Proton therapy for the management of localized prostate cancer: Long-term clinical outcomes at a comprehensive cancer center.

BACKGROUND AND PURPOSE: Proton therapy (PT) has emerged as a standard-of-care treatment option for localized prostate cancer at our comprehensive cancer center. However, there are few large-scale analyses examining the long-term clinical outcomes. Therefore, this article aims to evaluate the long-term effectiveness and toxicity of PT in patients with localized prostate cancer. MATERIALS AND METHODS: Review of 2772 patients treated from May 2006 through January 2020. Disease risk was stratified according to National Comprehensive Cancer Network guidelines as low [LR, n = 640]; favorable-intermediate [F-IR, n = 850]; unfavorable-intermediate [U-IR, n = 851]; high [HR, n = 315]; or very high [VHR, n = 116]. Biochemical failure and toxicity were analyzed using Kaplan-Meier estimates and multivariate models. RESULTS: The median patient age was 66 years; the median follow-up time was 7.0 years. Pelvic lymph node irradiation was prescribed to 28 patients (1%) (2 [0.2%] U-IR, 11 [3.5%] HR, and 15 [12.9%] VHR). The median dose was 78 Gy in 1.8-2.0 Gy(RBE) fractions. Freedom from biochemical relapse (FFBR) rates at 5 years and 10 years were 98.2% and 96.8% for the LR group; 98.3% and 93.6%, F-IR; 94.2% and 90.2%, U-IR; 94.3% and 85.2%, HR; and 86.1% and 68.5%, VHR. Two patients died of prostate cancer. Overall rates of late grade ≥ 3 GU and GI toxicity were 0.87% and 1.01%. CONCLUSIONS: Proton therapy for localized prostate cancer demonstrated excellent clinical outcomes in this large cohort, even among higher-risk groups with historically poor outcomes despite aggressive therapy.

Exploring Psychosocial Dynamics Underpinning Driver Identity in an Older Adult Sample.

Many older adults consider driving a crucial aspect of their daily routine and the prospect of driving cessation to be disruptive to their current lifestyle. Driving cessation is associated with multiple adverse consequences, including poorer health trajectories, and increased depressive symptoms. Research suggests that driving cessation may be disruptive to identity. This study aimed to explore the characteristics that are associated with driver identity and whether identity impacted people's readiness for mobility changes. Of interest was whether stopping driving was perceived as either a positive or negative event. Participants, (N = 410) older adults recruited via Prolific survey panel between July and November 2021, responded to questions about transport and travel behaviors, driver identity, and perceptions of mobility changes. Driving cessation was generally perceived as a negative change. However, individuals with self-reported low readiness for mobility change also had higher overall scores for Identity, and for the subscales, Centrality and Ingroup Affect. These findings suggest that people with more concerns for mobility transition may think about and have more of an emotional investment regarding driving. The findings provide novel insight into the psychosocial dynamics of driving and the factors that influence driver identity, however further research, co-designed with older drivers and retired drivers is required.

Rates of progression of carotid in-stent stenosis and clinical outcomes.

BACKGROUND: We previously reported the incidence of ≥50% and ≥80% carotid in-stent stenosis. In the present study, we analyzed the rate of progression of in-stent stenosis and clinical outcomes with longer follow-up. METHODS: We performed a retrospective analysis of prospectively collected data for 450 patients who had undergone transfemoral carotid artery stenting with longer follow-up (mean, 70 months). The progression of in-stent stenosis was defined as stenosis advancing to a higher severity of disease (ie, from <50% to ≥50% and from ≥50% to ≥80%). Kaplan-Meier analysis was used to estimate the rate of progression from <50% to ≥50% and ≥50% to ≥80%, the overall rates of ≥50% and ≥80% in-stent stenosis, and survival at 1, 3, 5, and 10 years. RESULTS: At a mean follow-up of 70.3 months (range, 1-222 months), 121 of 446 patients (27%) had had progression to ≥50% and 39 (8.7%) to ≥80% in-stent stenosis. Of the 406 patients whose first duplex ultrasound findings were normal or showed in-stent stenosis of <50%, 82 had had progression from normal or <50% to ≥50% in-stent stenosis at a mean of 51.7 months (range, 1-213 months). Of the 121 patients with ≥50% stenosis, 14 (11.6%) had experienced progression to ≥80% at a mean of 33.6 months (range, 6-89 months). Of the 82 patients with progression from <50 to ≥50%, 10 (12%) had experienced a neurologic event (eight transient ischemic attacks [TIAs] and two strokes). Of the 14 with progression from ≥50% to ≥80%, 2 (14.3%) had experienced a TIA, and the remaining patients were asymptomatic. Of the 39 patients with ≥80% in-stent stenosis, 9 (23%) had experienced a neurologic event (eight TIAs and one contralateral stroke). Overall, 13 of the 121 patients with late ≥50% restenosis (10.7%) had experienced a neurologic event (10 ipsilateral TIA, 2 ipsilateral stroke, and 1 contralateral stroke. Thus, 12 of 446 patients (2.7%) had experienced an ipsilateral TIA or stroke at a mean follow-up of 70 months. The rates of freedom from <50% to ≥50% in-stent stenosis progression were 93%, 85%, 78%, and 66% at 1, 3, 5, and 10 years. The rates of freedom from progression from ≥50% to ≥80% in-stent stenosis were 89%, 81%, and 77% at 1, 3, and 5 years, respectively. The overall rates of freedom from ≥50% in-stent stenosis and ≥80% in-stent stenosis were 86%, 77%, 71%, and 59% and 96%, 93%, 91%, and 84% at 1, 3, 5, and 10 years, respectively. Finally, the stroke survival rates were 95%, 80%, 63%, and 31% at 1, 3, 5, and 10 years, respectively. CONCLUSIONS: The rate of progression of carotid in-stent stenosis was modest, with a low incidence of stroke events. Therefore, the use of duplex ultrasound surveillance after carotid artery stenting should be selective and its benefits and utility perhaps reevaluated.

Beam-Specific Spot Guidance and Optimization for PBS Proton Treatment of Bilateral Head and Neck Cancers.

PURPOSE: A multi-field optimization (MFO) technique that uses beam-specific spot placement volumes (SPVs) and spot avoidance volumes (SAVs) is introduced for bilateral head and neck (H&N) cancers. These beam-specific volumes are used to guide the optimizer to consistently achieve optimal organ-at-risk (OAR) sparing with target coverage and plan robustness. MATERIALS AND METHODS: Implementation of this technique using a 4-beam, 5-beam, and variant 5-beam arrangement is discussed. The generation of beam-specific SPVs and SAVs derived from target and OARs are shown. The SPVs for select fields are further partitioned into optimization volumes for uniform dose distributions that resemble those of single-field optimization (SFO). A conventional MFO plan that does not use beam-specific spot placement guidance (MFOcon) and an MFO plan that uses only beam-specific SPV (MFOspv) are compared with current technique (MFOspv/sav), using both simulated scenarios and forward-calculated plans on weekly verification computed tomography (VFCT) scans. RESULTS: Dose distribution characteristics of the 4-beam, 5-beam, and variant 5-beam technique are demonstrated with discussion on OAR sparing. When comparing the MFOcon, MFOspv, and MFOspv/sav, the MFOspv/sav is shown to have superior OAR sparing in 9 of the 14 OARs examined. It also shows clinical plan robustness when evaluated by using both simulated uncertainty scenarios and forward-calculated weekly VFCTs throughout the 7-week treatment course. CONCLUSION: The MFOspv/sav technique is a systematic approach using SPVs and SAVs to guide the optimizer to consistently reach desired OAR dose values and plan robustness.

ATM Paradoxically Promotes Oncogenic Transformation via Transcriptional Reprogramming.

The role of the ataxia-telangiectasia-mutated (ATM) gene in human malignancies, especially in solid tumors, remains poorly understood. In the present study, we explored the involvement of ATM in transforming primary human cells into cancer stem cells. We show that ATM plays an unexpected role in facilitating oncogene-induced malignant transformation through transcriptional reprogramming. Exogenous expression of an oncogene cocktail induced a significant amount of DNA double-strand breaks in human fibroblasts that caused persistent activation of ATM, which in turn enabled global transcriptional reprogramming through chromatin relaxation, allowing oncogenic transcription factors to access chromatin. Consistently, deficiencies in ATM significantly attenuated oncogene-induced transformation of human cells. In addition, ATM inhibition significantly reduced tumorigenesis in a mouse model of mammary cancer. ATM and cellular DNA damage response therefore play a previously unknown role in facilitating rather than suppressing oncogene-induced malignant transformation of mammalian cells. SIGNIFICANCE: These findings uncover a novel pro-oncogenic role for ATM and show that contrary to established theory, ATM does not always function as a tumor suppressor; its function is however dependent on cell type.

Endogenous Retrovirus Activation as a Key Mechanism of Anti-Tumor Immune Response in Radiotherapy.

The generation of DNA double-strand breaks has historically been taught as the mechanism through which radiotherapy kills cancer cells. Recently, radiation-induced cytosolic DNA release and activation of the cGAS/STING pathway, with ensuing induction of interferon secretion and immune activation, have been recognized as important mechanisms for radiation-mediated anti-tumor efficacy. Here we demonstrate that radiation-induced activation of endogenous retroviruses (ERVs) also plays a major role in regulating the anti-tumor immune response during irradiation. Radiation-induced ERV-associated dsRNA transcription and subsequent activation of the innate antiviral MDA5/MAVS/TBK1 pathway led to downstream transcription of interferon-stimulated genes. Additionally, genetic knockout of KAP1, a chromatin modulator responsible for suppressing ERV transcription sites within the genome, enhanced the effect of radiation-induced anti-tumor response in vivo in two different tumor models. This anti-tumor response was immune-mediated and required an intact host immune system. Our findings indicate that radiation-induced ERV-dsRNA expression and subsequent immune response play critical roles in clinical radiotherapy, and manipulation of epigenetic regulators and the dsRNA-sensing innate immunity pathway could be promising targets to enhance the efficacy of radiotherapy and cancer immunotherapy.

Antibacterial action of functional silicon dioxide: an investigation of the attachment and separation of bacteria.

Bactericidal proteins from the Moringa oleifera seed are reported to be suitable alternatives to conventional methods of bacterial reduction in water. In this study the cationic bactericidal M. oleifera proteins were isolated by attachment onto the surface of silicon dioxide. This functionalised SiO2(ƒ-SiO2) was then exposed to Escherichia coli and Micrococcus luteus to examine whether the ƒ-SiO2 could be used to inactivate the bacteria. The effect of the non-ionic surfactant dodecyl glucoside on the attachment of these bacteria to the ƒ-SiO2 was examined with the aim of developing a method of reusable bacterial inactivation. The primary result of this study was that the E. coli could be readily separated from the ƒ-SiO2, allowing the ƒ-SiO2 to be used for further bacterial inactivation. The regeneration of the ƒ-SiO2 was demonstrated using fluorescence microscopy on bacterial cells stained with propidium iodide, and zeta potential measurements. Future applications of this work include a reusable method of removing bacteria from contaminated water.

CRISPR/Cas9-Mediated BRCA1 Knockdown Adipose Stem Cells Promote Breast Cancer Progression.

BACKGROUND: The tumor microenvironment within the breast is rich in adipose elements. The interaction between adipose cells and breast cancer is poorly understood, particularly as it pertains to patients with genetic susceptibility to breast cancer. This study focuses on the phenotype of human adipose-derived stem cells with the BRCA1 mutation and the effect they may have on breast cancer cell behavior. METHODS: CRISPR/Cas9 was used to generate de novo BRCA1-knockdown human adipose-derived stem cells. The effect of the BRCA1 knockdown on the adipose-derived stem cell phenotype was compared to wild-type adipose-derived stem cells and patient-derived breast adipose-derived stem cells with known BRCA1 mutations. Interactions between adipose-derived stem cells and the MDA-MB-231 breast cancer cell line were evaluated. RESULTS: BRCA1-knockdown adipose-derived stem cells stimulated MDA-MB-231 proliferation (1.4-fold increase on day 4; p = 0.0074) and invasion (2.3-fold increase on day 2; p = 0.0171) compared to wild-type cells. Immunofluorescence staining revealed higher levels of phosphorylated ataxia telangiectasia-mutated activation in BRCA1-knockdown cells (72.9 ± 5.32 percent versus 42.9 ± 4.97 percent; p = 0.0147), indicating higher levels of DNA damage. Beta-galactosidase staining demonstrated a significantly higher level of senescence in BRCA1-knockdown cells compared with wild-type cells (7.9 ± 0.25 percent versus 0.17 ± 0.17 percent; p < 0.0001). Using quantitative enzyme-linked immunosorbent assay to evaluate conditioned media, the authors found significantly higher levels of interleukin-8 in BRCA1-knockdown cells (2.57 ± 0.32-fold; p = 0.0049). CONCLUSIONS: The authors show for the first time that the BRCA1 mutation affects the adipose-derived stem cell phenotype. Moreover, CRISPR/Cas9-generated BRCA1-knockdown adipose-derived stem cells stimulate a more aggressive behavior in breast cancer cells than wild-type adipose-derived stem cells. This appears to be related to increased inflammatory cytokine production by means of a DNA damage-mediated cell senescence pathway.

Clinical examination of proton pencil beam scanning on a moving anthropomorphic lung phantom.

The objective of this study was to examine the use of proton pencil beam scanning for the treatment of moving lung tumors. A single-field uniform dose proton pencil beam scanning (PBS) plan was generated for the standard thorax phantom designed by the Imaging and Radiation Oncology Core (IROC) Houston QA Center. Robust optimization, including range and setup uncertainties as well as volumetric repainting, was used for the plan. Patient-specific quality assurance (QA) measurements were performed using both a water tank and a custom heterogeneous QA phantom. A custom moving phantom was used to find the optimal number of volumetric repainting. Both analytical and Monte Carlo (MC) algorithms were used for dose calculation and their accuracies were compared with actual measurements. A single ionization chamber, a 2-dimensional ionization chamber array, thermoluminescent dosimeters (TLDs), and films were used for dose measurements. The optimal number of volumetric repainting was found to be 4 times in our system. The mean dose overestimations on a moving target by analytical and MC algorithms based on a time-averaged computed tomography (CT) image of the phantom were found to be 4.8% and 2.4%, respectively. The mean gamma indexes for analytical and MC algorithms were 91% and 96%, respectively. The MC dose algorithm calculation was found to have a better agreement with measurements compared with the analytical algorithm. When treating moving lung tumors using proton PBS, the techniques of robust optimization, volumetric repainting, and MC dose calculation were found effective. Extra care needs to be taken when an analytical dose calculation algorithm is used.

Four-dimensional Plan Optimization for the Treatment of Lung Tumors Using Pencil-beam Scanning Proton Radiotherapy.

Purpose  This study aimed to evaluate the effectiveness of four-dimensional (4D) robust optimization for proton pencil-beam scanning (PBS) treatment of lung tumors. Patients and methods  In seven patients with lung cancer, proton beam therapy was planned using 4D robust optimization over 4D computed tomography (CT) data sets. The gross target volume (GTV) was contoured based on individual breathing phases, and a 5-mm expansion was used to generate the clinical target volume (CTV) for each phase. The 4D optimization was conducted directly on the 4D CT data set. The robust optimization settings included a CT Hounsfield unit (HU) uncertainty of 4% and a setup uncertainty of 5 mm to obtain the CTV. Additional target dose objectives such as those for the internal target volume (ITV) as well as the organ-at-risk (OAR) dose requirements were placed on the average CT. For comparison, three-dimensional (3D) robust optimization was also performed on the average CT. An additional verification 4D CT was performed to verify plan robustness against inter-fractional variations. Results  Target coverages were generally higher for 4D optimized plans. The difference was most pronounced for ITV V70Gy when evaluating individual breathing phases. The 4D optimized plans were shown to be able to maintain the ITV coverage at full prescription, while 3D optimized plans could not. More importantly, this difference in ITV V70Gy between the 4D and 3D optimized plans was also consistently observed when evaluating the verification 4D CT, indicating that the 4D optimized plans were more robust against inter-fractional variations. Less difference was seen between the 4D and 3D optimized plans in the lungs criteria: V5Gy and V20Gy. Conclusion  The proton PBS treatment plans optimized directly on the 4D CT were shown to be more robust when compared to those optimized on a regular 3D CT. Robust 4D optimization can improve the target coverage for the proton PBS lung treatments.

Randomized Trial of Hypofractionated, Dose-Escalated, Intensity-Modulated Radiation Therapy (IMRT) Versus Conventionally Fractionated IMRT for Localized Prostate Cancer.

PURPOSE: Hypofractionated radiotherapy delivers larger daily doses of radiation and may increase the biologically effective dose delivered to the prostate. We conducted a randomized trial testing the hypothesis that dose-escalated, moderately hypofractionated intensity-modulated radiation therapy (HIMRT) improves prostate cancer control compared with conventionally fractionated IMRT (CIMRT) for men with localized prostate cancer. PATIENTS AND METHODS: Men were randomly assigned to 75.6 Gy in 1.8-Gy fractions delivered over 8.4 weeks (CIMRT) or 72 Gy in 2.4 Gy fractions delivered over 6 weeks (HIMRT, biologically equivalent to 85 Gy in 1.8-Gy fractions assuming prostate cancer α-to-ß ratio of 1.5). Failure was defined as prostate-specific antigen (PSA) failure (nadir plus 2 ng/mL) or initiation of salvage therapy. Modified Radiation Therapy Oncology Group criteria were used to grade late (≥ 90 days after completion of radiotherapy) GI and genitourinary toxicity. RESULTS: Most of the 206 men (72%) had cT1, Gleason score 6 or 7 (99%), and PSA level ≤ 10 ng/mL (90%) disease. Androgen deprivation therapy was received by 24%. With a median follow-up of 8.5 years, men treated with HIMRT experienced fewer treatment failures (n = 10) than men treated with CIMRT (n = 21; P = .036). The 8-year failure rate was 10.7% (95% CI, 5.8% to 19.1%) with HIMRT and 15.4% (95% CI, 9.1% to 25.4%) with CIMRT. There was no difference in overall survival ( P = .39). There was a nonsignificant increase in late grade 2 or 3 GI toxicity with HIMRT (8-year 5.0% v 12.6%; P = .08). However, GI toxicity was only 8.6% when rectal volume receiving 65 Gy of HIMRT was ≤ 15%. Late genitourinary toxicity was similar ( P = .84). There was no grade 4 toxicity. CONCLUSION: The results of this randomized trial demonstrate superior cancer control for men with localized prostate cancer who receive dose-escalated moderately hypofractionation radiotherapy while shortening treatment duration.

Novel roles of apoptotic caspases in tumor repopulation, epigenetic reprogramming, carcinogenesis, and beyond.

Apoptotic caspases have long been studied for their roles in programmed cell death and tumor suppression. With recent discoveries, however, it is becoming apparent these cell death executioners are involved in additional biological pathways beyond killing cells. In some cases, apoptotic cells secrete growth signals to stimulate proliferation of neighboring cells. This pathway functions to regenerate tissues in multiple organisms, but it also poses problems in tumor resistance to chemo- and radiotherapy. Additionally, it was found that activation of caspases does not irreversibly lead to cell death, contrary to the established paradigm. Sub-lethal activation of caspases is evident in cell differentiation and epigenetic reprogramming. Furthermore, evidence indicates spontaneous, unprovoked activation of caspases in many cancer cells, which plays pivotal roles in maintaining their tumorigenicity and metastasis. These unexpected findings challenge current cancer therapy approaches aimed at activation of the apoptotic pathway. At the same time, the newly discovered functions of caspases suggest new treatment approaches for cancer and other pathological conditions in the future.

Patient-reported Urinary, Bowel, and Sexual Function After Hypofractionated Intensity-modulated Radiation Therapy for Prostate Cancer: Results From a Randomized Trial.

OBJECTIVES: Hypofractionated prostate radiotherapy may increase biologically effective dose delivered while shortening treatment duration, but information on patient-reported urinary, bowel, and sexual function after dose-escalated hypofractionated radiotherapy is limited. We report patient-reported outcomes (PROs) from a randomized trial comparing hypofractionated and conventional prostate radiotherapy. METHODS: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity-modulated radiation therapy (CIMRT, 75.6 Gy in 1.8 Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4 Gy fractions). Questionnaires assessing urinary, bowel, and sexual function were completed pretreatment and at 2, 3, 4, and 5 years after treatment. RESULTS: Of 203 eligible patients, 185 were evaluable for PROs. A total of 173 completed the pretreatment questionnaire (82 CIMRT, 91 HIMRT) and 102 completed the 2-year questionnaire (46 CIMRT, 56 HIMRT). Patients who completed PROs were similar to those who did not complete PROs (all P>0.05). Patient characteristics, clinical characteristics, and baseline symptoms were well balanced between the treatment arms (all P>0.05). There was no difference in patient-reported bowel (urgency, control, frequency, or blood per rectum), urinary (dysuria, hematuria, nocturia, leakage), or sexual symptoms (erections firm enough for intercourse) between treatment arms at 2, 3, 4, and 5 years after treatment (all P>0.01). Concordance between physician-assessed toxicity and PROs varied across urinary and bowel domains. DISCUSSION: We did not detect an increase in patient-reported urinary, bowel, and sexual symptom burden after dose-escalated intensity-modulated prostate radiation therapy using a moderate hypofractionation regimen (72 Gy in 2.4 Gy fractions) compared with conventionally fractionated radiation.

Moringa oleifera functionalised sand - reuse with non-ionic surfactant dodecyl glucoside.

Moringa oleifera seeds are well known for their ability to cause flocculation in turbid water and facilitate bacterial inhibition. These effects are due to the cationic polypeptide MO2.1, which affects the surface charge of suspended particles and causes lysis of bacterial cells. However, the attachment of bacteria to MO2.1 prevents further bacterial attachment, reducing the effectiveness of the seeds. This research investigated the effect of surfactants on functionality and reuse of Moringa seeds to develop a sustainable water treatment technique. The seed extracts (MO2.1) were used with a functionalised sand system, and the sands were exposed to commercially available (ionic and non-ionic) surfactants, dodecyl glucoside and sodium dodecyl sulfate. Artificially polluted water contaminated with Escherichia coli was used to evaluate the efficiency of the system. The non-ionic surfactant was found to be effective at separating E. coli from the functionalised sand without the detachment of the MO2.1 and subsequent loss of the system efficiency. This was successfully repeated four times. The results demonstrated a sustainable, reusable technique to inhibit bacterial contamination in water.

Long-term economic value of hypofractionated prostate radiation: Secondary analysis of a randomized trial.

PURPOSE: Moderately hypofractionated intensity modulated radiation therapy (HIMRT) for prostate cancer shortens the treatment course while providing outcomes comparable with those of conventional intensity modulated radiation therapy (CIMRT). To determine the long-term economic value of HIMRT, including the costs of managing long-term radiation toxicities, a cost minimization analysis compared CIMRT with dose-escalated HIMRT using patient-level data from a randomized trial. METHODS AND MATERIALS: Men with localized prostate cancer were randomized to CIMRT (75.6 Gy in 42 fractions over 8.4 weeks) or HIMRT (72 Gy in 30 fractions over 6 weeks). A decision tree modeled trial probabilities of maximum late bowel and urinary toxicities using patient-level data with a median follow-up of 6 years. Costs were estimated from the healthcare perspective using the 2014 national reimbursement rates for services received. Patient-level institutional costs, adjusted to 2014 dollars, verified reimbursements. A sensitivity analysis assessed model uncertainty. RESULTS: The cost for HIMRT and toxicity management was $22,957, saving $7,000 compared with CIMRT ($30,241). CIMRT was the common factor among the 5 most influential scenarios that contributed to total costs. Toxicity represented a small part (<10%) of the average total cost for patients with either grade 2-3 bowel toxicity or grade 2-3 urinary toxicity. However, toxicity management reached up to 26% of the total cost for patients with both high-grade bowel and urinary toxicities. There was no threshold at which CIMRT became the less costly regimen. Institutional costs confirmed the economic value of HIMRT ($6,000 in savings). CONCLUSIONS: HIMRT is more cost-efficient than CIMRT for treating prostate cancer, even when taking into account the costs related to late radiation toxicities. HIMRT enhances the value of prostate radiation when compared with CIMRT.

Quantitative analysis of treatment process time and throughput capacity for spot scanning proton therapy.

PURPOSE: To determine the patient throughput and the overall efficiency of the spot scanning system by analyzing treatment time, equipment availability, and maximum daily capacity for the current spot scanning port at Proton Therapy Center Houston and to assess the daily throughput capacity for a hypothetical spot scanning proton therapy center. METHODS: At their proton therapy center, the authors have been recording in an electronic medical record system all treatment data, including disease site, number of fields, number of fractions, delivered dose, energy, range, number of spots, and number of layers for every treatment field. The authors analyzed delivery system downtimes that had been recorded for every equipment failure and associated incidents. These data were used to evaluate the patient census, patient distribution as a function of the number of fields and total target volume, and equipment clinical availability. The duration of each treatment session from patient walk-in to patient walk-out of the spot scanning treatment room was measured for 64 patients with head and neck, central nervous system, thoracic, and genitourinary cancers. The authors retrieved data for total target volume and the numbers of layers and spots for all fields from treatment plans for a total of 271 patients (including the above 64 patients). A sensitivity analysis of daily throughput capacity was performed by varying seven parameters in a throughput capacity model. RESULTS: The mean monthly equipment clinical availability for the spot scanning port in April 2012-March 2015 was 98.5%. Approximately 1500 patients had received spot scanning proton therapy as of March 2015. The major disease sites treated in September 2012-August 2014 were the genitourinary system (34%), head and neck (30%), central nervous system (21%), and thorax (14%), with other sites accounting for the remaining 1%. Spot scanning beam delivery time increased with total target volume and accounted for approximately 30%-40% of total treatment time for the total target volumes exceeding 200 cm(3), which was the case for more than 80% of the patients in this study. When total treatment time was modeled as a function of the number of fields and total target volume, the model overestimated total treatment time by 12% on average, with a standard deviation of 32%. A sensitivity analysis of throughput capacity for a hypothetical four-room spot scanning proton therapy center identified several priority items for improvements in throughput capacity, including operation time, beam delivery time, and patient immobilization and setup time. CONCLUSIONS: The spot scanning port at our proton therapy center has operated at a high performance level and has been used to treat a large number of complex cases. Further improvements in efficiency may be feasible in the areas of facility operation, beam delivery, patient immobilization and setup, and optimization of treatment scheduling.

The Influence of Age and Comorbidity on the Benefit of Adding Androgen Deprivation to Dose-escalated Radiation in Men With Intermediate-risk Prostate Cancer.

OBJECTIVE: Androgen deprivation therapy (ADT) can improve outcomes for men with intermediate-risk prostate cancer (IR-PrCa) receiving external-beam radiotherapy (EBRT). Older men and men with significant comorbidity may be more susceptible to the harms of ADT, therefore we aimed to determine whether these men benefit from ADT. METHODS: The adult comorbidity evaluation-27 index categorized severity of comorbidity in 636 men treated for IR-PrCa with dose-escalated EBRT (>75 Gy). The cohort was dichotomized at median age of 70. Multivariate Cox proportional hazard analysis evaluated the association of ADT with failure-free survival (FFS) for each age and comorbidity subgroup. RESULTS: A total of 48% of men were 70 years and above. After adjustment for tumor characteristics, the addition of ADT to EBRT was associated with improved FFS for both men below 70 years of age (adjusted hazard ratio [AHR] 0.44; 95% confidence interval [CI], 0.19-0.99; P=0.046) and men 70 years and above (AHR 0.23; 95% CI, 0.06-0.91; P=0.035). ADT improved FFS for men below 70 years who had no or mild comorbidity (AHR 0.25; 95% CI, 0.09-0.73; P=0.011) but not for men below 70 years who had moderate or severe comorbidity (AHR 1.62; 95% CI, 0.35-7.49; P=0.537). Similarly, in men 70 years and above, there was a trend for improved FFS with ADT in healthy men (AHR 0.10; 95% CI, 0.01-1.08; P=0.058) but not in men with moderate to severe comorbidity (AHR 0.38; 95% CI, 0.06-2.56; P=0.318). CONCLUSIONS: The addition of ADT to dose-escalated EBRT can improve outcomes for both younger and older men with IR-PrCa. This benefit was more pronounced in healthy men.

Relationship between illness uncertainty, anxiety, fear of progression and quality of life in men with favourable-risk prostate cancer undergoing active surveillance.

OBJECTIVES: To evaluate prospectively the associations between illness uncertainty, anxiety, fear of progression and general and disease-specific quality of life (QoL) in men with favourable-risk prostate cancer undergoing active surveillance (AS). PATIENTS AND METHODS: After meeting stringent enrollment criteria for an AS cohort study at a single tertiary care cancer centre, 180 men with favourable-risk prostate cancer completed questionnaires at the time of enrollment and every 6 months for up to 30 months. Questionnaires assessed illness uncertainty, anxiety, prostate-specific QoL (using the Expanded Prostate Cancer Index Composite [EPIC] scale) and general QoL (using the 12-time short-form health survey [SF-12]) and fear of progression. We used linear mixed-model analyses and multilevel mediation analyses. RESULTS: Sexual scores on the EPIC scale significantly declined over time (P < 0.05). Illness uncertainty was a significant predictor of all EPIC summary scores, SF-12 physical component summary (PCS) scores, mental component summary (MCS) scores and fear of progression scores (all P < 0.05), after controlling for demographic and clinicopathological factors. Anxiety predicted all EPIC summary, MCS and fear of progression scores (all P < 0.05) but not PCS scores (P = 0.08). Scores on PCS, MCS, EPIC summary scales (except sexual scale), and fear of progression did not change significantly over the study period (all P > 0.10). CONCLUSION: Over the 2.5-year follow-up, QoL remained stable; only sexual function scores significantly declined. Illness uncertainty and anxiety were significant predictors of general and prostate-specific QoL and fear of progression. Interventions to reduce uncertainty and anxiety may enhance QoL for men with prostate cancer on AS.

Disease reclassification risk with stringent criteria and frequent monitoring in men with favourable-risk prostate cancer undergoing active surveillance.

OBJECTIVES: To determine the frequency of disease reclassification and to identify clinicopathological variables associated with it in patients with favourable-risk prostate cancer undergoing active surveillance (AS). PATIENTS AND METHODS: We assessed 191 men, selected by what may be the most stringent criteria used in AS studies yet conducted, who were enrolled in a prospective cohort AS trial. Clinicopathological characteristics were analysed in a multivariate Cox proportional hazards regression model. Key features were an extended biopsy with a single core positive for Gleason score (GS) 3 + 3 (<3 mm) or 3 + 4 (<2 mm) and a prostate-specific antigen (PSA) level <4 ng/mL (adjusted for prostate volume). Biopsies were repeated every 1-2 years and clinical evaluations every 6 months. Disease was reclassified when PSA level increased by 30% from baseline, or when biopsy tumour length increased beyond the enrolment criteria, more than one positive core was detected or any grade increased to a dominant 4 pattern or any 5 pattern. RESULTS: Disease was reclassified in 32 patients (16.8%) including upgrading to GS 4 + 3 in five patients (2.6%). The median (interquartile range) follow-up time among survivors was 3 (1.9-4.6) years. Overall, 13 of the 32 (40.6%) had incremental increases in GS. Tumour length (hazard ratio 2.95, 95% confidence interval [CI] 1.34-6.46; P = 0.007) and older age (hazard ratio 1.05, 95% CI 1.00-1.09; P = 0.05) were identified as significant and marginally significant predictors of disease reclassification, respectively. Disease remained stable in 83.2% of patients. CONCLUSION: The need persists for improvements in risk stratification and predictive indicators of cancer progression.

Proton Beam Therapy for Localized Prostate Cancer: Results from a Prospective Quality-of-Life Trial.

PURPOSE: To report prostate cancer outcomes, toxicity, and quality of life (QOL) in men treated with proton beam therapy (PBT). PATIENTS AND METHODS: Patients were enrolled in a prospective trial. All participants received 75.6 to 78 Gy (RBE). Up to 6 months of luteinizing hormone-releasing hormone agonist therapy was allowed. The Phoenix definition defined biochemical failure. Modified Radiation Therapy Oncology Group criteria defined toxicity. Expanded Prostate Cancer Index Composite questionnaires objectified QOL. Clinically significant QOL decrement was defined as ≥0.5 × baseline standard deviation. RESULTS: In total, 423 men were analyzed. The National Comprehensive Cancer Network risk classification was used (low 43%; intermediate 56%; high 1%). At the 5.2-year median follow-up, overall and disease-specific survival rates were 99.8% and 100%, respectively. Cumulative biochemical failure rate was 5.2% (95% confidence interval [CI] = 3.0%-8.3%); acute grade 2 genitourinary (GU) toxicity was 46.3%; acute grade 2 gastrointestinal (GI) toxicity was 5.0% (95% CI = 3.1%-7.3%). There was no acute grade ≥3 GI or GU toxicity. Cumulative late grade 2 GU and GI toxicity was 15.9% (95% CI = 13%-20%) and 9.7% (95% CI = 6.5%-12%), respectively. There were 2 grade 3 late GI toxicities (rectal bleeding) and no late grade ≥3 GU toxicity. The 4-year mean Expanded Prostate Cancer Index Composite urinary, bowel, sexual, and hormonal summary scores (range; standard deviation) were 89.7 (43.8-100; 11), 91.3 (41.1-94.6; 10), 57.8 (0.0-96.2; 27.1), and 92.2 (25-95.5; 10.5), respectively. Compared with baseline, there was no clinically significant decrement in urinary, sexual, or hormonal QOL after treatment completion. A modest (<10 points), yet clinically significant, decrement in bowel QOL was appreciated throughout follow-up. CONCLUSION: Contemporary PBT resulted in excellent biochemical control, minimal risk of higher-grade toxicity, and modest QOL decrement. Further investigation comparing PBT with alternative prostate cancer treatment strategies are warranted.