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.

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.

Contemporary prostate cancer treatment choices in multidisciplinary clinics referenced to national trends.

BACKGROUND: The purpose of this study was to assess treatment choices among men with prostate cancer who presented at The University of Texas MD Anderson Cancer Center multidisciplinary (MultiD) clinic compared with nationwide trends. METHODS: In total, 4451 men with prostate cancer who presented at the MultiD clinic from 2004 to 2016 were analyzed. To assess nationwide trends, the authors analyzed 392,710 men with prostate cancer who were diagnosed between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. The primary endpoint was treatment choice as a function of pretreatment demographics. RESULTS: Univariate analyses revealed similar treatment trends in the MultiD and SEER cohorts. The use of procedural forms of definitive therapy decreased with age, including brachytherapy and prostatectomy (all P < .05). Later year of diagnosis/clinic visit was associated with decreased use of definitive treatments, whereas higher risk grouping was associated with increased use (all P < .001). Patients with low-risk disease treated at the MultiD clinic were more likely to receive nondefinitive therapy than patients in SEER, whereas the opposite trend was observed for patients with high-risk disease, with a substantial portion of high-risk patients in SEER not receiving definitive therapy. In the MultiD clinic, African American men with intermediate-risk and high-risk disease were more likely to receive definitive therapy than white men, but for SEER the opposite was true. CONCLUSIONS: Presentation at a MultiD clinic facilitates the appropriate disposition of patients with low-risk disease to nondefinitive strategies of patients with high-risk disease to definitive treatment, and it may obviate the influence of race.

Favorable vs Unfavorable Intermediate-Risk Prostate Cancer: A Review of the New Classification System and Its Impact on Treatment Recommendations.

The population of patients with intermediate-risk prostate cancer are a large and heterogeneous group with highly variable prognoses, which present a challenge to efforts to develop standardized treatment recommendations. New classification systems have been proposed that modify the existing National Comprehensive Cancer Network guidelines and that subdivide men with intermediate-risk prostate cancer into favorable and unfavorable subgroups. This review will examine the changing landscape of intermediate-risk prostate cancer and the effects on treatment decisions that may result from this new classification. The literature provides evidence that men with favorable intermediate-risk prostate cancer have prostate cancer-specific mortality and all-cause mortality rates similar to the rates in patients with low-risk prostate cancer and thus may be candidates for active surveillance, dose-escalated radiation therapy without short-term androgen deprivation therapy (ADT), or, interestingly, standard-dose radiation therapy plus short-term ADT. Conversely, patients with unfavorable intermediate-risk prostate cancer have prostate cancer-specific mortality and all-cause mortality rates similar to the rates in patients with high-risk prostate cancer. These patients would not be candidates for active surveillance and may in fact require long-term ADT in addition to standard-dose or dose-escalated radiation therapy instead of 4 to 6 months of ADT.

Prostate cancer treatment and survival: evidence for men with prevalent comorbid conditions.

BACKGROUND: The absence of evidence-based guidelines for prostate cancer treatment led the Institute of Medicine to include localized prostate cancer treatment among the 25 most important topics for comparative effectiveness research. OBJECTIVE: This study compared prostate cancer treatment and survival in men with and without prevalent comorbid conditions. RESEARCH DESIGN: The sample comprised elderly men, aged 66 years and older, extracted from SEER-Medicare data, between 2004 and 2009 (N=73,563). Treatment and survival for men with at least 1 of 4 prevalent comorbid conditions were compared with men who did not have any of the 12 Charlson comorbid conditions. The sample was stratified by comorbid condition and low-risk, intermediate-risk, and high-risk disease. RESULTS: Over half of men received some form of cancer-directed treatment, irrespective of comorbid condition. Men who have congestive heart failure (CHF) or multiple comorbid conditions were less likely to be treated, whereas men with diabetes were more likely to be treated. With the exception of men with CHF, men with comorbid conditions and low-risk disease received no survival benefit from any type of treatment. CONCLUSIONS: Most men received treatment, particularly radiation therapy, regardless of comorbid condition. The evidence suggests more caution should be used when treating men with low-risk disease and comorbid conditions as they are at risk for adverse events and additional medical costs, without a survival benefit.

Elective irradiation of pelvic lymph nodes during postprostatectomy salvage radiotherapy.

BACKGROUND: Success rates with salvage radiotherapy (SRT) in men who have a postprostatectomy biochemical relapse are suboptimal. One treatment-intensification strategy includes elective irradiation of the pelvic lymph nodes with whole pelvis radiotherapy (WPRT). METHODS: An inter-institutional retrospective cohort study compared outcomes for patients who received SRT at 2 separate academic institutions with disparate treatment paradigms: almost exclusively favoring WPRT (n = 112) versus limiting treatment to the prostate bed (PBRT) (n = 135). Patients were excluded if they had lymph node involvement or if they received androgen-deprivation therapy. The Cox proportional hazards model was used to adjust for potential confounders. RESULTS: In total, 247 patients were analyzed with a median follow-up of 4 years. The pre-SRT prostate-specific antigen (PSA) level (adjusted hazard ratio [HR], 1.58; P < .0001) and a Gleason score of 8 to 10 (adjusted HR, 3.21; P < .0001) were identified as independent predictors of increased risk of biochemical PSA progression after SRT. However, WPRT was not independently associated with biochemical progression-free survival in the multivariate model (adjusted HR, 0.79; P = .20). Neither low-risk patients nor high-risk patients (defined a priori by a preoperative PSA level ≥20 ng/mL, a pathologic Gleason score between 8 and 10, or pathologic T3 tumor classification) benefited from WPRT. Overall survival was similar between treatment groups. When restricting the analysis to patients with pre-SRT PSA levels ≥0.4 ng/mL (n = 139), WPRT was independently associated with a 53% reduction in the risk of biochemical progression (adjusted HR, 0.47; P = .031). CONCLUSIONS: WPRT did not improve outcomes among the entire group but was independently associated with improved biochemical control among patients with pre-SRT PSA levels ≥0.4 ng/mL.

Identifying appropriate patients for early salvage radiotherapy after prostatectomy.

PURPOSE: It remains unclear whether relapsed prostate specific antigen at postprostatectomy salvage radiotherapy impacts outcomes as long it is 1.0 ng/ml or less. MATERIALS AND METHODS: We performed a retrospective cohort study of 197 patients treated with salvage radiotherapy in the setting of detectable relapsed prostate specific antigen 1.0 ng/ml or less. Patients were excluded from analysis if they had lymph node involvement or received androgen deprivation therapy. Freedom from prostate specific antigen progression after salvage radiotherapy was analyzed by a Cox regression model. RESULTS: Median relapsed prostate specific antigen was 0.33 ng/ml (range 0.07 to 1.0). There was 86% freedom from prostate specific antigen progression at a median followup of 52 months. Relapsed prostate specific antigen (HR 1.9, p = 0.004), Gleason score 8-10 (HR 5.2, p <0.001) and negative margin status (HR 2.0, p = 0.02) were independently associated with an increased risk of prostate specific antigen progression after salvage radiotherapy. We identified interaction between relapsed prostate specific antigen and Gleason score (p = 0.04) but not margin status. A significant association was noted between higher relapsed prostate specific antigen and prostate specific antigen progression after salvage radiotherapy in patients with Gleason score 8-10 but not 7 or less. In patients with Gleason score 8-10 the rate of freedom from prostate specific antigen progression at 53 months was 77% vs 26% when salvage radiotherapy was initiated at a relapsed prostate specific antigen of 0.33 or less vs 0.34 to 1.0 ng/ml (log rank p = 0.003). CONCLUSIONS: Different relapsed prostate specific antigen thresholds for unsuccessful salvage radiotherapy may exist based on Gleason score. These data suggest that patients with Gleason score 8-10 should be offered salvage radiotherapy at the earliest detectable relapsed prostate specific antigen, even 0.33 ng/ml or less. Those with Gleason score 7 or less may have the opportunity to be followed with serial prostate specific antigen measurements to improve risk stratification, and delay and/or avoid the potential toxicity of salvage radiotherapy.

Comparisons of treatment optimization directly incorporating systematic patient setup uncertainty with a margin-based approach.

PURPOSE: To develop a probabilistic treatment planning (PTP) method which is robust to systematic patient setup errors and to compare PTP plans with plans generated using a planning target volume (PTV) margin optimized to give the same target coverage probability as the PTP plan. METHODS: Plans adhering to the RTOG-0126 protocol are developed for 28 prostate patients using PTP and margin-based planning. For PTP, an objective function that simultaneously considers multiple possible patient positions is developed. PTP plans are optimized using clinical target volume (CTV) structures and organ at risk (OAR) structures. The desired CTV coverage probability is 95%. Plans that cannot achieve a 95% CTV coverage probability are re-optimized with a desired CTV coverage probability reduced by 5% until the desired CTV coverage probability is achieved. Margin-based plans are created which achieve the same CTV coverage probability as the PTP plans by iterative adjustment of the CTV-to-PTV margin. Postoptimization, probabilistic dose-volume coverage metrics are used to compare the plans. RESULTS: For equivalent target coverage probability, PTP plans significantly reduce coverage probability for rectum objectives (-17% for D(35) < 65 Gy, p = 0.0010; -23% for D(25) < 70 Gy, p < 0.0001; and -27% for D(15) < 75 Gy, p < 0.0001). Physician assessment indicates PTP plans are entirely preferred 71% of the time while margin-based plans are entirely preferred 7% of the time. CONCLUSIONS: For plans having the same target coverage probability, PTP has potential to reduce rectal doses while maintaining CTV coverage probability. In blind comparisons, physicians prefer PTP plans over optimized margin plans.

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.

Salvage radiation in men after prostate-specific antigen failure and the risk of death.

BACKGROUND: A survival benefit has been observed with salvage radiation therapy (RT) for prostate-specific antigen (PSA) failure after radical prostatectomy (RP) in men with rapid rises in PSA doubling time (DT, < 6 months). Whether such a benefit exits in men with a protracted PSA rise in DT (≥ 6 months) is unclear and was examined in the current study. METHODS: Of 4036 men who underwent RP at Duke University between 1988 and 2008, 519 experienced a PSA failure, had complete data, and were the subjects of this study. Univariate and multivariate Cox regression analyses were performed to evaluate whether salvage RT in men with either a rapid (< 6 months) or a protracted (≥ 6 months) PSA DT was associated with the risk of all-cause mortality adjusting for age at the time of PSA failure, known prostate cancer prognostic factors, and cardiac comorbidity. RESULTS: After a median follow-up of 11.3 years after PSA failure, 195 men died. Salvage RT was associated with a significant reduction in all-cause mortality for men with either a PSA DT of < 6 months (adjusted hazard ratio [AHR], 0.53; P = .02) or a PSA DT of ≥ 6 months (AHR, 0.52; P = .003). In a subset of patients with comorbidity data at the time of PSA failure, salvage RT remained associated with a significant reduction in all-cause mortality for both men with a PSA DT of < 6 months (AHR, 0.35; P = .042) or a PSA DT of ≥ 6 months (AHR, 0.60; P = .04). CONCLUSIONS: Salvage RT for PSA DTs less than or in excess of 6 months is associated with a decreased risk in all-cause mortality.

Investigations of interference between electromagnetic transponders and wireless MOSFET dosimeters: a phantom study.

PURPOSE: To evaluate both the Calypso Systems' (Calypso Medical Technologies, Inc., Seattle, WA) localization accuracy in the presence of wireless metal-oxide-semiconductor field-effect transistor (MOSFET) dosimeters of dose verification system (DVS, Sicel Technologies, Inc., Morrisville, NC) and the dosimeters' reading accuracy in the presence of wireless electromagnetic transponders inside a phantom. METHODS: A custom-made, solid-water phantom was fabricated with space for transponders and dosimeters. Two inserts were machined with positioning grooves precisely matching the dimensions of the transponders and dosimeters and were arranged in orthogonal and parallel orientations, respectively. To test the transponder localization accuracy with/without presence of dosimeters (hypothesis 1), multivariate analyses were performed on transponder-derived localization data with and without dosimeters at each preset distance to detect statistically significant localization differences between the control and test sets. To test dosimeter dose-reading accuracy with/without presence of transponders (hypothesis 2), an approach of alternating the transponder presence in seven identical fraction dose (100 cGy) deliveries and measurements was implemented. Two-way analysis of variance was performed to examine statistically significant dose-reading differences between the two groups and the different fractions. A relative-dose analysis method was also used to evaluate transponder impact on dose-reading accuracy after dose-fading effect was removed by a second-order polynomial fit. RESULTS: Multivariate analysis indicated that hypothesis 1 was false; there was a statistically significant difference between the localization data from the control and test sets. However, the upper and lower bounds of the 95% confidence intervals of the localized positional differences between the control and test sets were less than 0.1 mm, which was significantly smaller than the minimum clinical localization resolution of 0.5 mm. For hypothesis 2, analysis of variance indicated that there was no statistically significant difference between the dosimeter readings with and without the presence of transponders. Both orthogonal and parallel configurations had difference of polynomial-fit dose to measured dose values within 1.75%. CONCLUSIONS: The phantom study indicated that the Calypso System's localization accuracy was not affected clinically due to the presence of DVS wireless MOSFET dosimeters and the dosimeter-measured doses were not affected by the presence of transponders. Thus, the same patients could be implanted with both transponders and dosimeters to benefit from improved accuracy of radiotherapy treatments offered by conjunctional use of the two systems.

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.

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.

Targeting the TGF-beta1 pathway to prevent normal tissue injury after cancer therapy.

With >10,000,000 cancer survivors in the U.S. alone, the late effects of cancer treatment are a significant public health issue. Over the past 15 years, much work has been done that has led to an improvement in our understanding of the molecular mechanisms underlying the development of normal tissue injury after cancer therapy. In many cases, these injuries are characterized at the histologic level by loss of parenchymal cells, excessive fibrosis, and tissue atrophy. Among the many cytokines involved in this process, transforming growth factor (TGF)-beta1 is thought to play a pivotal role. TGF-beta1 has a multitude of functions, including both promoting the formation and inhibiting the breakdown of connective tissue. It also inhibits epithelial cell proliferation. TGF-beta1 is overexpressed at sites of injury after radiation and chemotherapy. Thus, TGF-beta1 represents a logical target for molecular therapies designed to prevent or reduce normal tissue injury after cancer therapy. Herein, the evidence supporting the critical role of TGF-beta1 in the development of normal tissue injury after cancer therapy is reviewed and the results of recent research aimed at preventing normal tissue injury by targeting the TGF-beta1 pathway are presented.

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.

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.