Adjuvant vs. salvage radiation therapy in men with high-risk features after radical prostatectomy: Survey of North American genitourinary expert radiation oncologists

INTRODUCTION: The management of patients with high-risk features after radical prostatectomy (RP) is controversial. Level 1 evidence demonstrates that adjuvant radiation therapy (RT) improves survival compared to no treatment; however, it may overtreat up to 30% of patients, as randomized clinical trials (RCTs) using salvage RT on observation arms failed to reveal a survival advantage of adjuvant RT. We, therefore, sought to determine the current view of adjuvant vs. salvage RT among North American genitourinary (GU) radiation oncology experts. METHODS: A survey was distributed to 88 practicing North American GU physicians serving on decision-making committees of cooperative group research organizations. Questions pertained to opinions regarding adjuvant vs. salvage RT for this patient population. Treatment recommendations were correlated with practice patterns using Fisher's exact test. RESULTS: Forty-two of 88 radiation oncologists completed the survey; 23 (54.8%) recommended adjuvant RT and 19 (45.2%) recommended salvage RT. Recommendation of active surveillance for Gleason 3+4 disease was a significant predictor of salvage RT recommendation (p=0.034), and monthly patient volume approached significance for recommendation of adjuvant over salvage RT; those seeing <15 patients/month trended towards recommending adjuvant over salvage RT (p=0.062). No other demographic factors approached significance. CONCLUSIONS: There is dramatic polarization among North American GU experts regarding optimal management of patients with high-risk features after RP. Ongoing RCTs will determine whether adjuvant RT improves survival over salvage RT. Until then, the almost 50/50 division seen from this analysis should encourage practicing clinicians to discuss the ambiguity with their patients

Is moderate hypofractionation accepted as a new standard of care in north america for prostate cancer patients treated with external beam radiotherapy? Survey of genitourinary expert radiation oncologists

INTRODUCTION: Several recent randomized clinical trials have evaluated hypofractionated regimens against conventionally fractionated EBRT and shown similar effectiveness with conflicting toxicity results. The current view regarding hypofractionation compared to conventional EBRT among North American genitourinary experts for management of prostate cancer has not been investigated. MATERIALS AND METHODS: A survey was distributed to 88 practicing North American GU physicians serving on decision - making committees of cooperative group research organizations. Questions pertained to opinions regarding the default EBRT dose and fractionation for a hypothetical example of a favorable intermediate - risk prostate cancer (Gleason 3 + 4). Treatment recommendations were correlated with practice patterns using Fisher's exact test. RESULTS: Forty - two respondents (48%) completed the survey. We excluded from analysis two respondents who selected radical hypofractionation with 5 - 12 fractions as a preferred treatment modality. Among the 40 analyzed respondents, 23 (57.5%) recommend conventional fractionation and 17 (42.5%) recommended moderate hypofractionation. No demographic factors were found to be associated with preference for a fractionation regimen. Support for brachytherapy as a first choice treatment modality for low - risk prostate cancer was borderline significantly associated with support for moderate hypofractionated EBRT treatment modality (p = 0.089). CONCLUSIONS: There is an almost equal split among North American GU expert radiation oncologists regarding the appropriateness to consider moderately hypofractionated EBRT as a new standard of care in management of patients with prostate cancer. Physicians who embrace brachytherapy may be more inclined to support moderate hypofractionated regimen for EBRT. It is unclear whether reports with longer followups will impact this balance, or whether national care and reimbursement policies will drive the clinical decisions. In the day and age of patient - centered care delivery, patients should receive an objective recommendation based on available clinical evidence. The stark division among GU experts may influence the design of future clinical trials utilizing EBRT for patients with prostate cancer

Dramatic polarization in genitourinary expert opinions regarding the clinical utility of positron emission tomography (PET) imaging in prostate cance

OBJECTIVES: To ascertain the opinions of North American genitourinary (GU) experts regarding inclusion of technologies such as prostate - specific membrane antigen (PSMA) and C - 11 choline positron emission tomography (PET) into routine practice. MATERIALS AND METHODS: A survey was distributed to North American GU experts. Questions pertained to the role of PSMA and C - 11 PET in PCa management. Participants were categorized as "supporters" or "opponents" of incorporation of novel imaging techniques. Opinions were correlated with practice patterns. RESULTS: Response rate was 54% and we analyzed 42 radiation oncologist respondents. 17 participants (40%) have been in practice for > 20 years and 38 (90%) practice at an academic center. 24 (57%) were supporters of PSMA and 29 (69%) were supporters of C - 11. Supporters were more likely to treat pelvic nodes (88% vs. 56%, p < 01) and trended to be more likely to treat patients with moderate or extreme hypofractionation (58% vs. 28%, p = 065). Supporters trended to be more likely to offer brachytherapy boost (55% vs. 23%, p = 09), favor initial observation and early salvage over adjuvant radiation (77% vs. 55%, p = 09), and to consider themselves expert brachytherapists (69% vs. 39%, p = 09). CONCLUSIONS: There is a polarization among GU radiation oncology experts regarding novel imaging techniques. A correlation emerged between support of novel imaging and adoption of treatment approaches that are clinically superior or less expensive. Pre - existing biases among GU experts on national treatment - decision panels and leaders of cooperative group studies may affect the design of future studies and influence the adoption of these technologies in clinical practice

Impact of hospital volume on mortality for brain metastases treated with radiation

BACKGROUND: The impact of hospital volume on cancer patient survival has been demonstrated in the surgical literature, but sparsely for patients receiving radiation therapy (RT). This analysis addresses the impact of hospital volume on patients receiving RT for the most common central nervous system tumor: brain metastases.   MATERIALS AND METHODS: Analysis was conducted using the National Cancer Database (NCDB) from 2010–2015 for patients with metastatic brain disease from lung cancer, breast cancer, and colorectal cancer requiring RT. Hospital volume was stratified as high-volume (≥ 12 brain RT/year), moderate (5–11 RT/year), and low (&lt; 5 RT/year). The effect of hospital volume on overall survival was assessed using a multivariable Cox regression model. RESULTS: A total of 18,841 patients [9479 (50.3%) men, 9362 (49.7%) women; median age 64 years] met the inclusion criteria. 16.7% were treated at high-volume hospitals, 36.5% at moderate-volume, and the remaining 46.8% at low-volume centers. Multivariable analysis revealed that mortality was significantly improved in high-volume centers (HR: 0.95, p = 0.039) compared with low-volume centers after accounting for multiple demographics including age, sex, race, insurance status, income, facility type, Charlson-Deyo score and receipt of palliative care. CONCLUSION: Hospitals performing 12 or more brain RT procedures per year have significantly improved survival in brain metastases patients receiving radiation as compared to lower volume hospitals. This finding, independent of additional demographics, indicates that the increased experience associated with increased volume may improve survival in this patient population

Impact of hospital volume on mortality for brain metastases treated with radiation

Background: The impact of hospital volume on cancer patient survival has been demonstrated in the surgical literature, but sparsely for patients receiving radiation therapy (RT). This analysis addresses the impact of hospital volume on patients receiving RT for the most common central nervous system tumor: brain metastases. Materials and methods: Analysis was conducted using the National Cancer Database (NCDB) from 2010-2015 for patients with metastatic brain disease from lung cancer, breast cancer, and colorectal cancer requiring RT. Hospital volume was stratified as high-volume (≥ 12 brain RT/year), moderate (5-11 RT/year), and low (< 5 RT/year). The effect of hospital volume on overall survival was assessed using a multivariable Cox regression model. Results: A total of 18,841 patients [9479 (50.3%) men, 9362 (49.7%) women; median age 64 years] met the inclusion criteria. 16.7% were treated at high-volume hospitals, 36.5% at moderate-volume, and the remaining 46.8% at low-volume centers. Multivariable analysis revealed that mortality was significantly improved in high-volume centers (HR: 0.95, p = 0.039) compared with low-volume centers after accounting for multiple demographics including age, sex, race, insurance status, income, facility type, Charlson-Deyo score and receipt of palliative care. Conclusion: Hospitals performing 12 or more brain RT procedures per year have significantly improved survival in brain metastases patients receiving radiation as compared to lower volume hospitals. This finding, independent of additional demographics, indicates that the increased experience associated with increased volume may improve survival in this patient population

Cleavages within the Prodomain Direct Intracellular Trafficking and Degradation of Mature Bone Morphogenetic Protein-4

Pro bone morphogenetic protein-4 (BMP-4) is initially cleaved at a consensus furin motif adjacent to the mature ligand domain (the S1 site), and this allows for subsequent cleavage at an upstream motif (the S2 site). Previous studies have shown that S2 cleavage regulates the activity and signaling range of mature BMP-4, but the mechanism by which this occurs is unknown. Here, we show that the pro- and mature domains of BMP-4 remain noncovalently associated after S1 cleavage, generating a complex that is targeted for rapid degradation. Degradation requires lysosomal and proteosomal function and is enhanced by interaction with heparin sulfate proteoglycans. Subsequent cleavage at the S2 site liberates mature BMP-4 from the prodomain, thereby stabilizing the protein. We also show that cleavage at the S2, but not the S1 site, is enhanced at reduced pH, consistent with the possibility that the two cleavages occur in distinct subcellular compartments. Based on these results, we propose a model for how cleavage at the upstream site regulates the activity and signaling range of mature BMP-4 after it has been released from the prodomain

RTHP-12. NATIONWIDE DISTRIBUTION OF LINEAR ACCELERATOR VERSUS GAMMA KNIFE STEREOTACTIC RADIOSURGERY UTILIZATION FOR METASTATIC BRAIN DISEASE IN ACADEMIC VERSUS COMMUNITY HOSPITALS

INTRODUCTION Single-fraction stereotactic radiosurgery (SRS) is often the preferred treatment modality for metastatic brain disease, particularly when patients have a small enough volume of disease to preclude whole brain radiation therapy and its associated permanent cognitive morbidity. The two predominant SRS treatment modalities are Gamma Knife and linear accelerator (LINAC). The recent impact of SRS modality in academic versus community hospital settings in the United States (US) since the 2013 implementation of the American Tax Payer Relief Act (ATRA) has yet to be examined. METHODS Brain metastases patients from non-small cell lung cancer (NSCLC) throughout the United States having undergone SRS were identified using the 2010–2016 National Cancer Data Base (NCDB). SRS utilization in academic versus community (non-academic) hospitals was identified and assessed. RESULTS Of the 4,012 SRS patients examined, the majority (64%) were treated at academic hospitals. Beginning in 2014, LINAC SRS rapidly increased in popularity compared to GKRS, reversing an annual decline in utilization originating from 2011. The 63% LINAC composition of SRS cases at non-academic centers in 2016 was an all-time high, a 12% increase from a year earlier. This was markedly different than SRS utilization at academic hospitals, where despite a steady increase in LINAC SRS since 2013, GKRS remained the predominant SRS modality, comprising 73% of cases in 2016. CONCLUSIONS The implementation of LINAC over Gamma Knife SRS in the non-academic hospital setting has markedly increased in the timespan since ATRA implementation, comprising more than 60% of SRS cases compared to only 27% of academic hospital SRS cases in 2016. These findings indicate that without the substantially increased Medicare reimbursement advantage formerly associated with Gamma Knife compared to LINAC prior to ATRA, the non-academic setting may be more sensitive than academic centers to conditions optimizing reimbursement

RTHP-06. IMPACT OF THE AMERICAN TAX PAYER RELIEF ACT ON STEREOTACTIC RADIOSURGERY UTILIZATION IN THE UNITED STATES

INTRODUCTION For brain metastases, single-fraction stereotactic radiosurgery (SRS) spares appropriately chosen patients from the invasiveness of operative intervention and the permanent cognitive morbidity of whole brain radiation. SRS is delivered predominantly via two modalities: Gamma Knife, and linear accelerator (LINAC). The implementation of the American Tax Payer Relief Act (ATRA) in 2013 represented the first time limitations specifically targeting SRS reimbursement were introduced into federal law. The subsequent impact of the ATRA on SRS utilization in the United States (US) has yet to be examined. METHODS The National Cancer Data Base (NCDB) from 2010–2016 identified brain metastases patients from non-small cell lung cancer (NSCLC) throughout the US having undergone SRS. Utilization between GKRS and LINAC was assessed before (2010–2012) versus after (2013–2016) ATRA implementation. Utilization was adjusted for several variables, including patient demographics and healthcare system characteristics. RESULTS From 2012 to 2013, there was a substantial decrease of LINAC SRS in favor of GKRS overall (37% to 28%) and individually in both academic and non-academic centers. Over the three-year span immediately preceding ATRA implementation, 65.8% received GKRS and the remaining 34.2% receiving LINAC. In the four years immediately following ATRA implementation 68.0% received GKRS compared with 32% receiving LINAC; these differences were not statistically significant. CONCLUSIONS ATRA implementation in 2013 caused an initial spike in Gamma Knife SRS utilization, followed by a steady decline, similar to rates prior to implementation. These findings are indicative that the ATRA provision mandating Medicare reduction of outpatient payment rates for Gamma Knife to be equivalent with those of LINAC SRS had a significant short-term impact on the radiosurgical treatment of metastatic brain disease throughout the US. Such findings should serve as a reminder of the importance and impact of public policy on treatment modality utilization by physicians and hospitals

The A391E mutation enhances FGFR3 activation in the absence of ligand

AbstractThe A391E mutation in the transmembrane domain of fibroblast growth factor receptor 3 leads to aberrant development of the cranium. It has been hypothesized that the mutant glutamic acid stabilizes the dimeric receptor due to hydrogen bonding and enhances its ligand-independent activation. We previously tested this hypothesis in lipid bilayers and showed that the mutation stabilizes the isolated transmembrane domain dimer by −1.3°kcal/mol. Here we further test the hypothesis, by investigating the effect of the A391E mutation on the activation of full-length fibroblast growth factor receptor 3 in Human Embryonic Kidney 293T cells in the absence of ligand. We find that the mutation enhances the ligand-independent activation propensity of the receptor by −1.7°kcal/mol. This value is consistent with the observed strength of hydrogen bonds in membranes, and supports the above hypothesis