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Supplementary Data from Pharmacokinetic Analysis and Phase 1 Study of MRX-1024 in Patients Treated with Radiation Therapy with or without Cisplatinum for Head and Neck Cancer

Purpose: A previous study reported radiation protection from mucosal injury with D-methionine (D-met) in preclinical evaluation; therefore, the pharmacokinetics, safety, and utility of D-met were evaluated clinically.Experimental Design: The pharmacokinetics of D-met following oral administration of a bioavailable formulation (MRX-1024) was evaluated in normal volunteers. Subsequently, 25 patients were enrolled on a phase 1 study of MRX-1024 concurrent with radiation therapy (RT) with or without weekly cisplatinum. Toxicity and mucosal events were evaluated weekly.Results: Oral MRX-1024 resulted in rapid and dose-dependent increases in plasma D-met concentrations with a half-life of 3 hours. When administered concurrent with RT without chemotherapy, it was associated with a modest increase in grade 2 (two of six patients) and grade 3 (one of six patients) emesis. In those treated with MRX-1024 along with RT and weekly cisplatinum, there was no appreciable increase in emesis. Overall, five patients withdrew from the study due to emesis (four grade 2 and one grade 3). Only one incidence of dose-limiting toxicity (grade 3 emesis) was identified in 25 patients (4%). Finally, in 18 evaluable patients treated with MRX-1024 at 100 mg/kg twice daily (BID), the incidence of severe (grade 3) oral mucositis was 6% (1 of 18) with no grade 4 mucositis.Conclusions: There is a dose-dependent increase in D-met exposure following MRX-1024 administration at 50 and 100 mg/kg, and MRX-1024 is safe for use concurrent with combined radiation and chemotherapy. The observed rate of mucositis seems less than that for similar treatment regimens within the published literature. Clin Cancer Res; 16(9); 2666–76. ©2010 AACR.

Purpose: Oral mucositis is a common acute morbidity associated with radiation and/or chemotherapy treatment for cancer. d-Methionine (d-Met), the dextro-isomer of the common amino acid l-methionine, has been documented to protect normal tissues from a diverse array of oxidative insults.Experimental Design: We evaluated if d-Met could selectively prevent radiation-induced oral mucositis using in vitro cell culture models as well as an in vivo model of radiation injury to the oral mucosa in C3H mice.Results: Unlike free-radical scavengers, which protected both normal and transformed tumor cells in vitro from radiation-induced cell death, treatment with d-Met in culture protected nontransformed primary human cells from radiation-induced cell death (protective factor between 1.2 and 1.6; P < 0.05) whereas it did not confer a similar protection on transformed tumor cells. d-Met treatment also provided significant protection to normal human fibroblasts, but not to tumor cell lines, from radiation-induced loss of clonogenicity (protection factor, 1.6 ± 0.15). d-Met treatment did not alter DNA damage (as measured by histone phosphorylation) following irradiation but seemed to selectively mitigate the loss of mitochondrial membrane potential in nontransformed cells, whereas it did not provide a similar protection to tumor cells. Tumor control of implanted xenografts treated with radiation or concurrent cisplatin and radiation was not altered by d-Met treatment. Pharmacokinetics following administration of a liquid suspension of d-Met in rats showed 68% bioavailability relative to i.v. administration. Finally, in a murine model of mucositis, a dose-dependent increase in protection was observed with the protective factor increasing from 1.6 to 2.6 over a range of oral d-Met doses between 200 and 500 mg/kg (P < 0.0003).Conclusions:d-Met protected normal tissues, but not tumor cells, in culture from radiation-induced cell death; it also protected normal cells from radiation-induced mucosal injury in a murine model but did not alter tumor response to therapy. Further studies on the use of d-Met to protect from oral mucositis are warranted.

Supplementary Data from Inhibition of mTOR Radiosensitizes Soft Tissue Sarcoma and Tumor Vasculature

Supplementary Data from Evaluation of d-Methionine as a Novel Oral Radiation Protector for Prevention of Mucositis

Background Diffusion-weighted magnetic resonance imaging (DWI) provides a measurement of tumor cellularity. We evaluated the potential of apparent diffusion coefficient (ADC) values obtained from post-external beam radiation therapy (EBRT) DWI and prior to brachytherapy (BT) to predict for complete metabolic response (CMR) in bulky cervical cancer. Methods Clinical and DWI (b value = 500 s/mm2) data were obtained from patients undergoing interstitial BT with high-risk clinical target volumes (HR-CTVs) > 30cc. Gross tumor was contoured on co-registered T2 weighted images and 90th percentile ADC values were calculated. Patients were stratified by CMR (defined by PET-CT at three months post-BT). Relation of CMR with 90th percentile ADC values and other clinical factors (International Federation of Gynecology and Obstetrics (FIGO) stage, histology, tumor and HR-CTV size, pre-treatment hemoglobin, and age) was assessed both in univariate and multivariate logistic regression analyses. Youden’s J statistic was used to identify a threshold value. Results Among 45 patients, twenty-eight (62%) achieved a CMR. On univariate analysis for CMR, only 90th percentile ADC value was significant (p = 0.029) while other imaging and clinical factors were not. Borderline significant factors were HR-CTV size (p = 0.054) and number of chemotherapy cycles (p = 0.078). On multivariate analysis 90th percentile ADC (p < 0.0001) and HR-CTV size (p < 0.003) were highly significant. Patients with 90th percentile ADC values above 2.10 x10− 3 mm2/s were 5.3 (95% CI, 1.34–24.4) times more likely to achieve CMR. Conclusions Clinical DWI may serve to risk-stratify patients undergoing interstitial BT for bulky cervical cancer.

OBJECTIVE To evaluate the long-term bowel-associated quality of life (QOL) in men after radiotherapy (RT) for prostate cancer with and without the use of rectal hydrogel spacer. PATIENTS AND METHODS The patients' QOL was examined using the Expanded Prostate Cancer Index Composite (EPIC) and mean changes from baseline in EPIC domains were evaluated. A total of 215 patients from a randomised multi-institutional trial of RT, with or without hydrogel spacer, with a QOL endpoint were pooled with 165 non-randomised patients from a single institution with prospective QOL collection in patients with or without hydrogel spacer. The proportions of men with minimally important differences (MIDs) relative to pre-treatment baseline in the bowel domain were tested using repeated measure logistic models with a pre-specified threshold for clinically significant declines (≥5 equivalent to MIDx1 and ≥10 equivalent to MIDx2). RESULTS A total of 380 men were evaluated (64% with spacer and 36% without) with QOL data being available for 199 men with >24 months of follow-up [median (range) 39.5 (31-71.4) months]. Treatment with spacer was associated with less decline in average long-term bowel QOL (89.4 for control and 94.7 for spacer) with differences at >24 months meeting the threshold of a MID difference between cohorts (bowel score difference from baseline: control = -5.1, spacer = 0.3, difference = -5.4; P

Previously a phase III trial of a hydrogel rectal spacer during prostate radiation therapy found decreased toxicity and a clinically significant improvement in bowel quality of life (QOL) at 3 years by the Expanded Prostate Cancer Index. We performed a secondary analysis to identify men less likely to benefit.Clinical and dosimetric data for the 222 patients enrolled on the SpaceOAR phase III trial were analyzed. The volume of rectum treated to 70 Gy (V70) and the quantitative analysis of normal tissue effects in the clinic (QUANTEC) rectal dose goals were used as surrogates for clinical benefit and plan quality. Mean bowel QOL was assessed at 15 and 36 months posttreatment and the likelihood of 1× (5 points) or 2× (10 points) minimally important difference changes were assessed.Rectal V70 was correlated with physician scored toxicity (P = .033) and was used as a surrogate for plan quality. There was no correlation between prostate volume and rectal V70 (r = 0.077). Rectal V70 pre- and post-hydrogel was 13% and 3% for the smallest prostates (40 mL) and 12% and 2% for the largest (80 mL). The relative reduction in rectal V70 of 78% did not vary by prespacer V70, but the absolute reduction was greater for a higher V70. All spacer plans met the 5 QUANTEC rectal dose constraints, although 92% of control plans met all constraints. At 3 years, those not meeting all QUANTEC goals had a 15.0-point (standard deviation 15.1) decline, control patients meeting QUANTEC goals had a 4.0-point (9.5) decline, and spacer had0.5 (7.6; P.01). Previous surgery was not correlated with QOL (P = .8). Across prognostic groups, including age, body mass index, previous surgery, target volume, or quality of radiation plans, there was no statistically significant heterogeneity in the relative benefit of spacer in decreasing the risk of 1× or 2× the minimally important difference declines.There was little heterogeneity in the likelihood of spacer reducing the risk of declines in bowel QOL across clinical and dosimetric variables. Even for the95% of plans meeting QUANTEC rectal criteria, hydrogel spacer provided potentially meaningful benefits.

Metastatic prostate cancer remains lethal with a 5-year survival rate of about 30%, indicating the need for better treatment options. Novel antiandrogens (NAA)—enzalutamide and abiraterone—have been the mainstay of treatment for advanced disease since 2011. In patients who progress on the first NAA, responses to the second NAA are infrequent (25–30%) and short-lasting (median PFS ~3 months). With the growing adoption of NAA therapy in pre-metastatic castration-resistant settings, finding better treatment options for first-line mCRPC has become an urgent clinical need. The regulatory approval of two PARP inhibitors in 2020—rucaparib and olaparib—has provided the first targeted therapy option for patients harboring defects in selected DNA damage response and repair (DDR) pathway genes. However, a growing body of preclinical and clinical data shows that co-inhibition of AR and PARP induces synthetic lethality and could be a promising therapy for patients without any DDR alterations. In this review article, we will investigate the limitations of NAA monotherapy, the mechanistic rationale for synthetic lethality induced by co-inhibition of AR and PARP, the clinical data that have led to the global development of a number of these AR and PARP combination therapies, and how this may impact patient care in the next 2–10 years.

Objective: This exploratory Phase 2 clinical trial is the first determining safety and efficacy of oral D-methionine (D-met) in reducing cisplatin-induced ototoxicity.Design: Randomised parallel do...

BackgroundRates of shared decision making (SDM) are relatively low in early stage prostate cancer decisions, as patients’ values are not well integrated into a preference-sensitive treatment decision. The study objectives were to develop a SDM training video, measure usability and satisfaction, and determine the effect of the intervention on preparing patients to participate in clinical appointments.MethodsA randomized controlled trial was conducted to compare a plain-language decision aid (DA) to the DA plus a patient SDM training video. Patients with early stage prostate cancer completed survey measures at baseline and after reviewing the intervention materials. Survey items assessed patients’ knowledge, beliefs related to SDM, and perceived readiness/intention to participate in their upcoming clinical appointment.ResultsOf those randomized to the DA + SDM video group, most participants (91%) watched the video and 93% would recommend the video to others. Participants in the DA + SDM video group, compared to the DA-only group, reported an increased desire to participate in the decision (mean = 3.65 v. 3.39, P < 0.001), less decision urgency (mean = 2.82 v. 3.39, P < 0.001), and improved self-efficacy for communicating with physicians (mean = 4.69 v. 4.50, P = 0.05). These participants also reported increased intentions to seek a referral from a radiation oncologist (73% v. 51%, P = 0.004), to take notes (mean = 3.23 v. 2.86, P = 0.004), and to record their upcoming appointments (mean = 1.79 v. 1.43, P = 0.008).ConclusionsA novel SDM training video was accepted by patients and changed several measures associated with SDM. This may be a scalable, cost-effective way to prepare patients with early stage prostate cancer to participate in their clinical appointments. [Box: see text]

Purpose The purpose of this study was to delineate a scoring system to maximize the ethical allocation of proton beam therapy (PBT) and determine what factors are associated with receipt of PBT, including the role of specific insurance providers. Methods and Materials Our scoring system was developed in collaboration with a multidisciplinary panel of experts. Patients submitted for PBT consideration were assigned a score by committee at a weekly peer-reviewed session at a time when our center was operating at capacity. Univariate analysis and multivariable analysis of initial and final insurance response were performed. Results One hundred ninety-seven patients were prospectively reviewed. Ninety-three percent of patients with Medicaid coverage, 88% of patients with Medicare, and 78% of patients with private insurance were ultimately approved for PBT. Median time to final insurance response was 12 days (interquartile range, 9-18 days) for patients who were ultimately denied PBT coverage. Having primary provider C (odds ratio [OR], 14; 95% confidence interval [CI], 1.20-1.96; P = .033) or third party providers A (OR, 4.22; 95% CI, 1.71-10.9; P = .002) or B (OR, 5.28; 95% CI, 1.56-17.2; P = .006) was significantly associated with final insurance denial for PBT on univariate analysis. Total score (OR, 0.79; 95% CI, 0.67-0.90; P = .002) and having coverage through third party provider A (OR, 24.2; 95% CI, 9.51-68.9; P Conclusions Our scoring system was significantly associated with receipt of proton beam therapy. Certain insurance providers are less likely to approve PBT for patients, all else being equal. Such a scoring system could be implemented effectively at other PBT facilities, and additional work is needed in ensuring patients with the most to gain from PBT will be approved by their insurance providers.

Purpose This study aimed to evaluate the impact on spine growth in children with medulloblastoma using either photon or electron craniospinal irradiation (CSI). Methods and materials This was a single institution retrospective review of children who were treated with CSI for medulloblastoma. Spine growth was measured on magnetic resonance imaging scans at defined locations on the basis of a published predictive model of spine growth after CSI. Differences between spine growth in the anterior, middle, and posterior aspect of the designated vertebral segments were also assessed. Differences between the groups treated with photons or electrons were assessed with student’s t test. Results A total of 19 patients (10 patients treated with electrons and 9 with photons) with a median follow-up time of 45.5 months (confidence interval, 34.9-55.1 months) were evaluated. Patients treated with electrons were younger than those who received photons (5.1 years [range, 3.8-9.0 years] vs 9.6 years [range, 3.5-12.9 years]); however, there were no differences in other clinical characteristics, treatment, or follow-up between the groups. Spine growth rate for patients treated with electrons fit the predictive model (104% ± 5.2%), but patients treated with photons had growth that was faster than predicted by the model (150% ± 47%) and different from that observed with electrons. The differences between treatment the modalities were statistically significant (P = .03). For patients treated with photons, there were no statistical differences between the growth rate of the anterior vertebral body compared with the posterior aspect, but for patients treated with electrons, a faster spine growth in the anterior L1-L5 lumbar spine was observed compared with the posterior lumbar spine (3.90 vs 2.52 mm/year; P = .006) without differences in the cervical or thoracic spine. Conclusions The use of electrons to treat the craniospinal axis in children with medulloblastoma resulted in no significant difference in spine growth compared with the predicted spine growth on the basis of previously published models using photons, but with a clinically insignificant faster spine growth rate in the anterior lumbar spine.

To evaluate the long-term bowel-associated quality of life (QOL) in men after radiotherapy (RT) for prostate cancer with and without the use of rectal hydrogel spacer.The patients' QOL was examined using the Expanded Prostate Cancer Index Composite (EPIC) and mean changes from baseline in EPIC domains were evaluated. A total of 215 patients from a randomised multi-institutional trial of RT, with or without hydrogel spacer, with a QOL endpoint were pooled with 165 non-randomised patients from a single institution with prospective QOL collection in patients with or without hydrogel spacer. The proportions of men with minimally important differences (MIDs) relative to pre-treatment baseline in the bowel domain were tested using repeated measure logistic models with a pre-specified threshold for clinically significant declines (≥5 equivalent to MIDx1 and ≥10 equivalent to MIDx2).A total of 380 men were evaluated (64% with spacer and 36% without) with QOL data being available for 199 men with24 months of follow-up [median (range) 39.5 (31-71.4) months]. Treatment with spacer was associated with less decline in average long-term bowel QOL (89.4 for control and 94.7 for spacer) with differences at24 months meeting the threshold of a MID difference between cohorts (bowel score difference from baseline: control = -5.1, spacer = 0.3, difference = -5.4; P 0.001). When evaluated over time men without spacer were more likely to have MIDx1 (5 points) declines in bowel QOL (P = 0.01). At long-term follow-up MIDx1 was 36% without spacer vs 14% with spacer (P 0.001; odds ratio [OR] 3.5, 95% CI 1.7-6.9) while MIDx2 was seen in 19% vs 6% (P = 0.008; OR 3.6, 95% CI 1.4-9.1). The use of spacer was associated with less urgency with bowel movements (P = 0.002) and fewer loose stools (P = 0.009), as well as less bother with urgency (P = 0.007) and frequency of bowel movements (P = 0.009).In this pooled analysis of QOL after prostate RT with up to 5 years of follow-up, use of a rectal spacer was associated with preservation of bowel QOL. This QOL benefit was preserved with long-term follow-up.

Objective To provide an update on SpaceOAR System, a Food and Drug Administration–approved hydrogel indicated to create distance between the prostate and the rectum which has been studied in phase 2 and 3 clinical trials. Here, we review and summarize these clinical results including the safety of prostate-rectum spacer application technique, the implant quality and resulting rectal dose reduction, acute and long-term rectal, urinary, and sexual toxicity, as well as patient-reported outcomes. Materials and Methods A prospective, randomized patient-blinded clinical study was performed comparing image-guided intensity modulated prostate radiotherapy (79.2 Gy in 44 fractions) in men with or without prostate-rectum hydrogel spacer. Patients were followed up for 3 years, allowing assessment of long-term safety and efficacy. Results Spacer application was well tolerated with a 99% technical success rate. The mean additional space created between the prostate and the rectum was just over 1 cm, which allowed significant rectum and penile bulb radiation dose reduction, resulting in less acute pain, lower rates of late rectal toxicity, and improved bowel and urinary quality of life (QOL) scores from 6 months onward. Improvements in sexual QOL were also observed at 37 months in baseline-potent men, with 37.5% of control and 66.7% of spacer men capable of “erections sufficient for intercourse.” Conclusion Prostate-rectum hydrogel spacer application is a relatively safe technical procedure that is well tolerated and has a high technical success rate. Spacer application significantly reduces rectal radiation dose and results in long-term reductions in rectal toxicity, as well as improvements in bowel, urinary, and sexual QOL.

Commissioning a new treatment planning system (TPS) involves many time-consuming tasks. We investigated the role that knowledge-based planning (KBP) can play in aiding a clinic's transition to a new TPS. Sixty clinically treated prostate/prostate bed intensity-modulated radiation therapy (IMRT) plans were exported from an in-house TPS and were used to create a KBP model in a newly implemented commercial application. To determine the benefit that KBP may have in a TPS transition, the model was tested on 2 groups of patients. Group 1 consisted of the first 10 prostate/prostate bed patients treated in the commercial TPS after the transition from the in-house TPS. Group 2 consisted of 10 patients planned in the commercial TPS after 8 months of clinical use. The KBP-generated plan was compared with the clinically used plan in terms of plan quality (ability to meet planning objectives and overall dose metrics) and planning efficiency (time required to generate clinically acceptable plans). The KBP-generated plans provided a significantly improved target coverage (p = 0.01) compared with the clinically used plans for Group 1, but yielded plans of comparable target coverage to the clinically used plans for Group 2. For the organs at risk, the KBP-generated plans produced lower doses, on average, for every normal-tissue objective except for the maximum dose to 0.1 cc of rectum. The time needed for the KBP-generated plans ranged from 6 to 15 minutes compared to 30 to 150 and 15 to 60 minutes for manual planning in Groups 1 and 2, respectively. KBP is a promising tool to aid in the transition to a new TPS. Our study indicates that high-quality treatment plans could have been generated in the newly implemented TPS more efficiently compared with not using KBP. Even after 8 months of the clinical use, KBP still showed an increase in plan quality and planning efficiency compared with manual planning.

Objective To elucidate the functional erection rate after prostate stereotactic body radiotherapy (SBRT) and to develop a comprehensive prognostic model of outcomes after treatment. Patients and Methods Between 2008 and 2013, 373 consecutive men with localized prostate cancer were treated with SBRT at a single academic institution as part of a prospective clinical trial or prospective registry. Prospective longitudinal patient-reported health-related quality of life (HRQoL) data was collected using the Expanded Prostate Cancer Index Composite (EPIC)-26 instrument. Functional erections were strictly defined as ‘firm enough for intercourse’ according to EPIC-26. Detailed comorbidity data were also collected. Logistic regression models were used to predict 24- and 60-month functional erection rates. Observed erection rates after SBRT were compared with those after other radiation therapies (external beam radiation therapy [EBRT] and brachytherapy) using prospectively validated models. Results The median (interquartile range) follow-up was 56 (37–73) months and the response rate at 2 years was 84%. For those with functional erections at baseline, 57% and 45% retained function at 24 and 60 months, respectively. On multivariable analysis for 24-month erectile function, significant variables included higher baseline sexual HRQoL (adjusted odds ratio [aOR] 1.55 per 10 points, 95% confidence interval [CI] 1.37–1.74; P < 0.001) and older age (aOR 0.66 per 10 years, 95% CI 0.43–1.00; P = 0.05). At 60 months, baseline HRQoL and age remained associated with erectile function, along with body mass index (aOR 0.45, 95% CI 0.26–0.78; P < 0.001). The 24- and 60-month models had excellent discrimination (c-index 0.81 and 0.84, respectively). Erection rates after SBRT were not statistically different from model-predicted rates after EBRT or brachytherapy for the whole cohort and the cohort with baseline erectile function. Conclusions Intermediate- to long-term post-SBRT erectile function results are promising and not significantly different from other radiotherapy techniques. Clinicians can use our prognostic model to counsel patients regarding expected erectile function after SBRT.

SpaceOAR, a Food and Drug Administration-approved hydrogel intended to create a rectal-prostate space, was evaluated in a single-blind phase III trial of image guided intensity modulated radiation therapy. A total of 222 men were randomized 2:1 to the spacer or control group and received 79.2 Gy in 1.8-Gy fractions to the prostate with or without the seminal vesicles. The present study reports the final results with a median follow-up period of 3 years.Cumulative (Common Terminology Criteria for Adverse Events, version 4.0) toxicity was evaluated using the log-rank test. Quality of life (QOL) was examined using the Expanded Prostate Cancer Index Composite (EPIC), and the mean changes from baseline in the EPIC domains were tested using repeated measures models. The proportions of men with minimally important differences (MIDs) in each domain were tested using repeated measures logistic models with prespecified thresholds.The 3-year incidence of grade ≥1 (9.2% vs 2.0%; P=.028) and grade ≥2 (5.7% vs 0%; P=.012) rectal toxicity favored the spacer arm. Grade ≥1 urinary incontinence was also lower in the spacer arm (15% vs 4%; P=.046), with no difference in grade ≥2 urinary toxicity (7% vs 7%; P=0.7). From 6 months onward, bowel QOL consistently favored the spacer group (P=.002), with the difference at 3 years (5.8 points; P.05) meeting the threshold for a MID. The control group had a 3.9-point greater decline in urinary QOL compared with the spacer group at 3 years (P.05), but the difference did not meet the MID threshold. At 3 years, more men in the control group than in the spacer group had experienced a MID decline in bowel QOL (41% vs 14%; P=.002) and urinary QOL (30% vs 17%; P=.04). Furthermore, the control group were also more likely to have experienced large declines (twice the MID) in bowel QOL (21% vs 5%; P=.02) and urinary QOL (23% vs 8%; P=.02).The benefit of a hydrogel spacer in reducing the rectal dose, toxicity, and QOL declines after image guided intensity modulated radiation therapy for prostate cancer was maintained or increased with a longer follow-up period, providing stronger evidence for the benefit of hydrogel spacer use in prostate radiation therapy.

BACKGROUND Atypical teratoid/rhabdoid tumors (AT/RTs) are rare aggressive central nervous system tumors. The use of radiation therapy (RT) remains controversial, especially for patients younger than three years of age. The purpose of the current investigation is to robustly analyze the impact of RT among pediatric AT/RT patients using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS SEER 18 Custom Data registries were queried for AT/RT (ICD-0-3 9508/3). A total of 190 pediatric AT/RT patients were identified, of whom 102 underwent surgery + chemotherapy and 88 underwent trimodality therapy. Univariate and multivariable analyses using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment weighting was performed to account for indication bias. The landmark method was used to account for immortal time bias. RESULTS The majority of patients were

Purpose We sought to develop a quality surveillance program for approximately 15,000 US veterans treated at the 40 radiation oncology facilities at the Veterans Affairs (VA) hospitals each year. Methods and Materials State-of-the-art technologies were used with the goal to improve clinical outcomes while providing the best possible care to veterans. To measure quality of care and service rendered to veterans, the Veterans Health Administration established the VA Radiation Oncology Quality Surveillance program. The program carries forward the American College of Radiology Quality Research in Radiation Oncology project methodology of assessing the wide variation in practice pattern and quality of care in radiation therapy by developing clinical quality measures (QM) used as quality indices. These QM data provide feedback to physicians by identifying areas for improvement in the process of care and identifying the adoption of evidence-based recommendations for radiation therapy. Results Disease-site expert panels organized by the American Society for Radiation Oncology (ASTRO) defined quality measures and established scoring criteria for prostate cancer (intermediate and high risk), non-small cell lung cancer (IIIA/B stage), and small cell lung cancer (limited stage) case presentations. Data elements for 1567 patients from the 40 VA radiation oncology practices were abstracted from the electronic medical records and treatment management and planning systems. Overall, the 1567 assessed cases passed 82.4% of all QM. Pass rates for QM for the 773 lung and 794 prostate cases were 78.0% and 87.2%, respectively. Marked variations, however, were noted in the pass rates for QM when tumor site, clinical pathway, or performing centers were separately examined. Conclusions The peer-review protected VA-Radiation Oncology Surveillance program based on clinical quality measures allows providers to compare their clinical practice to peers and to make meaningful adjustments in their personal patterns of care unobtrusively.

BACKGROUND/PURPOSE: Stratification of Gleason score (GS) into three categories (2-6, 7, and 8-10) may not fully utilize its prognostic discrimination, with Gleason Pattern 5 (GP5) previously identified as an independent adverse factor. MATERIALS/METHODS: Patients treated on RTOG 9202 (n = 1292) or RTOG 9902 (n = 378) were pooled and assessed for association of GS and GP5 on biochemical failure (BF), local failure (LF), distant metastasis (DM), and overall survival (OS). Fine and Gray’s regression and cumulative incidence methods were used for univariate and multivariate analyses. RESULTS: With median follow-up of 9.4 years, patients with GS 8-10 with GP5 had worse outcome than GS 4+4 for DM on both RTOG9202 (p=0.038) and RTOG9902 (p

We applied an established prognostic model to high-risk prostate cancer (HRPC) patients treated with radiotherapy (RT) and evaluated the influence of clinical and treatment variables on treatment outcomes.In total, 1075 HRPC patients undergoing definitive radiotherapy (RT) between 1995 and 2010 were retrospectively reviewed. Median follow-up was 62.3 months. Patients received either dose-escalated external beam radiotherapy (n=628, EBRT) or combined-modality radiotherapy (n=447, pelvic RT and low-dose rate brachytherapy boost, CMRT). 82.9% received androgen-deprivation therapy (ADT). A prognostic model stratified patients into predefined groups (good, intermediate, and poor). Kaplan-Meier methods and Cox proportional hazards regressions assessed biochemical failure (BF), distant metastasis (DM), prostate cancer-specific mortality (PCSM) and overall mortality (OM). C-indices analyzed predictive value.The model was prognostic; C-indices for BF, DM, PCSM and OM were: 0.62, 0.64, 0.61, and 0.57. On multivariate analysis, CMRT and longer ADT (≥24 mo) were associated with improved BF, DM, and PCSM. Gleason score (GS) 9-10 was the strongest predictor of PCSM. C-indices for BF, DM, PCSM, and OM using a 4-compartment model incorporating GS 9-10 were: 0.62, 0.65, 0.68, and 0.56. In poor-prognosis patients (GS 8-10+additional risk factors), CMRT+LTADT (12 mo) had 10-year PCSM (3.7%±3.6%), comparing favorably to 25.8%±9.2% with EBRT+LTADT.The model applies to high-risk RT patients; GS 9-10 remains a powerful predictor of PCSM. Comparing similar prognosis patients, CMRT is associated with improved disease-specific outcomes relative to EBRT. In poor-prognosis patients, CMRT+LTADT yields superior 10-year PCSM, potentially improving RT treatment personalization for those with HRPC.

214 Background: Multiple authorities including an NCI Taskforce have recommended routine evaluation of patient reported outcomes (PRO) in cancer care. The Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) is a single-page quality-of-life (QOL) tool which is easily integrated into routine clinical practice. The EPIC-CP has 5 domains (each scored 0-12). The present study evaluated whether early clinically significant changes in EPIC-CP were correlated with later changes in patients undergoing definitive radiotherapy (RT) for prostate cancer. Methods: A cohort of 979 patients including the PROSTQA study and 3 other institutions with prospective QOL data pooled for analysis were evaluated for patient-reported outcomes. Patients were treated with definitive low-dose rate brachytherapy (n=284), intensity-modulated RT (n=251), or stereotactic body RT (n=444). EPIC-CP scores were derived based upon responses to the EPIC-26. Data were evaluated using minimal clinically important difference (MCID) thresholds to compare QOL at 1-2 months and 24 months from baseline. Univariate analysis was used to assess the correlation between early and late MCID changes. Results: On univariate analysis, early ≥1 MCID change from baseline was strongly associated with a late ≥1 MCID across all 5 domains (urinary incontinence, urinary irritation/obstruction, bowel, sexual, and vitality/hormonal) within EPIC-CP and for the overall EPIC-CP score (Table). When MCID was instead defined as 1 or 3, early toxicity remained predictive of late toxicity for all domains and the overall EPIC-CP score. Conclusions: The EPIC-CP is an easy-to-use QOL assessment with clinically relevant outcomes. Early QOL decline was strongly associated with late QOL decline in patients undergoing definitive RT for prostate cancer across all EPIC-CP domains. Patients with early QOL decline may be candidates for early QOL-based interventions to alleviate their late toxicity burden from treatment. [Table: see text]

BACKGROUND Stereotactic body radiation therapy (SBRT) for localized prostate cancer involves high-dose-per-fraction radiation treatments. Its use is increasing, but concerns remain about treatment-related toxicity. The authors assessed the incidence and predictors of a global decline in health-related quality of life (HRQOL) after prostate SBRT. METHODS From 2008 to 2014, 713 consecutive men with localized prostate cancer received treatment with SBRT according to a prospective institutional protocol. Expanded Prostate Cancer Index Composite (EPIC-26) HRQOL data were collected at baseline and longitudinally for 5 years. EPIC-26 is comprised of 5 domains. The primary endpoint was defined as a decline exceeding the clinically detectable threshold in ≥4 EPIC-26 domains, termed multidomain decline. RESULTS The median age was 69 years, 46% of patients had unfavorable intermediate-risk or high-risk disease, and 20% received androgen-deprivation therapy. During 1 to 3 months and 6 to 60 months after SBRT, 8% to 15% and 10% to 11% of patients had multidomain declines, respectively. On multivariable analysis, lower baseline bowel HRQOL (odds ratio, 1.8; 95% confidence interval, 1.2-2.7; P < .01) and baseline depression (odds ratio, 5.7; 95% confidence interval, 1.3-24.3; P = .02) independently predicted for multidomain decline. Only 3% to 4% of patients had long-term multidomain declines exceeding twice the clinical threshold, and 30% of such declines appeared to be related to prostate cancer treatment or progression of disease. CONCLUSIONS Prostate SBRT has minimal long-term impact on multidomain decline, and the majority of more significant multidomain declines appear to be unrelated to treatment. This emphasizes the importance of focusing not only on the side effects of prostate cancer treatment but also on other comorbid illnesses that contribute to overall HRQOL. Cancer 2017;123:1635-1642. © 2017 American Cancer Society.

Purpose To determine whether a dose-response relationship exists for salvage radiation therapy (RT) of biochemical failure after prostatectomy for prostate cancer. Methods and Materials Individual data from 1108 patients who underwent salvage RT at 10 academic centers were pooled. The cohort was enriched for selection criteria more likely associated with tumor recurrence in the prostate bed (margin positive and pre-RT prostate-specific antigen [PSA] level of ≤2.0 ng/mL) and without the confounding of planned androgen suppression. The cumulative incidence of biochemical failure and distant metastasis over time was computed, and competing risks hazard regression models were used to investigate the association between potential predictors and these outcomes. The association of radiation dose with outcomes was the primary focus. Results With a 65.2-month follow-up duration, the 5- and 10-year estimates of freedom from post-RT biochemical failure (PSA level >0.2 ng/mL and rising) was 63.5% and 49.8%, respectively, and the cumulative incidence of distant metastasis was 12.4% by 10 years. A Gleason score of ≥7, higher pre-RT PSA level, extraprostatic tumor extension, and seminal vesicle invasion were associated with worse biochemical failure and distant metastasis outcomes. A salvage radiation dose of ≥66.0 Gy was associated with a reduced cumulative incidence of biochemical failure, but not of distant metastasis. Conclusions The use of salvage radiation doses of ≥66.0 Gy are supported by evidence presented in the present multicenter pooled analysis of individual patient data. The observational reporting method, limited sample size, few distant metastasis events, modest follow-up duration, and elective use of salvage therapy might have diminished the opportunity to identify an association between the radiation dose and this endpoint.

Safe maximal surgical resection is the initial treatment of choice for pediatric brainstem low-grade gliomas. Optimal therapy for incompletely resected tumors or that progress after surgery is uncertain. We reviewed the clinical characteristics, therapy, and outcomes of all children with nontectal brainstem low-grade gliomas treated at the University of Michigan between 1993 and 2013. Median age at diagnosis was 6 years; histology was confirmed in 23 of 25 tumors, 64% were pilocytic astrocytoma. Nineteen patients underwent initial tumor resection; 14/19 received no upfront adjuvant therapy. Eight patients in the study had progressive disease; 5 initially resected tumors received chemotherapy at tumor relapse, all with partial or complete radiographic responses. Ten-year progression-free survival is 71% and overall survival, 100%. This single-institution retrospective study demonstrates excellent survival rates for children with brainstem low-grade gliomas. The efficacy of the well-tolerated chemotherapy in this series supports its role in the treatment of unresectable or progressive brainstem low-grade gliomas.

Purpose The new short Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) patient-reported health-related quality of life (HRQOL) tool has removed the rectal bleeding question from the previous much longer version, EPIC-26. Herein, we assess the impact of losing the dedicated rectal bleeding question in 2 independent prospective multicenter cohorts. Methods and Materials In a prospective multicenter test cohort (n=865), EPIC-26 patient-reported HRQOL data were collected for 2 years after treatment from patients treated with prostate radiation therapy from 2003 to 2011. A second prospective multicenter cohort (n=442) was used for independent validation. A repeated-effects model was used to predict the change from baseline in bowel summary scores from longer EPIC instruments using the change in EPIC-CP bowel summary scores with and without rectal bleeding scores. Results Two years after radiation therapy, 91% of patients were free of bleeding, and only 2.6% reported bothersome bleeding problems. Correlations between EPIC-26 and EPIC-CP bowel scores were very high ( r 2 =0.90-0.96) and were statistically improved with the addition of rectal bleeding information ( r 2 =0.94-0.98). Considering all patients, only 0.2% of patients in the test cohort and 0.7% in the validation cohort reported bothersome bleeding and had clinically relevant HRQOL changes missed with EPIC-CP. However, of the 2.6% (n=17) of men with bothersome rectal bleeding in the test cohort, EPIC-CP failed to capture 1 patient (6%) as experiencing meaningful declines in bowel HRQOL. Conclusions Modern prostate radiation therapy results in exceptionally low rates of bothersome rectal bleeding, and

Purpose We aimed to update a previously published, multi-institutional nomogram of outcomes for salvage radiotherapy (SRT) following radical prostatectomy (RP) for prostate cancer, including patients treated in the contemporary era. Methods Individual data from node-negative patients with a detectable post-RP prostate-specific antigen (PSA) treated with SRT with or without concurrent androgen-deprivation therapy (ADT) were obtained from 10 academic institutions. Freedom from biochemical failure (FFBF) and distant metastases (DM) rates were estimated, and predictive nomograms were generated. Results Overall, 2,460 patients with a median follow-up of 5 years were included; 599 patients (24%) had a Gleason score (GS) ≤ 6, 1,387 (56%) had a GS of 7, 244 (10%) had a GS of 8, and 230 (9%) had a GS of 9 to 10. There were 1,370 patients (56%) with extraprostatic extension (EPE), 452 (18%) with seminal vesicle invasion (SVI), 1,434 (58%) with positive surgical margins, and 390 (16%) who received ADT (median, 6 months). The median pre-SRT PSA was 0.5 ng/mL (interquartile range, 0.3 to 1.1). The 5-yr FFBF rate was 56% overall, 71% for those with a pre-SRT PSA level of 0.01 to 0.2 ng/mL (n = 441), 63% for those with a PSA of 0.21 to 0.50 ng/mL (n = 822), 54% for those with a PSA of 0.51 to 1.0 ng/mL (n = 533), 43% for those with a PSA of 1.01 to 2.0 ng/mL (n = 341), and 37% for those with a PSA > 2.0 ng/mL (n = 323); P < .001. On multivariable analysis, pre-SRT PSA, GS, EPE, SVI, surgical margins, ADT use, and SRT dose were associated with FFBF. Pre-SRT PSA, GS, SVI, surgical margins, and ADT use were associated with DM, whereas EPE and SRT dose were not. The nomogram concordance indices were 0.68 (FFBF) and 0.74 (DM). Conclusion Early SRT at low PSA levels after RP is associated with improved FFBF and DM rates. Contemporary nomograms can estimate individual patient outcomes after SRT in the modern era.

There has been a recent proposal to change the grading system of prostate cancer into a five-tier grade grouping system. The prognostic impact of this has been demonstrated in regards only to biochemical recurrence-free survival (bRFS) with short follow-up (3 years).Between 1990 and 2013, 847 consecutive men were treated with definitive external beam radiation therapy at a single academic center. To validate the new grade grouping system, bRFS, distant metastases-free survival (DMFS) and prostate cancer-specific survival (PCSS) were calculated. Adjusted Kaplan-Meier and multivariable Cox regression analyses were performed to assess the independent impact of the new grade grouping system. Discriminatory analyses were performed to compare the commonly used three-tier Gleason score system (6, 7 and 8-10) to the new system.The median follow-up of our cohort was 88 months. The 5-grade groups independently validated differing risks of bRFS (group 1 as reference; adjusted hazard ratio (aHR) 1.35, 2.16, 1.79 and 3.84 for groups 2-5, respectively). Furthermore, a clear stratification was demonstrated for DMFS (aHR 2.03, 3.18, 3.62 and 13.77 for groups 2-5, respectively) and PCSS (aHR 3.00, 5.32, 6.02 and 39.02 for groups 2-5, respectively). The 5-grade group system had improved prognostic discrimination for all end points compared with the commonly used three-tiered system (that is, Gleason score 6, 7 and 8-10).In a large independent radiotherapy cohort with long-term follow-up, we have validated the bRFS benefit of the proposed five-tier grade grouping system. Furthermore, we have demonstrated that the system is highly prognostic for DMFS and PCSS. Grade group 5 had markedly worse outcomes for all end points, and future work is necessary to improve outcomes in these patients.

Objectives The aim of this study was to report treatment outcomes in patients with very high-risk prostate cancer (VHRPC) treated with dose-escalated radiotherapy. Methods We conducted a retrospective multi-institutional review on patients with VHRPC (those with at least 2 high-risk factors of prostate-specific antigen >20 ng/mL, Gleason score 8 to 10, or clinical T3 to T4 stage), treated with either dose-escalated external-beam radiotherapy (EBRT) or combined-modality radiotherapy (CMRT) consisting of pelvic irradiation and permanent interstitial brachytherapy. Results A total of 238 patients with VHRPC were identified. Of them, 69% of patients received EBRT and 31% received CMRT; 88% received androgen-deprivation therapy (ADT), 56% for ≥24 months (long-term ADT). The majority (69%) of patients were above 65 years old and were less likely to receive CMRT than younger patients (25% vs. 43%, P=0.006), although they did not differ from younger patients in tumor characteristics. Median follow-up was 61 months (interquartile range, 38 to 93 mo). Biochemical progression-free survival (BPFS), distant metastasis-free survival (DMFS), and cancer-specific survival (CSS) for all patients at 8 years were (±SE): 50.6%±4.7%, 68.5%±4.3%, 78.7%±3.8%, respectively, and were similar for patients 65 years and below versus above 65 years old (BPFS: HR=0.88, P=0.56; DMFS: HR=0.79, P=0.40; CSS HR=0.99, P=0.99). After adjustment for patient, tumor, and treatment-related covariates on multivariate analysis, CMRT was associated with improved BPFS (HR=0.44, P=0.012) with trends for DMFS (HR=0.52, P=0.10) and CSS (HR=0.55, P=0.21), whereas long-term ADT was independently associated with improved BPFS (HR=0.40, P=0.019), CSS (HR=0.20, P=0.002), and PCSM (HR=0.25, P=0.004). Conclusions Dose-escalated EBRT or CMRT with long-term ADT resulted in favorable clinical outcomes for patients with VHRPC.

OBJECTIVES To assess the performance of the Cancer of the Prostate Risk Assessment (CAPRA) prognostic tool for freedom-from-metastases (FFM) and cause-specific survival (CSS) in patients with localized prostate cancer treated with definitive external beam radiotherapy (EBRT), and to determine whether the performance of CAPRA is influenced by androgen deprivation therapy (ADT) use or the presence of Gleason pattern 5 (GP-5). MATERIALS AND METHODS A total of 612 patients from a prospective database of 718 patients treated with dose-escalated EBRT from 1998 to 2008 who met CAPRA scoring criteria were included in the study. Performance of CAPRA and association of CAPRA score, GP-5 and short-term or long-term ADT use (STAD or LTAD, respectively) with FFM and CSS were evaluated using Cox models. The impact of ADT use on accuracy of the CAPRA-based CaPSURE model for CSS was assessed. The discriminatory ability of the CAPRA model and modified models incorporating GP-5 and ADT use were compared using the C-index. RESULTS Increasing CAPRA score correlated with worse FFM and CSS, and was prognostic for FFM and CSS for the overall cohort. CAPRA showed poorer discrimination for FFM and CSS in patients treated with EBRT+LTAD than those who received EBRT alone or EBRT+STAD. The addition of GP-5 and ADT use to CAPRA score increased the predictive accuracy of the CAPRA model for both FFM (C-index 0.809 vs. 0.779, P

Background In prostate cancer, end points that reliably portend prognosis and treatment benefit (surrogate end points) can accelerate therapy development. Although surrogate end point candidates have been evaluated in the context of radiotherapy and short-term androgen deprivation (AD), potential surrogates under long-term (24 month) AD, a proven therapy in high-risk localized disease, have not been investigated. Materials and Methods In the NRG/RTOG 9202 randomized trial (N = 1,520) of short-term AD (4 months) versus long-term AD (LTAD; 28 months), the time interval free of biochemical failure (IBF) was evaluated in relation to clinical end points of prostate cancer–specific survival (PCSS) and overall survival (OS). Survival modeling and landmark analysis methods were applied to evaluate LTAD benefit on IBF and clinical end points, association between IBF and clinical end points, and the mediating effect of IBF on LTAD clinical end point benefits. Results LTAD was superior to short-term AD for both biochemical failure (BF) and the clinical end points. Men remaining free of BF for 3 years had relative risk reductions of 39% for OS and 73% for PCSS. Accounting for 3-year IBF status reduced the LTAD OS benefit from 12% (hazard ratio [HR], 0.88; 95% CI, 0.79 to 0.98) to 6% (HR, 0.94; 95% CI, 0.83 to 1.07). For PCSS, the LTAD benefit was reduced from 30% (HR, 0.70; 95% CI, 0.52 to 0.82) to 6% (HR, 0.94; 95% CI, 0.72 to 1.22). Among men with BF, by 3 years, 50% of subsequent deaths were attributed to prostate cancer, compared with 19% among men free of BF through 3 years. Conclusion The IBF satisfied surrogacy criteria and identified the benefit of LTAD on disease-specific survival and OS. The IBF may serve as a valid end point in clinical trials and may also aid in risk monitoring after initial treatment.

Background Limited data exist to guide the use of androgen deprivation therapy (ADT) for men treated with radiation therapy (RT) after radical prostatectomy (RP). The optimal duration of ADT in this setting is unknown. Objective To determine if the duration of ADT influences clinical outcomes for men receiving post-RP RT. Design, setting, and participants A total of 680 men who received adjuvant radiation therapy ( n =105) or salvage radiation therapy ( n =575) between 1986 and 2010 at a single tertiary care institution were reviewed retrospectively. Median follow-up post-RT was 57.8 mo. Intervention RT was delivered using three-dimensional conformal or intensity-modulated RT in 1.8-Gy fractions. For patients treated with ADT, >80% were treated with a gonadotropin-releasing hormone agonist with or without a nonsteroidal antiandrogen. Outcome measurements and statistical analysis Biochemical failure (BF), distant metastasis (DM), prostate cancer–specific mortality (PCSM), and overall mortality were assessed using Kaplan-Meier analysis and propensity score analysis. Results and limitations Overall, 144 patients (21%) received ADT with post-RP RT, most of whom had high-risk disease features such as Gleason score 8–10, seminal vesicle invasion, or pre-RT prostate-specific antigen >1 ng/ml. Median ADT duration was 12 mo (interquartile range: 6.0–23.7). Patients who received p =0.003) and DM (HR: 2.48; p =0.03) compared with patients receiving ≥12 mo of ADT. The 5-yr rates of DM were 6.0% and 23% for ≥12 and p =0.0004), DM (HR: 0.88; p =0.0004), and PCSM (HR: 0.90; p =0.037). These findings are limited by the retrospective nature of our analysis. Conclusions For men with high-risk disease features receiving ADT with post-RP RT, the duration of ADT is associated with clinical outcomes. Our findings suggest that for these men an extended course of ADT ≥12 mo may be preferable. Validation of our findings is needed. Patient summary We evaluated outcomes for men with high-risk disease features treated with androgen deprivation therapy (ADT) and radiotherapy after radical prostatectomy. Longer durations of ADT resulted in improved patient outcomes.

Purpose/Objective(s) We sought to assess the utility of docetaxel administered concurrently with salvage radiation therapy (SRT) following postprostatectomy biochemical failure (BF). Methods and materials Men with postprostatectomy BF were accrued on a single-arm phase 2 clinical trial. SRT doses ranged from 64.8 to 70.2 Gy and were delivered in 1.8-Gy fractions to the prostate bed alone as the clinical target volume with a +1-cm uniform planning target volume expansion. The primary endpoint was progression-free survival at 4 years compared with the Stephenson nomogram estimate. Kaplan-Meier methods were used to assess late toxicity, BF, and distant metastases. An unplanned matched-pair analysis was performed with 19 patients treated with SRT alone. Results Nineteen men were accrued and treated. Median follow-up was 4.8 years. Median pre-RT prostate-specific antigen level was 0.7 ng/mL (interquartile range, 0.4-1.3 ng/mL). All 8 cycles of docetaxel were completed in 17 (89%) patients. Acute grade 1-4 toxicities were observed in 79%, 50%, 58%, and 11%, respectively. A total of 68% of acute grade 1 toxicities were related to fatigue, urinary, or bowel symptoms. For grade 2 toxicities, 76% were related to neutropenia, fatigue, or urinary symptoms. Acute grade 3 and 4 toxicities were most commonly neutropenia (84% and 100%, respectively). All late toxicities were grade 1 to 2 with 89% related to bowel or urinary function. Predicted 4-year progression-free survival was 39% and observed was 42% (90% confidence interval [CI], 24-60). Matched-pair analysis demonstrated no significant improvement in BF ( P = .96, hazard ratio, 0.98; 90% CI, 0.4-2.3) or distant metastases ( P = .09; hazard ratio, 0.3; 90% CI, 0.07-1.2), and no difference between late bowel ( P = .60) or urinary toxicity ( P = .41). Conclusions Docetaxel can safely be administered concurrently with SRT without significantly impacting posttreatment toxicity. Neutropenia was the most significant acute toxicity. Given the small sample size, no clear clinical benefit was observed. Larger studies are needed to determine the efficacy of concurrent docetaxel in this setting.