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

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

Short-term ADT and Dose-escalated IMRT in Patients With Intermediate-risk Prostate Cancer: Benefit or Caution?

OBJECTIVES: In the era of dose-escalated prostate radiation therapy (RT), the use of androgen deprivation therapy (ADT) is undefined for intermediate-risk (IR) prostate cancer. There is growing concern of the risk of ADT to be detrimental to quality of life. This single-institution retrospective analysis aimed to evaluate outcomes of IR patients treated with dose-escalated intensity modulated radiation therapy (IMRT) with or without concurrent/adjuvant short-term ADT. MATERIALS AND METHODS: Data was collected from 260 consecutive patients treated with dose-escalated IMRT with daily image-guided RT for newly diagnosed IR prostate cancer. Biochemical recurrence-free survival (BCRFS), distant metastasis-free survival, prostate cancer-specific survival, and overall survival (OS) were calculated using Kaplan-Meier methodology. RESULTS: Median follow-up was 93 months. A total of 181 patients had unfavorable IR disease, and 36.2% (N=94) received ADT, with median ADT duration of 6 months. Seven-year BCRFS was 94.1% vs. 86.2% (P=0.067), for ADT and no ADT, respectively, and no difference in distant metastasis-free survival or prostate cancer-specific survival was observed. ADT was associated with significantly worse 7-year OS (80.0% vs. 91.3%, P=0.010). Analysis of the unfavorable IR cohort alone, showed similar results; 7-year BCRFS and 7-year OS in patients who received ADT versus no ADT were 93.7% vs. 85.9% (P=0.093), and 79.0% vs. 90.6% (P=0.019), respectively. CONCLUSIONS: In our 15-year experience treating IR prostate cancer with dose-escalated IMRT with daily image-guided RT, short-term concurrent ADT was associated with a statistically significant worse OS. Additional studies are needed to determine if ADT is beneficial or detrimental for patients with IR prostate cancer treated with dose-escalated radiation.

Longitudinal Detection of Radiation-Induced Peripapillary and Macular Retinal Capillary Ischemia Using OCT Angiography.

PURPOSE: To study longitudinal changes in retinal capillary circulation in eyes treated with iodine 125 (I125) plaque brachytherapy for uveal melanoma using OCT angiography (OCTA). DESIGN: Longitudinal prospective study of 21 patients undergoing treatment for uveal melanoma with I125 plaque brachytherapy. Eyes with melanoma were imaged with OCTA before treatment and at 12-month intervals until 2 years after brachytherapy. PARTICIPANTS: After institutional review board approval, participants were enrolled prospectively from an academic ocular oncology clinic. METHODS: Peripapillary (4.5 × 4.5-mm) and macular (3 × 3-mm) OCTA scans were acquired with AngioVue (Optovue, Inc, Fremont, CA). MAIN OUTCOME MEASURES: The peripapillary nerve fiber layer plexus capillary density (NFLP_CD), macular superficial vascular complex vessel density (mSVC_VD), and foveal avascular zone (FAZ) area were calculated. RESULTS: Before treatment, no significant difference was found in the NFLP_CD, mSVC_VD, or FAZ area between eyes with melanoma and normal fellow eyes. By 24 months, 11 eyes had developed clinical signs of radiation retinopathy, radiation optic neuropathy, or both. In treated eyes, the NFLP_CD (48.4±4.1%) was reduced at 12 months (46.7±5.0%; P = 0.04, Wilcoxon signed-rank test) and 24 months (44.5±6.1%; P < 0.001). Similarly, the mSVC_VD (48.4 2±3.6%) was reduced in treated eyes at 12 months (43.5±5.9%; P = 0.01) and 24 months (37.4±9.1%; P < 0.001). The FAZ area (0.26±0.11 mm2) increased in treated eyes at 12 months (0.35±0.22 mm2; P = 0.009) and 24 months (0.81±1.03 mm2; P = 0.001). When only eyes with clinically evident radiation changes were evaluated, the changes in NFLP_CD, mSVC_VD, and FAZ area were more pronounced. OCT angiography measurements correlated with both radiation dose and visual acuity. The mSVC_VD measured at 12 months was found to predict the development of clinically apparent radiation retinopathy within 1 year. CONCLUSIONS: OCT angiography demonstrated early emergence of peripapillary and macular capillary vasculature changes after I125 plaque brachytherapy. OCT angiography provided a quantitative measurement of retinal capillary changes associated with ischemia that correlated with visual acuity and radiation dose and may predict future development of radiation-induced retinal toxicity.

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

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

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

ABSTRACT 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 follow-ups 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.

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.

Quantitative OCT Angiography Evaluation of Peripapillary Retinal Circulation after Plaque Brachytherapy.

OBJECTIVE: To study peripapillary retinal capillary circulation in eyes treated with I-125 plaque brachytherapy for uveal melanoma using optical coherence tomography angiography (OCTA). DESIGN: Cross-sectional study of 10 subjects imaged with OCTA prior to uveal melanoma treatment and 15 subjects imaged after development of radiation retinopathy and/or optic neuropathy. PARTICIPANTS: Following IRB approval, subjects were enrolled from an academic ocular oncology clinical practice. All subjects had uveal melanoma in one eye and treatment with I-125 plaque brachytherapy was planned or had previously taken place. Patients with low vision at baseline and uncontrolled hypertension were excluded. In the post-treatment group, seven subjects were male and eight were female; age range 38 to 81 years. Visual acuities in the irradiated eyes ranged from 20/20 to counting fingers. Visual acuities in the untreated fellow eyes were 20/25 or better. METHODS: Peripapillary retinal capillary circulation was measured by OCTA (Optovue, Inc). 4.5×4.5 mm optic disc scans were obtained. 10 subjects were imaged prior to brachytherapy treatment and 15 subjects were imaged after development of clinically apparent radiation retinopathy and/or radiation optic neuropathy post-brachytherapy. MAIN OUTCOME MEASURES: The relationship of the peripapillary retinal capillary density (PPCD) as measured by OCTA to the calculated dose to the optic nerve (D50, the dose to 50% of the disc) and the LogMAR vision was evaluated. RESULTS: No significant difference was seen in the PPCD as measured by OCTA when comparing the eye with melanoma to the fellow eye prior to brachytherapy; however the PPCD was significantly lower in treated eyes (52.9% +/- 22.4%) than in fellow eyes that did not receive radiation (73.3% +/- 13.7%, p = 0.004). There was an inverse linear correlation between D50 and the PPCD (Pearson's; r= -0.528, P=0.043) and between visual acuity and the PPCD (Pearson's; r= -0.564, P=0.028). CONCLUSIONS: Among patients with clinically apparent radiation retinopathy and/or radiation optic neuropathy, PPCD was lower in the treated eye and correlated with the radiation dose to the optic nerve and the visual acuity. OCTA provides a measure of capillary changes following radiation, and may serve as a quantitative endpoint to address visual prognosis.

Epirubicin and Ifosfamide with Preoperative Radiation for High-Risk Soft Tissue Sarcomas.

BACKGROUND: The optimal treatment of high-risk soft tissue sarcomas (STS) of the extremities remains controversial. We report follow-up from a phase II study of dose-intense chemotherapy with preoperative hypofractionated radiation in this population supplemented with subsequent data from an extensive institutional experience using this regimen. METHODS: Patients with localized, intermediate- or high-grade STS of the extremity or body wall measuring > 5 cm were treated with epirubicin 30 mg/m2/day and ifosfamide 2.5 g/m2/day on days 1-4 every 21 days for 3 preoperative and 3 postoperative cycles. During cycle 2 of preoperative therapy, epirubicin was omitted, and a total of 28 Gy of radiation (8 fractions) was delivered. Twenty-five patients were treated on the phase II study (2002-2005). Fifty-one additional patients were identified from a retrospective chart review (2005-2014). RESULTS: The 5-year rates for overall survival, distant disease-free survival, and freedom from local regional failure were 70.4% (95% CI 59.2-83.7%), 55.9% (95% CI 44.5-70.2%), and 87.2% (95% CI 77.9-96.5%) respectively. Thirty-eight percent of tumors (29/76) demonstrated ≥ 90% pathologic response. Wound complications occurred in 32% (24/76) of patients. DISCUSSION: Treatment with preoperative radiation and pre- and post-operative epirubicin and ifosfamide was associated with favorable clinical outcomes. Survival and recurrence rates were comparable to those reported with other preoperative chemotherapy regimens in high-risk extremity sarcomas. Use of trimodality therapy should be considered for appropriate high-risk STS patients.

Safety and Efficacy of Accelerated Hypofractionation and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma Patients With Varying Degrees of Hepatic Impairment.

PURPOSE: To report the toxicities and outcomes for stereotactic body radiation therapy (SBRT) and accelerated hypofractionated radiation therapy (AHRT) in patients with Child-Pugh (CP) class A, B, or C and albumin-bilirubin (ALBI) score 1, 2, or 3 hepatocellular carcinoma. METHODS AND MATERIALS: We retrospectively reviewed the data from 146 patients with hepatocellular carcinoma who had undergone SBRT (50 Gy in 5 fractions) or AHRT (45 Gy in 18 fractions). The primary endpoint was liver toxicity, defined as an increase in the CP score of ≥2 within 6 months of radiation therapy. The secondary endpoints of ALBI change, overall survival, and local control were also calculated. RESULTS: The median follow-up was 23 months (range 1-59). Most received SBRT (72%), and 28% received AHRT. Of all 146 patients, 45 (31%) had a CP score elevation of ≥2 within 6 months of radiation therapy (RT) (27 patients [28%] with baseline CP-A/B7 and 18 [35%] with baseline CP-B8/B9/C cirrhosis; P = .45). On multivariate analysis, neither baseline CP nor ALBI score was predictive of toxicity. No patient with a decline in liver functionality of CP ≥2 within 6 months of RT returned to baseline at later time points. Eleven grade 4 toxicities were observed. The mean change in the raw ALBI score at ∼6 months was similar for all baseline ALBI groups. Twenty-two patients underwent orthotopic liver transplantation after RT, 13 of whom had baseline CP-B8/B9/C liver functionality. For all patients, the 1- and 2-year treated-lesion local control was greater for SBRT than for AHRT (2-year 94% vs 65%, P < .0001). CONCLUSIONS: The tolerability of SBRT or AHRT as measured by a CP score decline of ≥2 within 6 months of RT was similar across baseline liver functionality groups. Compared with AHRT, SBRT was associated with superior local control. Because the true tolerability of limited-volume RT for patients with CP-B or CP-C cirrhosis is unknown, prospective trials validating its safety and efficacy are warranted.

Current Practice Patterns Surrounding Fertility Concerns in Stage I Seminoma Patients: Survey of United States Radiation Oncologists.

PURPOSE: Patients with testicular seminoma may face fertility issues because of their underlying disease as well as treatments they undergo. The current patterns of practice among U.S. radiation oncologists aimed at assessing and preserving fertility in patients with Stage I seminoma are unknown. METHODS: We surveyed practicing U.S. radiation oncologists via an Institutional Review Board-approved online questionnaire. Respondents' characteristics and perceived patient infertility rates were analyzed for association with treatment recommendations. RESULTS: We received 353 responses, of whom one quarter (23%) consider themselves experts. A vast majority (84%) recommend observation as a default strategy. Fifty-two percent routinely advise fertility assessment for patients before observation or chemotherapy, and 74% routinely do so before adjuvant radiation therapy (RT). Forty-one percent and 43% believe that 10% and 30% of patients are infertile following orchiectomy, respectively. Thirty-seven percent and 22% believe infertility rates following para-aortic RT to be 30% and 50%, respectively. Eighty percent routinely use clamshell scrotal shielding. Responders with higher perceived infertility rates are more likely to recommend fertility assessment/sperm banking (Fisher's exact p < 0.0001). Responders who routinely advised fertility assessment were more likely to use clamshell shielding (Cochran-Armitage trend test p = 0.0007). Clamshell use was positively correlated with higher perceived infertility rates following para-aortic RT (Spearman's correlation coefficient = 0.006). CONCLUSIONS: Despite a clear knowledge of fertility issues in men diagnosed with seminoma, there is no universal adoption of fertility assessment among U.S. radiation oncologists.

The Relationships Between Spiritual Well-Being, Quality of Life, and Psychological Factors Before Radiotherapy for Prostate Cancer.

Given shifting trends of religious identities in the USA, better understanding the impact of patients' religious identities on health-related quality of life (QOL) may help tailor the use of psychological interventions. Men with prostate cancer (N = 43) completed measures of quality of life (QOL), spiritual well-being in two domains (i.e., Faith and Meaning/Peace), psychological state, and psychological trait before undergoing radiotherapy. We hypothesized that (1) higher existential Meaning/Peace would correlate with higher QOL and psychological trait protective factors (e.g., Agreeableness) and that (2) higher existential Meaning/Peace would correlate with lower depression, anxiety, and Neuroticism (i.e., a psychological trait risk factor). We did not anticipate similar relationships between religious Faith and QOL, depression, anxiety, or psychological traits and consider related analyses to be exploratory in nature. Meaning/Peace was indeed negatively associated with depression, anxiety, and Neuroticism. Meaning/Peace was positively correlated with Physical, Social, Functional, and Emotional well-being, as well as Extraversion. Religious Faith was positively associated with Functional well-being, but not the other state, trait, or QOL domains. In sum, prostate cancer patients' sense of existential Meaning/Peace prior to radiotherapy was associated with well-being in many domains, whereas religious Faith appeared less so.

Localized External Beam Radiation Therapy (EBRT) to the Pelvis Induces Systemic IL-1Beta and TNF-Alpha Production: Role of the TNF-Alpha Signaling in EBRT-Induced Fatigue.

Prostate cancer patients undergoing localized external beam radiation therapy (EBRT) can experience a progressive increase in fatigue, which can affect physical functioning and quality of life. The purpose of this study was to develop a mouse EBRT prostate cancer treatment model with which to determine the role of pro-inflammatory cytokines in the genesis of EBRT-related fatigue. We assessed voluntary wheel-running activity (VWRA) as a proxy for fatigue, food intake and body weight in male C57BL/6 mice undergoing EBRT to the pelvis. In the first experiment, anesthetized male C57BL/6 mice underwent fractionated EBRT to the pelvis for a total dose of 68.2 Gy, thereby mimicking a clinically relevant therapeutic dose and frequency. The day after the last treatment, levels of IL-1ß and TNF-α in plasma along with mRNA levels in liver, colon and whole brain were measured. EBRT-induced fatigue resulted in reduced body weight, diminished food intake, and increased plasma and tissue levels of IL-1ß and TNF-α. In a follow-up experiment, we used TNF-α-deficient mice to further delineate the role of TNF-α signaling in EBRT-induced sickness behavior. EBRT-induced changes in fatigue, food intake and body weight were no different between TNF-α deficient mice and their wild-type counterparts. Taken together our data demonstrate that a clinically relevant localized irradiation of the pelvis induces a systemic IL-1ß and TNF-α response and sickness behavior in mice, but the TNF-α signaling pathway alone does not independently mediate these effects.

Relationship between fatigue, sleep quality and inflammatory cytokines during external beam radiation therapy for prostate cancer: A prospective study.

BACKGROUND AND PURPOSE: Mechanisms of fatigue reported during radiotherapy are poorly defined but may include inflammatory cytokines and/or sleep disturbances. This prospective, longitudinal, phase II study assessed fatigue, sleep, and serum cytokine levels during radiotherapy for early-stage prostate cancer (PCa). MATERIAL AND METHODS: Twenty-eight men undergoing radiotherapy for early-stage PCa wore an Actiwatch Score to record fatigue level, sleep time, onset latency, efficiency and wake after sleep onset. Serum levels of IL-1α, IL-1ß, TNF-α, IL-6, IL-8, IL-10 and VEGF were measured weekly during radiotherapy. Patient reported quality of life (QOL) metrics were collected before and after treatment. Linear mixed effects models examined trajectories across treatment weeks. RESULTS: Fatigue increased across treatment weeks (P<.01), and fatigue was associated with decreased patient-reported QOL. Sleep efficiency increased across treatment weeks (rate of change over time=.29, P=.03), and sleep onset latency decreased (rate of change over time=.86, P=.06). IL-6 tended to increase during treatment (P=0.09), but none of the cytokine levels or sleep variables were significantly related to fatigue trajectories. CONCLUSIONS: Despite increased sleep efficiency across treatment weeks, fatigue significantly increased. Although IL-6 increased during the course of radiotherapy, cytokines levels were not associated with fatigue scores or sleep disturbance. Further studies are needed to define the mechanisms for fatigue during radiotherapy.

Evaluation of Soft Tissue Sarcoma Response to Preoperative Chemoradiotherapy Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

This study aims to assess the utility of quantitative dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) parameters in comparison with imaging tumor size for early prediction and evaluation of soft tissue sarcoma response to preoperative chemoradiotherapy. In total, 20 patients with intermediate- to high-grade soft tissue sarcomas received either a phase I trial regimen of sorafenib + chemoradiotherapy (n = 8) or chemoradiotherapy only (n = 12), and underwent DCE-MRI at baseline, after 2 weeks of treatment with sorafenib or after the first chemotherapy cycle, and after therapy completion. MRI tumor size in the longest diameter (LD) was measured according to the RECIST (Response Evaluation Criteria In Solid Tumors) guidelines. Pharmacokinetic analyses of DCE-MRI data were performed using the Shutter-Speed model. After only 2 weeks of treatment with sorafenib or after 1 chemotherapy cycle, Ktrans (rate constant for plasma/interstitium contrast agent transfer) and its percent change were good early predictors of optimal versus suboptimal pathological response with univariate logistic regression C statistics values of 0.90 and 0.80, respectively, whereas RECIST LD percent change was only a fair predictor (C = 0.72). Post-therapy Ktrans, ve (extravascular and extracellular volume fraction), and kep (intravasation rate constant), not RECIST LD, were excellent (C > 0.90) markers of therapy response. Several DCE-MRI parameters before, during, and after therapy showed significant (P < .05) correlations with percent necrosis of resected tumor specimens. In conclusion, absolute values and percent changes of quantitative DCE-MRI parameters provide better early prediction and evaluation of the pathological response of soft tissue sarcoma to preoperative chemoradiotherapy than the conventional measurement of imaging tumor size change.

Direct MRI-guided biopsy of the prostate: use of post-biopsy needle track imaging to confirm targeting.

PURPOSE: To report the observation that in-plane post-biopsy T2-weighted MRI often demonstrates the needle track as a transient visible linear tissue distortion during direct MRI-guided biopsy. MATERIALS AND METHODS: We retrospectively identified 11 prostatic lesions in 9 men that underwent direct MRI-guided biopsy and in which post-biopsy images were obtained in the plane of the biopsy needle. RESULTS: In 9 of 11 targets, a post-biopsy needle track was visible as a linear tissue distortion on in-plane T2-weighted images obtained at a mean interval of 6 min (range 3-15). In these nine cases, the needle track traversed the intended target, and the biopsy was positive for malignancy in six. Biopsy was positive in one of two cases where the needle track was not visible. In five targets, one or more delayed series were obtained after a mean interval of 21 min (range 8-33), showing the track was no longer visible (n = 3) or was of progressively decreased conspicuity (n = 2). CONCLUSION: Accurate targeting during direct MRI-guided biopsy of the prostate can be confirmed by obtaining post-biopsy in-plane images, since the needle track is usually visible as a transient linear tissue distortion.

Phase I trial of preoperative chemoradiation plus sorafenib for high-risk extremity soft tissue sarcomas with dynamic contrast-enhanced MRI correlates.

PURPOSE: We conducted a phase I trial of the addition of sorafenib to a chemoradiotherapy regimen in patients with high-risk (intermediate/high grade, >5 cm) extremity soft tissue sarcoma undergoing limb salvage surgery. We conducted a correlative study of quantitative dynamic contrast-enhanced MRI (DCE-MRI) to assess response to treatment. EXPERIMENTAL DESIGN: Patients were treated at increasing dose levels of sorafenib (200 mg daily, 400 mg daily, 400 mg twice daily) initiated 14 days before three preoperative and three postoperative cycles of epirubicin/ifosfamide. Radiation (28 Gy) was administered during cycle 2 with epirubicin omitted. The primary objective was to determine the maximum tolerated dose (MTD) of sorafenib. DCE-MRI was conducted at baseline, after 2 weeks of sorafenib, and before surgery. The imaging data were subjected to quantitative pharmacokinetic analyses. RESULTS: Eighteen subjects were enrolled, of which 16 were evaluable. The MTD of sorafenib was 400 mg daily. Common grade 3-4 adverse events included neutropenia (94%), hypophosphatemia (75%), anemia (69%), thrombocytopenia (50%), and neutropenic fever/infection (50%). Of note, 38% developed wound complications requiring surgical intervention. The rate of ≥95% histopathologic tumor necrosis was 44%. Changes in DCE-MRI biomarker ΔK(trans) after 2 weeks of sorafenib correlated with histologic response (R(2) = 0.67, P = 0.012) at surgery. CONCLUSION: The addition of sorafenib to preoperative chemoradiotherapy is feasible and warrants further investigation in a larger trial. DCE-MRI detected changes in tumor perfusion after 2 weeks of sorafenib and may be a minimally invasive tool for rapid assessment of drug effect in soft tissue sarcoma.

Real-time prostate motion assessment: image-guidance and the temporal dependence of intra-fraction motion.

BACKGROUND: The rapid adoption of image-guidance in prostate intensity-modulated radiotherapy (IMRT) results in longer treatment times, which may result in larger intrafraction motion, thereby negating the advantage of image-guidance. This study aims to qualify and quantify the contribution of image-guidance to the temporal dependence of intrafraction motion during prostate IMRT. METHODS: One-hundred and forty-three patients who underwent conventional IMRT (n=67) or intensity-modulated arc therapy (IMAT/RapidArc, n=76) for localized prostate cancer were evaluated. Intrafraction motion assessment was based on continuous RL (lateral), SI (longitudinal), and AP (vertical) positional detection of electromagnetic transponders at 10 Hz. Daily motion amplitudes were reported as session mean, median, and root-mean-square (RMS) displacements. Temporal effect was evaluated by categorizing treatment sessions into 4 different classes: IMRTc (transponder only localization), IMRTcc (transponder + CBCT localization), IMATc (transponder only localization), or IMATcc (transponder + CBCT localization). RESULTS: Mean/median session times were 4.15/3.99 min (IMATc), 12.74/12.19 min (IMATcc), 5.99/5.77 min (IMRTc), and 12.98/12.39 min (IMRTcc), with significant pair-wise difference (p<0.0001) between all category combinations except for IMRTcc vs. IMATcc (p>0.05). Median intrafraction motion difference between CBCT and non-CBCT categories strongly correlated with time for RMS (t-value=17.29; p<0.0001), SI (t-value=-4.25; p<0.0001), and AP (t-value=2.76; p<0.0066), with a weak correlation for RL (t-value=1.67; p=0.0971). Treatment time reduction with non-CBCT treatment categories showed reductions in the observed intrafraction motion: systematic error (Σ)<0.6 mm and random error (σ)<1.2 mm compared with ≤0.8 mm and <1.6 mm, respectively, for CBCT-involved treatment categories. CONCLUSIONS: For treatment durations >4-6 minutes, and without any intrafraction motion mitigation protocol in place, patient repositioning is recommended, with at least the acquisition of the lateral component of an orthogonal image pair in the absence of volumetric imaging.

Pelvic applications of MR-guided high intensity focused ultrasound.

MR-guided high intensity focused ultrasound (MRg HIFU) is a novel method of tissue ablation that incorporates high energy focused ultrasound for tissue heating and necrosis within an MR scanner that provides simultaneous stereotactic tissue targeting and thermometry. To date, MRg HIFU has been used primarily to treat uterine fibroids, but many additional applications in the pelvis are in development. This article reviews the basic technology of MRg HIFU, and the use of MRg HIFU to treat uterine fibroids, adenomyosis, and prostate cancer.

Advances in the multimodality management of high-risk prostate cancer.

Prostate cancer is a heterogeneous disease with marked variability in its natural progression and response to therapeutic interventions. It is the most commonly diagnosed visceral cancer of men living in western countries, yet it is life-threatening in only a minority of cases. Thus, appropriate patient selection for treatment based on tumor as well as patient characteristics is essential to achieve optimal outcomes. The combination of early cancer detection and technical improvements in local treatment has led to a reduction in disease burden and an increase in cancer survivorship. However, treatment failure remains common among high-risk cases.