Prevalence rates of late grade 2 GU toxicity at 1, 3, and 5 years rates were 15.4, 7.7, and 13.5%, respectively, with three grade 3 events (5.8%). The biochemical relapse free survival at 5 years was 88.3%. There were no local, regional, or distant failures, with all patients still alive at last follow up. CONCLUSION: Moderate hypofractionation of localized prostate cancer utilizing a SIB technique and LN coverage produces tolerable acute/late toxicity. Given equivalent efficacy between moderate hypofractionation schedules, the optimal regimen will be determined by long-term toxicity reported from both the physician and patient perspective. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT01117935, Date of Registration: 5/6/2010.

Stereotactic Body Radiation Therapy for the Definitive Treatment of Early Stage Kidney Cancer: A Survival Comparison With Surgery, Tumor Ablation, and Observation.

PURPOSE: Partial nephrectomy is the preferred definitive treatment for early stage kidney cancer, with tumor ablative techniques or active surveillance reserved for patients not undergoing surgery. Stereotactic body radiation therapy (SBRT) has emerged as a potential noninvasive alternative for patients with early stage kidney cancer not amenable to surgery, with early reports suggesting excellent rates of local control and limited toxicity. METHODS AND MATERIALS: The national cancer database from 2004 to 2014 was queried for patients who received a diagnosis of T1N0M0 kidney cancer. Treatments were categorized as surgery (partial or total nephrectomy), tumor ablation (cryoablation or thermal ablation), SBRT (radiation therapy in 5 fractions or less to a total biological effective dose [BED10] of 72 or more), or observation. A propensity score was generated by multinomial logistic regression. A Cox proportional hazards model was fit to determine association between overall survival and treatment group with propensity score adjustments for patient, demographic, and treatment characteristics. RESULTS: A total of 165,298 received surgery, 17,196 underwent tumor ablation, 104 underwent SBRT, and 18,241 were observed. Median follow-up was 51 months. On multivariable analysis, surgery, tumor ablation, and SBRT were associated with a decreased risk of death compared with observation, with hazard ratios of 0.25 (95% confidence interval, 0.24-0.26, P < .001), 0.36 (0.35-0.38, P < .001), and 0.56 (0.39-0.79, P < .001), respectively. When stratifying by BED10 and compared with observation, hazard ratio for risk of death for patients treated with SBRT to a BED10 ≥100 (n = 62) and a BED10 <100 (n = 42) was 0.34 (0.19-0.60, P < .001) and 0.90 (0.58-1.4, P = .64), respectively. CONCLUSIONS: In this population-based cohort, patients undergoing high-dose SBRT (BED10 ≥100) for early stage kidney cancer demonstrated longer survival compared with patients undergoing observation. This may be a promising noninvasive treatment option for nonsurgical candidates with prospective efficacy and safety assessments meriting study in future clinical trials.

Increased Frequency of Mesorectal and Perirectal LN Involvement in T4 Prostate Cancers.

PURPOSE: Patients with prostate cancer presenting with advanced T stage, mainly T4, might have a unique pattern of nodal failure and disease involvement that is not typically covered when local therapy is offered. We attempted to identify common sites of nodal disease presentation and failure for patients presenting with cT4 prostate cancer. METHODS AND MATERIALS: All patients with treatment-naïve cT4 prostate cancer were retrospectively identified. All patients were required to have a confirmed diagnosis reviewed by our genitourinary pathologist and completed baseline staging. Lymph node (LN) involvement and location at diagnosis were reviewed by a genitourinary radiologist. All patients' follow-up scans were also reviewed; based on LN size, imaging characteristics, and progression/regression characteristics on systemic therapy, the locations of sites of LN failure were recorded. For patients who underwent surgery, any pathologically involved LNs and their anatomic locations were recorded. A total of 103 patients met these criteria, with a median follow-up of 8 years (range, 0.5-14 years). RESULTS: Rectal involvement by the primary disease was associated with a higher risk of perirectal and mesorectal LN involvement (45%) relative to no rectal involvement (26%) (P < .05). These echelons are typically not covered with conventional pelvic external beam radiation therapy and are not routinely part of pelvic LN dissection in patients treated surgically. Conversely, bladder or pelvic side wall invasion did not correlate with increased frequency of involvement of perirectal/mesorectal LNs (P > .05). CONCLUSIONS: When offering local therapy, target modification to include the perirectal and mesorectal LNs should be considered for patients presenting with T4 prostate cancer with rectal involvement.

Quality comparison between three-dimensional T2-weighted SPACE and two-dimensional T2-weighted turbo spin echo magnetic resonance images for the brachytherapy planning evaluation of prostate and periprostatic anatomy.

PURPOSE: The purpose of this study was to compare an isotropic three-dimensional (3D) T2-weighted sequence sampling perfection with application-optimized contrasts by using flip angle evolution (SPACE) with an axial two-dimensional T2-weighted turbo spin echo (TSE) sequence with regard to overall image quality and the delineation of normal prostate and periprostatic anatomy for low-dose-rate prostate cancer brachytherapy planning evaluation. METHODS AND MATERIALS: Patients (n = 69) with prostate cancer who had pelvic magnetic resonance imaging (MRI) for low-dose-rate brachytherapy treatment planning were included. Three radiologists independently assessed the visibility of nine anatomic structures on each sequence by using a 5-point scale and overall image quality by using a 4-point scale. The significance of the differences in diagnostic performance was tested with a Wilcoxon signed rank test. RESULTS: No significant intersequence differences were found for most (7/9) anatomical structures and overall image quality. The mean scores for visibility of anatomical structures on the 3D SPACE and 2D TSE sequences, respectively, were as follows: the zonal anatomy (3.7; 3.9, p = 0.05), prostate capsule (3.9; 4.0, p = 0.08), neurovascular bundle (2.9; 2.9, p = 0.9), rectoprostatic angle (3.8; 3.8, p = 0.35), rectum (4.2; 4.3, p = 0.26), urethra (3.8; 3.9, p = 0.12), urinary bladder (4.6; 4.6, p = 0.61), and overall image quality (2.9; 2.9, p = 0.33). 3D SPACE was superior for delineation of the genitourinary diaphragm (3.8; 3.6, p = 0.003), whereas 2D TSE was superior for delineation of the seminal vesicles (3.5; 4.0, p < 0.0001). CONCLUSIONS: Anatomic delineation of the prostatic and periprostatic anatomy provided by the 3D SPACE sequence is as robust in quality as that provided by a conventional 2D TSE sequence with superior delineation of the genitourinary diaphragm. For MRI-based brachytherapy treatment planning, the 3D SPACE sequence with subcentimeter isotropic resolution can replace the 2D TSE sequence and be incorporated into standard MRI protocols.

Association of Sociodemographic and Health-Related Factors With Receipt of Nondefinitive Therapy Among Younger Men With High-Risk Prostate Cancer.

Importance: Multiple randomized clinical trials have shown that definitive therapy improves overall survival among patients with high-risk prostate cancer. However, many patients do not receive definitive therapy because of sociodemographic and health-related factors. Objective: To identify factors associated with receipt of nondefinitive therapy (NDT) among patients aged 70 years and younger with high-risk prostate cancer. Design, Setting, and Participants: This cohort study identified 72 036 patients aged 70 years and younger with high-risk prostate cancer and Charlson Comorbidity Index scores of 2 or less who were entered in the National Cancer Database between January 2004 and December 2014. Data analysis was conducted from November 2018 to December 2019. Exposure: Receipt of NDT as an initial treatment approach. Main Outcomes and Measures: Survival rates were compared based on receipt of definitive therapy or NDT, and sociodemographic and health-related factors were associated with the type of therapy received. Residual life expectancy was estimated from the National Center for Health Statistics to calculate person-years of life lost. Results: A total of 72 036 men with a median (range) age of 63 (30-70) years, Charlson Comorbidity Index scores of 2 or less, and high-risk prostate cancer without regional lymph node or distant metastatic disease were analyzed. Among eligible patients, 5252 (7.3%) received NDT as an initial therapeutic strategy. On univariate and multivariate analyses, NDT was associated with worse overall survival (univariate analysis hazard ratio, 2.54; 95% CI, 2.40-2.69; P < .001; multivariate analysis hazard ratio, 2.40; 95% CI, 2.26-2.56; P < .001). Compared with patients with private insurance or managed care, those with no insurance, Medicaid, or Medicare were more likely to receive systemic therapy only (no insurance: odds ratio [OR], 3.34; 95% CI, 2.81-3.98; P < .001; Medicaid: OR, 2.92; 95% CI, 2.48-3.43; P < .001; Medicare: OR, 1.36; 95% CI, 1.20-1.53; P < .001) or no treatment (no insurance: OR, 2.63; 95% CI, 2.24-3.08; P < .001; Medicaid: OR, 1.71; 95% CI, 1.45-2.01; P < .001; Medicare: OR, 1.14; 95% CI, 1.04-1.24; P = .004). Compared with white patients, black patients were more likely to receive systemic therapy only (OR, 1.93; 95% CI, 1.74-2.14; P < .001) or no treatment (OR, 1.46; 95% CI, 1.32-1.61; P < .001), and Hispanic patients were more likely to receive systemic therapy only (OR, 1.36; 95% CI, 1.13-1.64; P = .001) or no treatment (OR, 1.36; 95% CI, 1.14-1.60; P < .001). Between 2004 and 2014, patients without insurance or enrolled in Medicaid had 1.83-fold greater person-years of life lost compared with patients with private insurance (area under the curve, 77 600 vs 42 300 person-years of life lost). Conclusions and Relevance: In this study, receipt of NDT was associated with insurance status and race/ethnicity. While treatment decisions should be individualized for every patient, younger men with high-risk prostate cancer and minimal comorbidities should be encouraged to receive definitive local therapy regardless of other factors. These data suggest that significant barriers to life-extending treatment options for patients with prostate cancer remain.

MRI-assisted radiosurgery: A quality assurance nomogram for palladium-103 and iodine-125 prostate brachytherapy.

PURPOSE: We sought to develop an activity nomogram for magnetic resonance (MR)-planned permanent seed prostate brachytherapy to improve quality assurance through a secondary dosimetric check. METHODS AND MATERIALS: Patients undergoing MRI-assisted radiosurgery (MARS), whereby MRI is used for preoperative planning and postimplant dosimetry, were reviewed from May 2016 to September 2018. Planned activity (U) was fitted by MR-prostate volume (cc) via simple linear regression. Resulting monotherapy nomograms were compared with institutional nomograms from an ultrasound-planned cohort. Dosimetric coverage and external urinary sphincter (EUS) dose were also assessed for MR-planned patients. RESULTS: We identified 183 patients treated with MARS: 146 patients received palladium-103 (103Pd; 102 monotherapy and 44 boost), and 37 received iodine-125 (125I) monotherapy. Median prostate volume was 28 cc (interquartile range: 22-35). Lines of best fit for implant activity were U = 4.344 × (vol) + 54.13 (R2: 95%) for 103Pd monotherapy, U = 3.202 (vol) + 39.72 (R2: 96%) for 103Pd boost and U = 0.684 (vol) + 13.38 (R2: 96%) for 125I monotherapy. Compared with ultrasound, MR-planned nomograms had lower activity per volume (p < 0.05) for both 103Pd monotherapy (∼6%) and 125I monotherapy (∼11%), given a median size (30 cc) prostate. Across all MARS implants, postimplant dosimetry revealed a median V100% of 94% (interquartile range: 92-96%). Median EUS V125 was <1 cc for all patients, regardless of isotope. CONCLUSIONS: We developed a quality assurance nomogram for MR-planned prostate brachytherapy. When compared with ultrasound-planned, MR-planned monotherapy resulted in a lower activity-to-volume ratio while maintaining dosimetric coverage, likely secondary to EUS-sparing and reduced planning target margins.

Dose Escalation for Prostate Adenocarcinoma: A Long-Term Update on the Outcomes of a Phase 3, Single Institution Randomized Clinical Trial.

PURPOSE: To determine the long-term outcomes for prostate adenocarcinoma when escalating radiation dose from 70 Gy to 78 Gy. METHODS AND MATERIALS: Between 1993 and 1998, 301 patients with biopsy-proven clinical stage T1b-T3 prostate adenocarcinoma, any prostate-specific antigen level, and any Gleason score were randomized to 70 Gy in 35 fractions versus 78 Gy in 39 fractions of photon radiation therapy using a 4-field box technique without hormone deprivation therapy. The primary outcome was powered to detect a 15% difference in biochemical or clinical failure. Secondary outcomes included survival, prostate cancer mortality, biochemical failure, local failure, nodal failure, distant failure, and secondary malignancy rates. RESULTS: With a median follow-up of 14.3 years, the cumulative incidence of 15-year biochemical or clinical failure was 18.9% versus 12.0% in the 70 Gy versus 78 Gy arms, respectively (subhazard ratio [sHR], 0.61; 95% confidence interval [CI], 0.38-0.98; Fine-Gray P = .042). The 15-year cumulative incidence of distant metastasis was 3.4% versus 1.1%, respectively (sHR, 0.33; 95% CI, 0.13-0.82; Fine-Gray P = .018). The 15-year cumulative incidence of prostate cancer-specific mortality was 6.2% versus 3.2%, respectively, (sHR, 0.52; 95% CI, 0.27-0.98; Fine-Gray P = .045). There were no differences in overall survival (HR, 1.10; 95% CI, 0.84-1.45; log rank P = .469) or other-cause survival (sHR, 1.33; 95% CI, 0.99-1.79; Fine-Gray P = .061). Salvage therapy was more common in the 70 Gy arm, at 38.7% versus 21.9% in the 78 Gy arm (P = .002). There was a 2.3% secondary solid malignancy rate (1 bladder, 6 rectal) within the radiation treatment field, which was not significantly different between treatment arms. CONCLUSIONS: Dose escalation by 8 Gy (78 Gy vs 70 Gy) provided a sustained improvement in biochemical and clinical failure, which translated into lower salvage rates and improved prostate cancer-specific mortality, but not overall survival. Long-term follow-up demonstrated a low incidence of potential solid tumor secondary malignancies.

Analysis of the 2017 American Society for Radiation Oncology (ASTRO) Research Portfolio.

PURPOSE: Research in radiation oncology (RO) is imperative to support the discovery of new uses of radiation and improvement of current approaches to radiation delivery and to foster the continued evolution of our field. Therefore, in 2016, the American Society of Radiation Oncology performed an evaluation of research grant funding for RO. METHODS AND MATERIALS: Members of the Society of Chairs of Academic Radiation Oncology Programs (SCAROP) were asked about funded and unfunded grants that were submitted by their departments between the fiscal years 2014 and 2016. Grants were grouped according to broad categories defined by the 2017 American Society of Radiation Oncology Research Agenda. Additionally, active grants in the National Institutes of Health (NIH) Research Portfolio Online Reporting Tools database were collated using RO faculty names. RESULTS: Overall, there were 816 funded (44%) and 1031 unfunded (56%) SCAROP-reported grants. Total grant funding was over $196 million. The US government funded the plurality (42.2%; 345 of 816) of grants compared with nonprofit and industry funders. Investigators from 10 institutions accounted for >75% of funded grants. Of the funded grants, 43.5% were categorized as "genomic influences and targeted therapies." The proportion of funded to unfunded grants was highest within the category of "tumor microenvironment, normal tissue effects, and reducing toxicity" (53.4% funded). "New clinical trial design and big data" had the smallest share of SCAROP grant applications and the lowest percent funded (38.3% of grants). NIH grants to RO researchers in 2014 to 2016 accounted for $85 million in funding. From the 31 responding SCAROP institutions, there was a 28% average success rate for RO proposals submitted to the NIH during this period. CONCLUSIONS: Though RO researchers from responding institutions were relatively successful in obtaining funding, the overall amount awarded remains small. Continued advocacy on behalf of RO is needed, as well as investment to make research careers more attractive areas for emerging faculty.

Comparative Toxicities and Cost of Intensity-Modulated Radiotherapy, Proton Radiation, and Stereotactic Body Radiotherapy Among Younger Men With Prostate Cancer.

Purpose To compare the toxicities and cost of proton radiation and stereotactic body radiotherapy (SBRT) with intensity-modulated radiotherapy (IMRT) for prostate cancer among men younger than 65 years of age with private insurance. Methods Using the MarketScan Commercial Claims and Encounters database, we identified men who received radiation for prostate cancer between 2008 and 2015. Patients undergoing proton therapy and SBRT were propensity score-matched to IMRT patients on the basis of clinical and sociodemographic factors. Proportional hazards models compared the cumulative incidence of urinary, bowel, and erectile dysfunction toxicities by treatment. Cost from a payer's perspective was calculated from claims and adjusted to 2015 dollars. Results A total of 693 proton therapy patients were matched to 3,465 IMRT patients. Proton therapy patients had a lower risk of composite urinary toxicity (33% v 42% at 2 years; P < .001) and erectile dysfunction (21% v 28% at 2 years; P < .001), but a higher risk of bowel toxicity (20% v 15% at 2 years; P = .02). Mean radiation cost was $115,501 for proton therapy patients and $59,012 for IMRT patients ( P < .001). A total of 310 SBRT patients were matched to 3,100 IMRT patients. There were no significant differences in composite urinary, bowel, or erectile dysfunction toxicities between SBRT and IMRT patients ( P > .05), although a higher risk of urinary fistula was noted with SBRT (1% v 0.1% at 2 years; P = .009). Mean radiation cost for SBRT was $49,504 and $57,244 for IMRT ( P < .001). Conclusion Among younger men with prostate cancer, proton radiation was associated with significant reductions in urinary toxicity but increased bowel toxicity at nearly twice the cost of IMRT. SBRT and IMRT were associated with similar toxicity profiles; SBRT was modestly less expensive than IMRT.

Phase 1/2 study of hypofractionated intensity-modulated radiation therapy for prostate cancer including simultaneously integrated boost.

PURPOSE: This study evaluates the safety and efficacy of moderately hypofractionated radiation therapy (RT) with simultaneous integrated boost (HSIB) intensity modulated RT (IMRT) that includes coverage of the seminal vesicles (SVs) and pelvic lymph nodes (LNs). METHODS AND MATERIALS: Men with localized prostate cancer were prospectively enrolled in a phase 1/2 trial to receive HSIB-IMRT to the prostate, ± SV, ± pelvic LN using a risk-based method. Low-risk patients received 69.6 Gy to only the prostate in 29 fractions. Intermediate-risk (IR) and high-risk (HR) patients received 30 fractions with 72 Gy to the prostate, 54 Gy to the SV, and 50.4 Gy to the pelvic LN when risk of LN involvement exceeded 15% by the Roach formula. IR and HR patients received androgen deprivation therapy. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated with patient- and physician-reported surveys. RESULTS: Fifty-five men were enrolled, and 49 had at least 1 year of follow-up with 19.2% low-risk, 40.4% IR, and 40.4% HR disease. The median age was 69 years; median follow-up time was 36.9 months. Twenty-six patients received pelvic nodal HSIB-IMRT. At 2 years, the cumulative incidence of physician-reported late grade 2+ GU and GI toxicity was 32.6% and 18.4% respectively. At 2 years, only 10.2% grade 2+ GU toxicities and 2.0% grade 2+ GI toxicities remained unresolved. At last follow-up, the prevalence of unresolved physician-reported late grade 2+ GU and GI toxicity was 4.1% and 0%. The median patient-reported American Urologic Association-International Prostate Symptom Score fell from 10 at baseline to 7.5 at 2 years. The 3-year biochemical relapse-free survival rate for the cohort was 96%. CONCLUSIONS: HSIB-IMRT with risk-based nodal coverage results in excellent biochemical control. Although the cumulative incidence of physician-reported GU toxicity was higher than anticipated, late GI and GU toxicity was relatively transient.