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Objectives To test the validity of preoperative prostate-specific antigen velocity (PSAV) (the rate of PSA rise before diagnosis) as a predictor for relapse after radical prostatectomy, in the context of patient obesity as measured by body mass index (BMI). Methods The rates of biochemical relapse were examined among 215 patients who underwent radical prostatectomy between 1992 and 2005. Kaplan-Meier relapse rates as a function of preoperative PSAV 2 ng/mL/yr or less versus greater than 2 ng/mL/yr were compared in two groups: nonobese patients (normal to overweight, BMI less than 30 kg/m 2 ) and obese patients (mild to severely obese, BMI 30 kg/m 2 or greater). Results A preoperative PSAV greater than 2 ng/mL/yr was associated with higher relapse rates after radical prostatectomy compared with a PSAV of 2 ng/mL/yr or less, with 5-year relapse-free survival rates of 60% versus 70%, respectively ( P = 0.03). Prostate-specific antigen velocity was independently significant on multivariate analysis, along with biopsy Gleason score, percent positive cores, and BMI. In this study 24% of patients were obese. Prostate-specific antigen velocity greater than 2 ng/mL/yr was associated with higher relapse rates in nonobese patients ( P = 0.01) but not in obese patients ( P = 0.9). The two BMI groups did not differ with respect to any factors. Obese patients with slowly rising PSA (PSAV 2 ng/mL/yr or less) fared just as poorly as nonobese patients with rapidly rising PSA (PSAV greater than 2 ng/mL/yr). Obesity was independently associated with higher relapse rates. Conclusions Preoperative PSAV greater than 2 ng/mL/yr was associated with a higher risk of relapse after radical prostatectomy, but its clinical usefulness might be limited to nonobese patients. Obesity conferred higher relapse rates, regardless of other prognostic factors including preoperative PSAV.

PurposeIntegrating ultrasensitive prostate specific antigen with surveillance in patients at high risk after radical prostatectomy potentially optimizes treatment by correctly identifying recurrence, promoting an early salvage strategy and minimizing overtreatment. We tested the power of postoperative ultrasensitive prostate specific antigen to identify eventual biochemical failure.Materials and methodsWe identified 247 patients at high risk with a median followup of 44 months who underwent radical prostatectomy from 1991 to 2013. Each patient had extraprostatic extension and/or a positive margin. Surgical technique, initial prostate specific antigen, pathology findings and postoperative prostate specific antigen were analyzed. The ultrasensitive prostate specific antigen assay threshold was 0.01 ng/ml. Conventional biochemical relapse was defined as prostate specific antigen 0.2 ng/ml or greater. Kaplan-Meier and Cox multivariate analyses were done to compare the rates of ultrasensitive prostate specific antigen recurrence and conventional biochemical relapse.ResultsSensitivity analysis revealed that ultrasensitive prostate specific antigen 0.03 ng/ml or greater was the optimal threshold to identify recurrence. A first postoperative ultrasensitive value of 0.03 ng/ml or greater, Gleason grade, T stage, initial prostate specific antigen and margin status predicted conventional biochemical relapse. On multivariate analysis only a first postoperative ultrasensitive value of 0.03 ng/ml or greater, Gleason grade and T stage independently predicted conventional biochemical relapse. First postoperative ultrasensitive prostate specific antigen 0.03 ng/ml or greater conferred the highest risk (HR 8.5, p < 0.0001) and identified conventional biochemical relapse with greater sensitivity than undetectable first conventional prostate specific antigen (70% vs 46%). Any postoperative prostate specific antigen 0.03 ng/ml or greater captured all failures missed by the first postoperative value (100% sensitivity) with accuracy (96% specificity). Defining failure at an ultrasensitive value of 0.03 ng/ml or greater yielded a median lead time advantage of 18 months (mean 24) over the conventional definition of prostate specific antigen 0.2 ng/ml or greater.ConclusionsUltrasensitive prostate specific antigen 0.03 ng/ml or greater is an independent factor that identifies biochemical relapse more accurately than any traditional risk factors and confers a significant lead time advantage. This factor enables critical decisions on the timing of and indication for postoperative radiotherapy in patients at high risk after radical prostatectomy.

Background With sextant prostate biopsies, there is up to a 1-in-3 chance that the underlying pathologic Gleason grade is higher. Knowledge of the underlying grade might have significantly altered the therapeutic recommendations and management for patients electing radiotherapy for localized prostate cancer (e.g., eligibility for brachytherapy, androgen suppression with external beam radiotherapy, elective pelvic radiotherapy). This study examines the concordance patterns between biopsy and matched radical prostatectomy Gleason grade among patients undergoing an extended 10-core biopsy scheme to assess its reliability compared to sextant biopsies. Methods and materials Seventy-eight consecutive patients underwent an extended 10-core peripheral zone biopsy scheme (sextant plus two lateral mid and two lateral base biopsies) and subsequent radical prostatectomy at this institution between mid-2000 and mid-2003. No patient received androgen suppression. All histologic grading were made by a single pathologist (J.E.M.). Needle biopsies were characterized for location, linear involvement of cancer within positive cores, and total number of positive cores. Radical prostatectomy specimens were step-sectioned at 3-mm intervals and were characterized for total cancer volume and percentage of each Gleason grade present. Clinical parameters available included digital rectal exam, preoperative PSA, and ultrasound prostate volume. A "clinically significant" upgrading of the biopsy was defined as any of the following: (1) a biopsy Gleason score (bGS) of 6 to a pathologic GS (pGS) of 7 or higher, (2) a bGS 3 + 4 to a pGS of 4 + 3 or higher, and (3) a bGS of 7 to a pGS of 8 or higher. Statistical analyses were performed on the patterns Gleason score concordance between biopsies and matched radical prostatectomies. Results An exact Gleason score match between biopsy and prostatectomy was observed in 62% of patients using the sextant biopsy scheme (SB), an upgrading of 1 or more grade points was seen in 25% and a downgrading of 1 or more points in 13% for SB. These rates of grade discordance are comparable to those of published sextant series. An exact match using the extended biopsy scheme (EB) was 63% ( p = 0.61 compared with SB), whereas upgrading was 13% ( p = 0.045 compared with SB) and downgrading was 24% ( p = 0.06 compared with SB). A "clinically significant" upgrading as defined here was present in 38.1% of the SB group compared with 23.1% of the EB group ( p = 0.039). For patients with bGS of 6, a clinically significant upgrading occurred in 66.7% with SB and in 36.8% with EB ( p = 0.068). Upgrading of the primary Gleason grade from 3 to 4/5 was seen in 41.8% for the SB and in 25.5% for the EB group ( p = 0.078). No clinical factors (T-stage, PSA, prostate volume, % positive cores, linear extent of cancer) were found to predict for a clinically significant upgrading of biopsies on logistic regression analysis. Conclusions The extended 10-core biopsy scheme significantly improves on sextant biopsies in predicting the underlying pathologic Gleason score for prostate cancer. In particular, it is superior to sextant biopsies in revealing the presence of an underlying high-grade component. The potential clinical impact this improvement has for patients ultimately selecting radiotherapy suggests that an extended biopsy scheme should become the standard of care. Nevertheless, even with this improvement, there still remains up to a 1-in-5 chance that the underlying grade will be higher.

There is a clear dose response for localized prostate cancer radiotherapy and there probably is a radiobiological rationale for hypo-fractionation. Combining the two should maximize tumor control and increase the therapeutic ratio. This study examines the rationale and technical feasibility of CyberKnife radiotherapy (a robotic arm-driven linear accelerator) for localized prostate cancer. Its ability to deliver non-coplanar non-isocentric arcs can yield maximally conformal isodoses. It is the only integrated system capable of target position verification and real-time tracking during delivery of conformal stereotactic radiotherapy. Inverse planning with the CyberKnife is used to design a course of radiotherapy for localized prostate cancer. Fiducial markers within the gland are used to verify organ position and track organ motion via an orthogonal pair of electronic x-ray imaging devices and provide real-time feedback correction to the robotic arm during delivery. Conformal isodose curves and dose volume histograms (DVH) are used to compare with an optimized Intensity-Modulated Radiotherapy (IMRT) plan actually delivered to the study patient based upon CT scan-derived organ volumes. The CyberKnife can produce superior DVHs for sparing of rectum and bladder and excellent DVHs for target coverage compared with IMRT, and possesses dose heterogeneities to the same degree as IMRT plans. Because of the significantly longer delivery times required it would be best suited for hypo-fractionated regimens. Such dose regimens might allow for biologically equivalent dose escalation without increased normal tissue toxicity. Since the CyberKnife can verify organ position and motion and correct for this in real-time it is the ideal means of achieving such excellent DVHs without a compromise in doses to normal tissues. These capabilities are essential if one contemplates hypo-fractionated regimens with large dose-per-fraction sizes (>5Gy to 10Gy) and dose-escalation.

102 Background: Patients with Gleason score (GS) 9-10 prostate cancer (PCa) have a high risk of early biochemical recurrence (BCR). Salvage therapy options differ depending on the upfront management strategy. Patients who received upfront surgery (RP) may be curable with salvage external beam radiation therapy (EBRT). However those who underwent EBRT or EBRT with a brachytherapy boost (EBRT+BT) are less likely to receive local salvage therapy and are commonly treated with androgen deprivation therapy (ADT). In this study, we examine the risk of distant metastases (DM) and prostate-cancer specific mortality (PCSM) among patients with GS 9-10 PCa who had BCR following RP, EBRT, or EBRT+BT. Methods: 712 patients with GS 9-10 PCa treated between 2000-2013 at 12 institutions who had BCR were included (346 RP, 282 EBRT, 84 EBRT+BT). Time to DM and PCSM were compared between groups using Cox proportional hazards models with propensity score adjustment. Propensity scores were calculated using age, T-stage, PSA, and GS. Results: In patients who had a BCR, incidence rates of DM and PCSM after RP were 40% and 28%. Rates after EBRT were 60% and 46% and after EBRT+BT were 49% and 31%. Median times to DM and PCSM were 3.5 and 4.9 years after RP, 3.7 and 5.1 years after EBRT, and 3.3 and 6.8 years after EBRT+BT. The rates of local salvage RT and systemic salvage therapy among RP patients were 38% and 59%, respectively. Local and systemic salvage rates were 5% and 31% for EBRT patients and 5% and 28% for EBRT+BT patients. EBRT patients had a shorter time interval to DM compared with RP (HR 1.4, p = .02) and EBRT+BT (HR 1.9, p < .01). EBRT patients also had a shorter time interval to PCSM compared with RP (HR 1.5, p = .02). Conclusions: Among patients with GS 9-10 PCa who experience BCR after definitive management, those treated with EBRT have a shorter time interval to DM and PCSM compared with RP and EBRT+BT. While this analysis is confounded by the differential thresholds for diagnosing a BCR after different modalities, it does suggest that outcomes following BCR after EBRT+BT and RP are similar. It also suggests that extreme dose escalation delays the onset of DM and PCSM even after BCR, when compared with conventionally-dosed EBRT alone.

53 Background: The costs of treating localized, Gleason score 9 and 10 prostate cancer remain poorly described, especially when the particularly aggressive nature of the disease often requires a multimodal approach. We report the results of time-driven activity-based costing to assess the long-term costs of treating this subset of patients with either RALP, high-dose EBRT, or EBRT with a high-dose rate brachytherapy (BT) boost. Methods: Based on a multi-institutional cohort of 487 patients with Gleason score 9-10 prostate cancer, we generated process maps for each phase of care from the initial urologic visit through a median follow-up of 3.76 years, incorporating all prostate cancer treatment over this horizon. Costs were calculated per unit time, and the proportion of capacity for each step was determined. TDABC was defined as the sum of its resources. Results: Substantial cost variation was demonstrated between treatment modalities with an estimated median cost of $49,681 for EBRT, $35,140 for RALP, and $31,647 for EBRT + BT at 3.76 years. The primary driver in cost variation was the use of ADT. RALP (170 pts) ranged from $18,896 (29.5%) for no postoperative therapy to $63,270 for immediate long-term ADT (5.3%). EBRT (230 pts) had the greatest cost variation [Table 1]. Finally, EBRT + BT (336 pts) ranged from $26,522 for EBRT + BT alone (12.6%) to $37,834 for EBRT + BT + salvage ADT + HIFU (1.2%). Conclusions: Characterizing the costs associated with the distribution of treatments for men with high-risk prostate cancer is essential as we move towards health care accountability. There is substantial long-term cost variation between treatments in this subset of patients, and understanding these differences may affect treatment implications as we shift toward accountable payment models.[Table: see text]

84 Background: While a growing body of evidence supports the use of stereotactic body radiotherapy (SBRT) for the treatment of low- and intermediate-risk prostate adenocarcinoma (PCa), some trepidation exists regarding its long-term efficacy and safety. Methods: Men with low- and intermediate-risk PCa, as defined per the National Comprehensive Cancer Network guidelines, who were enrolled on various institutional phase II trials of SBRT between 2000-2012 were included in a multi-institutional consortium. Biochemical relapse (BCR) was defined as PSA > “nadir +2” or initiation of androgen deprivation therapy (ADT). Toxicity data were scored according to the CTCAE v 3.0 or Radiation Therapy Oncology Group scoring systems. Results: A total of 1644 men were eligible for analysis, with a median followup of 7.2 years. 297 patients (18.1%) had at least 9 years of followup. Fractionation schemes ranged from 33.50-40 Gy in 4-5 fractions. 892 patients had low-risk disease and 752 had intermediate-risk disease. 59 patients (3.6%) received short-term ADT. 100 patients (6.0%) experienced BCR, and 7 (0.4%) experienced distant metastases. No patients died of PCa. By Kaplan-Meier analysis, 5- and 10-year BCR-free survival rates were 98% and 94% in the low-risk group and 96% and 90% in the intermediate-risk group (p < 0.05 by log-rank test). 5- and 10-year overall survival rates were 93% and 86% in the low-risk group and 95% and 91% in the intermediate-risk group (p > 0.05 by log-rank test). Five patients (0.3%) experienced grade 3 acute genitourinary (GU) toxicities, including urinary retention, hematuria, and frequency. 30 (2%) experienced grade 3 late GU toxicity, including urinary strictures, hematuria, and retention. One late grade 4 GU toxicity (hemorrhagic urethritis) and one late grade 4 gastrointestinal toxicity (fistula-in-ano) were seen. Conclusions: To the best of our knowledge, this is the largest analysis of long-term outcomes following SBRT for PCa. The results indicate that SBRT has an efficacy and toxicity profile that compares favorably to more widespread forms of treatment, such as conventionally-fractionated external beam radiotherapy and brachytherapy.

Within the confines of least-squares operations, it is possible to quantify the effect of the addition of treatment fields or beamlets to a treatment plan. Using linear algebra and eigenvalue perturbation theory, the effect of the increase in number of treatments is shown to be equivalent to adding a perturbation operator. The effect of adding additional fields will be negligible if the perturbation operator is small. The correspondence of this approach to an earlier work in beam-orientation optimization is also demonstrated. Results are presented for prostate, spinal and head and neck cases, and the connection to beam-orientation optimization is examined.

Purpose: Permanent LDR brachytherapy and temporary HDR brachytherapy are competitive techniques for clinically localized prostate radiotherapy. Although a randomized trial will likely never be conducted comparing these two forms of brachytherapy, a comparative radiobiological modeling analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. Methods and Materials: Radiobiological models based upon the linear quadratic equations are presented for fractionated external beam, fractionated 192Ir HDR brachytherapy, and 125I and 103Pd LDR brachytherapy. These models incorporate the dose heterogeneities present in brachytherapy based upon patient-derived dose volume histograms (DVH) as well as tumor doubling times and repair kinetics. Radiobiological parameters are normalized to correspond to three accepted clinical risk factors based upon T-stage, PSA, and Gleason score to compare models with clinical series. Tumor control probabilities (TCP) for LDR and HDR brachytherapy (as monotherapy or combined with external beam) are compared with clinical bNED survival rates. Predictions are made for dose escalation with HDR brachytherapy regimens. Results: Model predictions for dose escalation with external beam agree with clinical data and validate the models and their underlying assumptions. Both LDR and HDR brachytherapy achieve superior tumor control when compared with external beam at conventional doses (

Three very well conducted and remarkably similar randomized trials (European Organization for Research and Treatment of Cancer [EORTC] 22911 [1], Southwest Oncology Group [SWOG] 8794 [2], and [Arbeitsgemeinschaft Radiologische Onkologie] 96-02 [3]) have shown that adjuvant radiotherapy (RT) directed at the prostate bed improves prostate-specific antigen (PSA) relapse-free survival compared with observation among patients with high-risk features. In these three trials, high-risk patients were characterized as having either positive surgical margins, extracapsular extension (pT3a), or seminal vesicle involvement (pT3b). In principle, ‘‘adjuvant’’ therapy implies treatment in the absence of measurable disease, and for prostate cancer this means an undetectable postoperative PSA level. These trials, conducted during the time periods of 1992‐2001 for EORTC, 1997‐2004 for ARO, and 1988‐1997 for SWOG, used the PSA assays available at those times. Those assays had a threshold of detection of 0.2 ng/mL. In fact, many of the patients in these adjuvant trials did have measurable PSA levels. In the EORTC trial 9% of patients had a PSA >0.2 ng/mL; in the SWOG trial 35% had PSA >0.2 ng/mL; and in the ARO trial (which had access to assays with lower threshold) 20% of patients had PSA >0.05‐0.1 ng/mL, and 59% of patients had PSA >0.03‐0.1 ng/mL. Since then, the threshold for ‘‘undetectable’’ PSA has been readjusted with the development of ultrasensitive PSA assays now able to detect levelsas lowas 0.01ng/mL. Within this framework then, many, if not most of the adjuvant trial patients would be categorized today as having measurable disease. By extrapolation, the median PSA level in the adjuvant trials is estimated to fall within the >0.05‐0.1-ng/mL range. In the era of ultrasensitive PSA assays, the question now facing clinicians and patients is this: even in the setting of high-risk features, is there any benefit of adjuvant RT if the PSA is undetectable with an ultrasensitive assay (i.e., PSA

Purpose To investigate correlates and predictors of outcomes of stereotactic body radiation therapy (SBRT) for patients with abdominal and pelvic oligometastases from different primary tumors. Methods and materials We evaluated outcomes of 38 consecutive patients with 44 unresectable nodal and soft-tissue oligometastases in the abdominal pelvic region who were treated with SBRT between November 2008 and April 2014. Thirty-two patients had solitary lesions and 6 patients had 2 lesions. The median prescription dose was 40 Gy (24-50 Gy) delivered in 4-5 fractions. The median gross tumor volume was 18.7 mL (0.7-194.1 mL). We evaluated tumor response, local control (LC), and overall survival (OS) rates as well as acute and chronic toxicities. Results At a median follow-up of 19 months (0.9-53.4 months), tumor responses were: complete response 31.8%, partial response 38.6%, standard deviation 20.5%, and progressive disease 9.1%. The overall 1- to 2-year LC and OS rates were 100%/75.1% (95% confidence interval [CI], 54.4%-88.4%) and 95.2% (95% CI, 82.8%-98.8%)/88.9% (95% CI, 68.1%-95.1%), respectively. On univariate analysis, increasing SBRT dose, smaller gross tumor volume, and asymptomatic lesions were associated with improved LC ( P = .01, P P = .01, respectively). On multivariate analysis, advanced original primary disease stage predicted for worse OS ( P = .001). One patient developed a colovesicular fistula at 20.9 months in the setting of local tumor progression with a volume of bowel receiving 20 Gy (V 20Gy ) = 26.9 mL. The overall mean bowel V 20Gy achieved was 16 ± 22.9 mL. Another patient had grade 2 proctitis at 13 months after SBRT. Pain relief was achieved in 81.8% of patients with symptomatic lesions (N = 11). Conclusions Our results suggest that SBRT doses 40-50 Gy in 5 fractions (biological effective dose 72-100 Gy 10 ) with bowel V 20Gy ≤20 mL are efficacious and associated with minimal toxicity for abdominal pelvic nodal and soft-tissue oligometastases. Palliation of symptoms is achievable in most patients with symptomatic lesions. SBRT for oligometastases may be a good alternative to systemic therapy in selected patients.

Stereotactic body radiation therapy (SBRT), a treatment procedure that uses large doses per fraction, is currently being used to treat prostate cancer with external radiation therapy in 4 to 5 treatments. Published series in the clinical use of SBRT in patients with localized prostate cancer demonstrate high efficacy within the available follow-up time periods. Rectal and sexual toxicity profiles have been favorable compared with other radiation techniques and surgery. Urinary toxicity profiles might be more comparable to those observed with brachytherapy, more pronounced in the acute setting. SBRT is technically more challenging, requiring precise geometric targeting with in-room image guidance. The use of large doses per fraction potentially provides unique biological effects on both tumor and normal tissues. Immunologic responses in normal tissues, local stromal microenvironment, and specific antigen-presenting cells induced by such high doses likely contribute to effective tumor kill. Ultimately, SBRT for prostate cancer offers significant logistical advantages, with increased convenience to patients and decreased overall cost to the health care delivery system.

INTRODUCTION AND OBJECTIVES: The impact of percutaneous nephrostolithotomy (PCNL) on renal function has long been a concern especially in the setting of multi-tract access. Previous studies have demonstrated minimal renal injury with PCNL when using serum creatinine and GFR as markers. Tc99m-MAG3 nuclear renography is a superior marker of renal function and may better elucidate injury. We hypothesize that multi-tract PCNL could negatively affect renal function as compared to single-access PCNL. METHODS: We performed a retrospective review of 307 consecutive patients undergoing PCNL from 2011-2012 at Wake Forest Baptist Health. A comparison of single and multi-access ( 2) PCNL was undertaken using Tc99m-MAG3 nuclear renogram parameters in addition to serum creatinine values. Other variables assessed include age, sex, and BMI. Data collected was within a year of PCNL treatment. Statistical analysis was performed with Statsplus . RESULTS: A total of 110 patients (74 single access, 36 multiple access) were identified for which pre and post-PCNL renograms were available. There was no significant differences in age, gender, BMI, serum creatinine, or MAG3 renogram derived T/2 between these cohorts. We noted a significant decrease in Tc99m-MAG3 split function in the operated kidney for patients with multiple access versus single access PCNL (-2.28%, p 0.05, respectively). Successive decrease in renal function was suggested with increasing number of percutaneous accesses into the kidney although this was not statistically significant (likely due to the low number of cases with more than 2 accesses [F(2,107)1⁄41.487, p1⁄40.23]). CONCLUSIONS: We present one of the largest series of renal function assessment with Tc99m-MAG3 nuclear renography in patients undergoing single versus multi-access percutaneous nephrostolithotomy. Multi-tract PCNL appears to be associated with a significant decline in renal function as assessed by Tc99m-MAG3 nuclear renography. This suggests that numerous accesses may exacerbate perioperative renal injury. Further review of patient and peri-operative parameters is needed to both further elucidate and to confirm this relationship.

The predictive value of Gleason grading from prostate needle biopsy was examined and the patterns of grade discordance with surgical specimens are discussed in terms of their clinical implications. Gleason scores from biopsy and matched radical prostatectomy specimens were compared in 428 consecutive patients. Patterns of concordance were examined with respect to numerical agreement as well as to whether differences result in a change in group assignment with respect to Gleason score group 2-4, 5-6, 7, and 8-10. The coefficient of agreement, kappa, and accuracy were used to measure predictive value. An exact Gleason score match was present in 41% of the cases, while 48% were undergraded and 17% overgraded. With respect to group assignment, 51% remained unchanged while 35% were undergraded and 14% overgraded. Kappa analysis yielded a value of 0.26, which represents a poor agreement beyond chance. A Gleason score of 5-6, 7, or 8 was reproduced in 52%, 53%, and 58% of cases, respectively. A systematic bias toward progressive undergrading of more well-differentiated cancers and overgrading of more poorly differentiated cancers on biopsy is suggested by the data. A pooled analysis with nine additional series (n = 2,687) confirms this conclusion. No correlation was found between the amount of tumor in the biopsy specimen and grade discordance. Biases in pathologic interpretation and sampling effects are suggested as responsible for grade discordance. Predictable differences exist between the histologic grade in prostate needle biopsies and the surgical specimen. Clinical staging of organ-confined prostate cancer should include the likelihood of histologic upgrading or downgrading when used to stratify patients for clinical trials, in comparing results among therapies based on biopsy grading and when recommending a radical therapy. Developing a methodology which reduces both sampling effects and pathologic interpretation bias would likely result in significantly improved accuracy of Gleason grading of prostate biopsies. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 305-311 (2000).

Potential reasons for discordance between the Gleason score in biopsies and surgical specimens are: 1) pathological interpretation bias, and 2) sampling effects. The importance of sampling effects in grading errors was examined in a series where the number of biopsy cores obtained was high. Biopsies were obtained using a technique whereby 18 directed cores were systematically obtained and mapped out within the gland. Gleason scores from biopsies and matched prostatectomy specimens were compared among 28 consecutive patients with localized prostate cancer. A pooled database from 10 series (n = 2,687) served as a baseline for comparison in the accuracy of Gleason score grading. With the present biopsy technique, an exact Gleason score match was achieved in 57% of cases, compared with the pooled database (PD) mean of 42% (P = 0.055), and was within 1 point in 93% of cases compared with 78% (PD) (P = 0.029). Upgrading of biopsies was seen in 35% of cases, compared with 43% (PD) (P = 0.19). With respect to Gleason score 7, an exact match was present in 78% of cases, compared with 63% (PD) (P = 0.17), and upgrading was 0%, compared with 20% (PD) (P = 0.07). The data suggest a significant reduction in grade errors by minimizing sampling effects, one that it is of the same order of magnitude as the reduction achieved from consensus pathologic evaluation. In our study, seven patients (25%) would have had their cancers missed altogether with sextant biopsies. Sampling effects may contribute significantly to grading errors in prostate needle biopsies, although a larger study is needed to confirm this. A methodology which adopts a higher number of cores combined with a consensus pathologic evaluation could potentially reduce grading errors substantially. The optimal number of cores remains to be determined in a larger study. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 326–330 (2000). © 2000 Wiley-Liss, Inc.

This editorial uses insights gained from mucosal tolerance studies in head and neck radiotherapy, together with standard Linear Quadratic radiotherapy modeling, to predict whether some hypofractionated prostate schedules could cause acute rectal mucosal reactions by using too short schedules. With conventional radiotherapy, including hypofractionation, we restrict total dose to a late normal tissue complications dose limit, depending on the tissue and volume irradiated, of 50 to 70–80 Gy equivalent total dose in 2-Gy fractions (EQD2). These late-effect dose–volume constraints are well reported in many publications. Some stereotactic body radiotherapy schedules give high doses and biologically effective doses (BED), and new information is still being obtained that might change accepted doses. But there is also the question of acute reactions; they are the main factor determining whether any fractionation schedule can be accepted as tolerable. Until recently acute reactions were checked for ‘‘tolerability’’ by irradiating the first few patients in any new schedule and observing their acute reactions to ensure healing within a reasonable time. We suggest that radiobiologic modeling (1) can now be used to predict whether proposed fractionation schemes are in danger of causing acute mucosal reactions in the treatment of prostate cancer. An additional potential hazard is the phenomenon of consequential late damage induced by very high acute reactions. This has been identified in animal experiments (2), although it has skeptics in clinical circles. The important difference between acute and late reactions is the time factor. Acute reactions are very sensitive to overall time, unlike late reactions. It means that if acute reactions are too severe, then a week added to the overall time can avoid some Grade 3 acute reactions, as shown below. It was not until 2003 that modeling was proposed to help predict whether any schedule might cause intolerable acute complications (1). This was based on the well-known linearquadratic formula used for predicting log cell kill in tumors

A surface-micromachined free-space micro-optical bench (FS-MOB) technology has been proposed to monolithically integrate micro-optical elements, optomechanical structures, micropositioners, and microactuators on the same substrate. Novel three-dimensional micro-optical elements have been fabricated by surface-micromachining techniques. The optical axes of these optical elements are parallel to the substrate, which enables the entire free-space optical system to be integrated on a single substrate. Mocro-scale Fresnel lenses, refractive microlenses, mirrors, beam-splitters, gratings, and precision optical mounts have been successfully fabricated and characterized. Integration of micro-optical elements with translation or rotation stages provides on chip optical alignment or optomechanical switching. This new free-space micro-optical bench technology could significantly reduce the size, weight, an cost of most optical systems, and could have a significant impact on optical switching, optical sensing and optical data storage systems as well as packaging of optoelectronic components.

Significant dosimetric improvement for radiation therapy using optimized noncoplanar fields has been previously demonstrated. The purpose here is to study the feasibility of optimized robotic noncoplanar radiation therapy, termed 4π therapy, for prostate cancer treatments on a conventional C-arm linac.Twelve low-risk prostate cancer patients previously treated by 2-arc volumetric modulated arc therapy (VMAT) were selected. Forty gray in 5 fractions were prescribed to cover 95% of the prostate planning target volume (PTV). To replan by 4π therapy, a column generation method was used to optimize beam orientations and fluence. A total of 30 beams were selected for each patient.Both planning methods provided adequate PTV coverage. Compared against VMAT plans, the 4π plan reduced the rectum V50%, V80%, V90%, D1cc, and the penile bulb maximum doses by 50%, 28%, 19% 11%, and 9% (P.005), respectively, and the mean body dose was reduced from 2.07 Gy to 1.75 Gy (P = .0001). The bladder dose was only slightly reduced.By optimizing beam angles and fluences in the noncoplanar solution space, superior prostate treatment plan quality was achieved compared against state of the art VMAT plans. The dosimetric potential for 4π therapy is established on an existing C-arm linac platform.

17 Background: Patients with localized prostate cancer (PCa) assimilate information from varying sources to inform their treatment decision. We assessed the impact of the primary information source used to select a modern radiation treatment on patient perceptions of their treatment experience and on treatment regret. Methods: Patients with favorable-risk PCa treated with SBRT, IMRT or HDR brachytherapy and at least one year of follow-up were surveyed. The questionnaire explored the decision-making experience, expected treatment experience vs. the reality, and treatment regret via a validated tool. Multivariate logistic regression adjusted for demographics, disease characteristics, treatment modality, time since treatment and current bowel, urinary and sexual function. Results: 322 consecutive patients were surveyed with an 86% (n = 276) response rate. 48% (n = 132) selected their radiation oncologist as the primary information source, 23% (n = 62) selected their urologist, 16% (n = 44) selected the internet, 6% (n = 17) selected other patients and 8% (n = 21) selected other. Overall, 13% (n = 36) endorsed treatment regret. 39% of patients who selected the internet as their primary information source reported their actual treatment experience to be worse than expected vs. 13% of respondents who selected their urologist, 12% who selected other patients, 2% who selected their radiation oncologist and 9% who selected other ( p< 0.01). Similarly, 43% who selected the internet as their primary information source endorsed treatment regret vs. 10% who selected their urologist, 7% who selected their radiation oncologist, 6% who selected other patients and 6% who selected other ( p< 0.01). On multivariate logistic regression, only patients who selected the internet as their primary information source were more likely to endorse treatment regret (OR = 46.5, p< 0.01) and were more likely to choose a treatment they thought ‘had the least side effects’ (OR = 2.1, p= 0.016). Conclusions: Patients who used the internet as their primary source of information had a worse perception of their treatment experience and had more treatment regret, highlighting the need for physicians to proactively counsel patients.

46 Background: Stereotactic body radiotherapy (SBRT) for high-risk prostate cancer (CaP) remains investigational not only due to undetermined efficacy but also due to concerns for the potential toxicity when the treatment volumes extend beyond the prostate gland itself. Methods: Men with high-risk CaP, as defined by Gleason score > = 8, clinical stage T3-T4, or initial PSA > = 20 ng/mL, were enrolled on a multicenter phase II trial and were treated with 40 Gy to prostate and 25 Gy to pelvic nodes in 5 fractions and 9 months neoadjuvant and concurrent ADT. Treatment with ADT and pelvic nodal radiation was at the discretion of the treating physician. Follow-up assessment was with CTCAE v4 and Expanded Prostate Composite Index (EPIC). Results: A total of 61 patients were treated, with a median follow-up of 12 months. Forty (64.4%) received ADT and 23 (37.1%) received nodal radiation. The median initial PSA was 8.1 ng/mL and 8% of patients had clinical T3-T4 disease; 45.9% and 39.3% had Gleason score 8 and 9-10 disease, respectively. No grade 3 or higher toxicities were seen. Rates of acute and late grade 2 genitourinary toxicities were 13.1% and 6.7%, respectively; rates of acute and late grade 2 gastrointestinal toxicities were 6.6% and 8.2%, respectively. Mean changes in EPIC urinary incontinence, urinary obstructive, and bowel domain scores at 4 months were -0.35, +1.44, and -2.38, respectively. For the 32 patients with evaluable EPIC scores at 12 months, mean changes on EPIC urinary incontinence, urinary obstructive, and bowel domain scores at 4 months were -1.04, -2.70, and -6.76, respectively. The percentages of patients with minimum clinically important change in EPIC urinary incontinence, urinary obstructive, and bowel domain scores at 4 months were 11.9%, 21.4%, and 26.2%, respectively. At 12 months, these figures were 13.9%, 30.6% and 27.8%. The receipt of ADT and/or nodal radiation had no significant effect on either physician- or patient-reported toxicity profiles (p > 0.1, Fisher’s exact test). Conclusions: SBRT regimens can be safely utilized to deliver the entire course in 5 treatment days in patients with high-risk localized CaP. Clinical trial information: NCT02296229.

7 Background: To compare the outcomes of a modern cohort of patients with Gleason Score (GS) 9-10 prostate adenocarcinoma (CaP) following treatment with external beam radiotherapy (EBRT), extremely dose-escalated radiotherapy (as exemplified by EBRT with a brachytherapy boost [EBRT+BT]), and radical prostatectomy (RP). Methods: One-thousand-and-one patients with biopsy GS 9-10 CaP who received definitive treatment between 2000 and 2013 were included (347 treated with EBRT, 330 with EBRT+BT, and 324 with RP). Kaplan-Meier analysis and multivariate Cox regression compared 5- and 10-year rates of distant metastasis-free survival (DMFS), cancer-specific survival (CSS), and overall survival (OS). Prostate cancer-mortality (PCSM) rates were compared with a competing risk analysis. Results: The median followup periods were 4.8, 6.4, and 5.1 years among patients receiving EBRT, EBRT + BT, and RP. The median doses among EBRT and EBRT+BT patients were equivalent to 78 Gy and 90 Gy in 2 Gy fractions. Over 90% of patients treated with EBRT or EBRT+BT received ADT (median durations of 18 months and 12 months, respectively). Nearly 40% of RP patients received postoperative RT, primarily in the salvage setting. Five- and 10-year DMFS rates were significantly higher with EBRT+BT (91.6% and 81.3%) than with EBRT (79.6% and 65.8%; p < 0.0001) or RP (77.9% and 60.1%; p < 0.0001). Five- and 10-year PCSM rates were significantly lower with EBRT+BT (3.8% and 14.1%) than with EBRT (10.3% and 25.2%; 5- and 10-year hazard ratios of 0.38 and 0.47; p = 0.003) or RP (8.9% and 20.3%; 5- and 10-year hazard ratios of 0.39 and 0.55; p = 0.02). Overall 5- and 10-year OS rates were 85.7% and 64.7% and were similar between cohorts (p > 0.1). Conclusions: Extremely dose-escalated radiotherapy offered improved systemic control and reduced PCSM when compared with either EBRT or RP. Notably, this was achieved despite a significantly shorter median duration of ADT than in the EBRT arm. This is hypothesis generating as it suggests that improved local control via dose-escalation may have systemic control and survival implications even for patients with very high risk disease.

176 Background: Although guidelines suggest that shorter course radiation treatments for patients with advanced cancer and painful bone metastases are most appropriate, treatment patterns in the United States are inconsistent with this approach. Methods: We implemented a provider-focused intervention at a university-based radiation oncology practice aimed at improving rates of shorter-course radiation treatments for patients with advanced cancer and painful bone metastases. The intervention involved key leaders of the practice participating in a RAND/UCLA Appropriateness Panel to review the latest guidelines and evidence and judge appropriateness of various treatment regimens as it pertained to their practice. These results were compared to current (7/2012-6/2013) practice patterns and presented to the faculty group. This exercise informed a template-based point of care intervention led by a clinical champion and leadership that focused on key aspects of clinical and patient-centered care including whether the bone metastases were complicated or uncomplicated, patient prognosis, extent of disease, and travel distance for the patient to the treatment site. We compared rates of lower burden treatment regimens (less than 10 fractions) for 81 pre-intervention patients with 107 metastases treated between 7/2012-6/2013 and 75 post-intervention patients with 94 metastases treated between 5/2015-1/2016. Results: Overall, painful bone metastases were treated with less than 10 fractions more often in the post-intervention period (38% v. 63%, p < 0.001). Uncomplicated bone metastases treated with conformal radiation were also more likely to be treated with less than 10 fractions in the post intervention period (19% v. 52%, p < 0.001). One quarter of metastases were treated with SBRT during both the pre and post-intervention periods. Conclusions: Leadership support, provider engagement in integrating guidelines into practice, and a note template with point of care clinical reminders can improve rates of appropriate, low-burden radiation oncology treatments for patients with advanced cancer.

Purpose/Objective(s): To compare outcomes of patients with Gleason score (GS) 9-10 prostate adenocarcinoma (CaP) following external beam radiation therapy (EBRT), extremely dose-escalated radiation therapy (as exemplified by EBRT with a brachytherapy boost [EBRT+BT]), and radical prostatectomy (RP).

The purpose of our study was to compare the apparent diffusion coefficient (ADC) derived from diffusion-weighted imaging (DWI) of prostate cancer (PCa) patients with three classes of pathological Gleason scores (GS). Patients whose GS met these criteria (GS 3 + 3 , GS 3 + 4 , and GS 4 + 3 ) were included in this study. The DWI was performed using 𝑏 values of 0, 50, and 400 s/mm2 in 44 patients using an endorectal coil on a 1.5T MRI scanner. The apparent diffusion coefficient (ADC) values were calculated from the DWI data of patients with three different Gleason scores. In patients with a high-grade Gleason score ( 4 + 3 ), the ADC values were lower in the peripheral gland tissue, pathologically determined as tumor compared to low grade ( 3 + 3 and 3 + 4 ). The mean and standard deviation of the ADC values for patients with GS 3 + 3 , GS 3 + 4 , and GS 4 + 3 were 1 . 1 3 5 ± 0 . 1 1 9 , 0 . 9 7 6 ± 0 . 1 0 3 and 0 . 8 3 1 ± 0 . 0 8 7 mm2/sec. The ADC values were statistically significant ( 𝑃 < 0 . 0 5 ) between the three different scores with a trend of decreasing ADC values with increasing Gleason scores by one-way ANOVA method. This study shows that the DWI-derived ADC values may help differentiate aggressive from low-grade PCa.

Hypofractionated radiotherapy has an intrinsically different normal tissue and tumor radiobiology. The results of a prospective trial of stereotactic body radiotherapy (SBRT) for prostate cancer with long-term patient-reported toxicity and tumor control rates are presented. Sixty-seven patients with clinically localized low-risk prostate cancer were enrolled from 2003 to 2009. Treatment consisted of 36.25 Gy in five fractions with CyberKnife®. No patient received hormone therapy. Median follow-up was 2.7 years. Significant late bladder and rectal toxicities were infrequent. There were no Grade 4 toxicities. RTOG Grade 3, 2, and 1 bladder toxicities were seen in 3% (two patients), 5% (three patients), and 23% (13 patients), respectively. Dysuria exacerbated by urologic instrumentation accounted for both patients with Grade 3 toxicity. Urinary incontinence, complete obstruction, or persistent hematuria was not observed. Rectal Grade 3, 2, and 1 toxicities were seen in 0%, 2% (one patient), and 12.5% (seven patients), respectively. Persistent rectal bleeding was not observed. Low-grade toxicities were substantially less frequent with QOD vs. QD dose regimen. There were two, biopsy-proven PSA failures with negative metastatic work-up. Median PSA at follow-up was 0.5 ± 0.72 ng/ml. The 5-year Kaplan–Meier PSA relapse-free survival was 94% (95% CI: 85–102%) and compares favorably with other definitive treatments. The current evidence supports consideration of SBRT among the therapeutic options for localized prostate cancer.

Purpose To determine the relationship between tumor control probability (TCP) and biological effective dose (BED) for radiation therapy in medically inoperable stage I non-small cell lung cancer (NSCLC). Methods and Materials Forty-two studies on 3-dimensional conformal radiation therapy (3D-CRT) and SBRT for stage I NSCLC were reviewed for tumor control (TC), defined as crude local control ≥ 2 years, as a function of BED. For each dose-fractionation schedule, BED was calculated at isocenter using the linear quadratic (LQ) and universal survival curve (USC) models. A scatter plot of TC versus BED was generated and fitted to the standard TCP equation for both models. Results A total of 2696 patients were included in this study (SBRT: 1640; 3D-CRT: 1056). Daily fraction size was 1.2-4 Gy (total dose: 48-102.9) with 3D-CRT and 6-26 (total dose: 20-66) with SBRT. Median BED was 118.6 Gy (range, 68.5-320.3) and 95.6 Gy (range, 46.1-178.1) for the LQ and USC models, respectively. According to the LQ model, BED to achieve 50% TC (TCD 50 ) was 61 Gy (95% confidence interval, 50.2-71.1). TCP as a function of BED was sigmoidal, with TCP ≥ 90% achieved with BED ≥ 159 Gy and 124 Gy for the LQ and USC models, respectively. Conclusions Dose-escalation beyond a BED 159 by LQ model likely translates into clinically insignificant gain in TCP but may result in clinically significant toxicity. When delivered with SBRT, BED of 159 Gy corresponds to a total dose of 53 Gy in 3 fractions at the isocenter.

Background: Allogeneic bone marrow transplantation (allo-BMT) is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT) activity are limited by graft-versus-host-disease (GVHD). Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1) is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models. Methods: We studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT) in mouse models. In vivo, Ceacam1(-/-) T cells caused increased GVHD mortality and GVHD of the colon, and greater numbers of donor T cells were positive for activation markers (CD25(hi), CD62L(lo)). Additionally, Ceacam1(-/-) CD8 T cells had greater expression of the gut-trafficking integrin α(4)β(7), though both CD4 and CD8 T cells were found increased numbers in the gut post-transplant. Ceacam1(-/-) recipients also experienced increased GVHD mortality and GVHD of the colon, and alloreactive T cells displayed increased activation. Additionally, Ceacam1(-/-) mice had increased mortality and decreased numbers of regenerating small intestinal crypts upon radiation exposure. Conversely, Ceacam1-overexpressing T cells caused attenuated target-organ and systemic GVHD, which correlated with decreased donor T cell numbers in target tissues, and mortality. Finally, graft-versus-tumor survival in a Ceacam1(+) lymphoma model was improved in animals receiving Ceacam1(-/-) vs. control T cells. Conclusions: We conclude that Ceacam1 regulates T cell activation, GVHD target organ damage, and numbers of donor T cells in lymphoid organs and GVHD target tissues. In recipients of allo-BMT, Ceacam1 may also regulate tissue radiosensitivity. Because of its expression on both the donor graft and host tissues, this suggests that targeting Ceacam1 may represent a potent strategy for the regulation of GVHD and GVT after allogeneic transplantation.

Purpose Salvage radiotherapy (SRT) after radical prostatectomy can potentially eradicate residual microscopic disease. Defining the optimal patient and treatment factors is essential and is particularly relevant within the context of adjuvant vs early vs delayed postoperative radiotherapy (RT). Methods and Materials A systematic review of all published SRT studies was performed to identify the pathologic, clinical, and treatment factors associated with relapse-free survival (RFS) after SRT. A total of 41 studies encompassing 5597 patients satisfied the study entry criteria. Radiobiologic interpretation of biochemical tumor control was used to provide the framework for the observed relationships. Results Prostate-specific antigen (PSA) level before SRT ( P P =.0052) had a significant and independent association with RFS. There was an average 2.6% loss of RFS for each incremental 0.1 ng/mL PSA at the time of SRT (95% CI, ∼2.2-3.1). With a PSA level of 0.2 ng/mL or less before SRT, the RFS approached 64%. The dose for salvage RT in the range of 60-70 Gy seemed to be on the steep part of the sigmoidal dose–response curve, with a dose of 70 Gy achieving 54% RFS compared with only 34% for 60 Gy. There was a 2% improvement in RFS for each additional Gy (95% CI, ∼0.9-3.2). The observed dose–response was less robust on sensitivity analysis. Conclusions This study provides Level 2a evidence for initiating SRT at the lowest possible PSA. Dose escalation is also suggested by the data. Progressively better tumor control rates with SRT after radical prostatectomy are achieved with a lower PSA at initiation and with a higher RT dose. Early salvage RT may be an equivalent strategy to adjuvant RT.

The hypofractionation of stereotactic body radiotherapy (SBRT) for prostate cancer has become a broad topic, and there are many aspects to consider before accepting this treatment into our clinics. Among the considerations are the data from the Stanford phase II trial, a seminal investigation into this area, which will be presented and reviewed here. A single-arm, prospective phase II trial was initiated at Stanford in December of 2003. This trial uses SBRT as monotherapy for 'low-risk' prostate cancer patients, and 69 patients have been entered to date. We have analyzed the patient data for the first 5 years of this study. For study entry, patients were required to have clinical stage T1c or T2a disease, prostate-specific antigen (PSA) ≤ 10 and a Gleason score of 3 + 3 (or 3 + 4 if the higher grade portion was of small volume, usually

Alloreactive T cells are crucial for graft-versus-host disease (GVHD) pathophysiology, and modulating their trafficking patterns has been efficacious in ameliorating experimental disease. We report in this paper that P-selectin, a glycoprotein found on resting and inflamed endothelium, is important for donor alloreactive T cells trafficking into GVHD target organs, such as the intestines and skin. Compared with wild-type (WT) recipients of allogeneic bone marrow transplantation, P-selectin−/− recipients exhibit decreased GVHD mortality and decreased GVHD of the skin, liver, and small bowels. This was associated with diminished infiltration of alloactivated T cells into the Peyer’s patches and small bowels, coupled with increased numbers of donor T cells in the spleen and secondary lymphoid organs (SLOs). Surprisingly, however, donor T cells deficient for P-selectin glycoprotein ligand 1, the most well described P-selectin ligand, mediated GVHD similar to WT T cells and accumulated in SLO and target organs in similar numbers as WT T cells. This suggests that P-selectin may be required for trafficking into inflamed tissues but not SLO and that donor T cells may use multiple P-selectin ligands apart from P-selectin glycoprotein ligand 1 to interact with P-selectin and traffic into inflamed tissues during GVHD. We conclude that targeting P-selectin may be a viable strategy for GVHD prophylaxis or treatment.