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Radiation therapy remains a standard treatment option for men with localized prostate cancer. Alone or in combination with androgen-deprivation therapy, it represents a curative treatment and has been shown to prolong survival in selected populations. In this article, the authors review recent advances in prostate radiation-treatment techniques, photon versus proton radiation, modification of treatment fractionation, and brachytherapy-all focusing on disease control and the impact on morbidity. Also discussed are refinements in the risk stratification of men with prostate cancer and how these are better for matching patients to appropriate treatment, particularly around combined androgen-deprivation therapy. Many of these advances have cost and treatment burden implications, which have significant repercussions given the prevalence of prostate cancer. The discussion includes approaches to improve value and future directions for research.

Purpose: SPINK1 overexpression has been described in prostate cancer and is linked with poor prognosis in many cancers. The objective of this study was to characterize the association between SPINK1 overexpression and prostate cancer–specific survival. Experimental Design: The study included 879 participants in the U.S. Physicians' Health Study and Health Professionals Follow-Up Study, diagnosed with prostate cancer (1983–2004) and treated by radical prostatectomy. Protein tumor expression of SPINK1 was evaluated by immunohistochemistry on tumor tissue microarrays. Results: Seventy-four of 879 (8%) prostate cancer tumors were SPINK1 positive. Immunohistochemical data were available for PTEN, p-Akt, pS6, stathmin, androgen receptor (AR), and ERG (as a measure of the TMPRSS2:ERG translocation). Compared with SPINK1-negative tumors, SPINK1-positive tumors showed higher PTEN and stathmin expression, and lower expression of AR (P < 0.01). SPINK1 overexpression was seen in 47 of 427 (11%) ERG-negative samples and in 19 of 427 (4%) ERG-positive cases (P = 0.0003). We found no significant associations between SPINK1 status and Gleason grade or tumor stage. There was no association between SPINK1 expression and biochemical recurrence (P = 0.56). Moreover, there was no association between SPINK1 expression and prostate cancer mortality (there were 75 lethal cases of prostate cancer during a mean of 13.5 years follow-up; HR = 0.71; 95% confidence interval, 0.29–1.76). Conclusions: Our results suggest that SPINK1 protein expression may not be a predictor of recurrence or lethal prostate cancer amongst men treated by radical prostatectomy. SPINK1 and ERG protein expression do not seem to be entirely mutually exclusive, as some previous studies have suggested. Clin Cancer Res; 20(18); 4904–11. ©2014 AACR.

Background The Radiation Therapy Oncology Group 96-01 randomized trial demonstrated the benefit of adding androgen deprivation therapy (ADT) to salvage radiotherapy for an increasing prostate-specific antigen (PSA) after prostatectomy, but it is unknown whether modern patients followed with ultrasensitive PSA and salvaged at a low PSA (ie, ≤ 0.5) also benefit from ADT. Patients and Methods The cohort comprised 108 patients who received radical prostatectomy (RP), were followed by ultrasensitive PSA, and received salvage radiotherapy at a PSA of 0.5 or less. Sixty patients had negative margins, and 48 patients had positive margins at RP. Cox multivariable regression analysis was performed to identify factors associated with time to secondary PSA failure and included PSA at salvage, year of treatment, Gleason score, ADT use, margin status, T stage, and PSA doubling time. Occurrence of distant metastases was documented. Results Median follow-up after radiation was 63.09 months. A total of 24 patients had a distant metastasis. In all patients, ADT use was associated with a decreased risk of recurrence (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.25-0.79; P = .006). On subgroup analysis, ADT was associated with a decreased risk of failure among patients with negative margins (HR, 0.27; 95% CI, 0.12-0.61; P = .002), but not among men with positive margins (HR, 0.78; 95% CI, 0.29-2.10; P = .63). Conclusions Even patients followed with ultrasensitive PSA and salvaged early with a PSA ≤ 0.5 seem to benefit from the addition of ADT to salvage radiation. However, this benefit seemed to be limited to men with negative margins; thus, men with positive margins and PSA ≤ 0.5 may be good candidates for salvage radiation alone.

To evaluate the relationship between age and race on the receipt of definitive therapy among men with high-risk prostate cancer (CaP).We used the Surveillance, Epidemiology and End Results Program to identify 62,644 men with high-risk CaP (PSA20 or Gleason 8-10 or stage ≥cT3a) diagnosed from 2004 to 2010. Multivariable logistic regression analysis modeled the interaction between age and race and its association with receipt of definitive therapy on 57,674 patients (47,879 white men; 9,795 African American [AA] men) with complete data on the covariates of interest.Among men age ≥70, AA men had a higher risk of CaP-specific mortality (PCSM) compared to white men after adjusting for sociodemographic and prostate cancer-specific factors (Adjusted HR 1.20; 95% CI 1.02-1.38; P=0.02). Nevertheless, a significant interaction between race and age was found (Pinteraction=0.01), such that the adjusted odds of receiving definitive treatment for AA vs. white was 0.67 (95% CI 0.62-0.73; P0.001) among men age70, but was 0.60 (95% CI 0.55-0.66; P0.001) among men age ≥70, suggesting increased racial disparity in the receipt of definitive treatment among older men.AA men with high-risk CaP are less likely to receive definitive therapy than white men. This disparity is significantly larger among men age ≥70, despite excess PCSM among AA men in this group. With a rapidly expanding population of older minority men, this disparity should be urgently addressed to prevent increasing disparities in cancer care.

To determine whether African Americans (AAs) with intermediate- to high-risk prostate cancer (PCa) receive similar treatment as white patients and whether any observed disparities are narrowing with time.We used Surveillance, Epidemiology, and End Results to identify 128,189 men with localized intermediate- to high-risk PCa (prostate-specific antigen ≥10 ng/mL, Gleason score ≥7, or T stage ≥T2b) diagnosed from 2004 to 2010. We used multivariate logistic regression analyses to determine the impact of race on the receipt of definitive treatment.AA men were significantly less likely to receive curative-intent treatment than white men (adjusted odds ratio [AOR], 0.82; 95% confidence interval [CI], 0.79-0.86; P .001). There was no evidence of this disparity narrowing over time (Pinteraction 2010 vs 2004 = .490). Disparities in the receipt of treatment between AA and white men were significantly larger in high-risk (AOR, 0.60; 95% CI, 0.56-0.64; P .001) than in intermediate-risk disease (AOR, 0.92; 95% CI, 0.88-0.97; P = .04; Pinteraction .001). After adjusting for treatment, demographics, and prognostic factors, AA men had a higher risk of prostate cancer-specific mortality (adjusted hazard ratio, 1.12; 95% CI, 1.01-1.25; P = .03).AA men with intermediate- to high-risk PCa are less likely to be treated with curative intent than white men. This disparity is worse in high-risk disease and is not improving over time. Factors underlying this treatment disparity should be urgently studied as it is a potentially correctable contributor to excess PCa mortality among AA patients.

To identify factors associated with weight gain at 1 year from initiation of androgen deprivation therapy (ADT).A retrospective review assessed weight change among 118 men with nonmetastatic prostate cancer treated with ADT for at least 6 months. Outcome associations were tested using 2-tailed t tests and linear regression.Men in our cohort had significant weight gain (+1.32 kg, P=.0005) in the 1 year after ADT initiation. Three risk factors for weight gain on ADT were identified as follows: age65 years (2.72 kg gained, P=.001), body mass index (BMI)30 (1.98 kg gained, P=.00002), and nondiabetic status (1.56 kg gained, P=.0003). Multivariable regression found both age65 years (beta=4.01, P=.02) and BMI30 (beta=3.57, P=.03) to be independently predictive of weight gain, whereas nondiabetic status was nonsignificantly predictive of weight gain (beta=2.14, P=.29). Weight change was further stratified by the total number of risk factors present (risk score): scores of 0, 1, 2, and 3 risk factors corresponded to weight changes of -1.10, +0.41, +1.34, and +3.79 kg, respectively (P-trend=.0005).Age65 years and BMI30 were both independently associated with weight gain 1 year after starting ADT. Increasing weight gain was also strongly associated with increasing number of baseline risk factors present. Despite traditional concerns about ADT in unhealthy men, these data suggest younger, healthier patients may be at higher risk for gaining weight on ADT and should be counseled accordingly.

Purpose To examine the impact of marital status on stage at diagnosis, use of definitive therapy, and cancer-specific mortality among each of the 10 leading causes of cancer-related death in the United States. Methods We used the Surveillance, Epidemiology and End Results program to identify 1,260,898 patients diagnosed in 2004 through 2008 with lung, colorectal, breast, pancreatic, prostate, liver/intrahepatic bile duct, non-Hodgkin lymphoma, head/neck, ovarian, or esophageal cancer. We used multivariable logistic and Cox regression to analyze the 734,889 patients who had clinical and follow-up information available. Results Married patients were less likely to present with metastatic disease (adjusted odds ratio [OR], 0.83; 95% CI, 0.82 to 0.84; P < .001), more likely to receive definitive therapy (adjusted OR, 1.53; 95% CI, 1.51 to 1.56; P < .001), and less likely to die as a result of their cancer after adjusting for demographics, stage, and treatment (adjusted hazard ratio, 0.80; 95% CI, 0.79 to 0.81; P < .001) than unmarried patients. These associations remained significant when each individual cancer was analyzed (P < .05 for all end points for each malignancy). The benefit associated with marriage was greater in males than females for all outcome measures analyzed (P < .001 in all cases). For prostate, breast, colorectal, esophageal, and head/neck cancers, the survival benefit associated with marriage was larger than the published survival benefit of chemotherapy. Conclusion Even after adjusting for known confounders, unmarried patients are at significantly higher risk of presentation with metastatic cancer, undertreatment, and death resulting from their cancer. This study highlights the potentially significant impact that social support can have on cancer detection, treatment, and survival.

In 1999 and 2000, 2 national guidelines recommended brachytherapy monotherapy (BT) primarily for treatment of low-risk prostate cancer but not high-risk prostate cancer. This study examined rates of BT use before and after publication of these guidelines, as compared with 4 other treatment options.From 1990 to 2011, 8128 men with localized prostate cancer (≤ T3cN0M0) were treated definitively within the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry with 1 of 5 primary treatments: BT, external beam radiotherapy (EBRT), EBRT with androgen deprivation therapy, EBRT+BT, or radical prostatectomy. Men were categorized into low-, intermediate-, and high-risk groups based on the guidelines' risk-group definitions. Within each risk group, logistic regression was used to estimate odds ratios (OR) comparing BT with other treatment options between the 1990-1998 and 1999-2011 periods, adjusting for age, disease characteristics, and clinic type.In total, 1117 men received BT alone for low- (n = 658), intermediate- (n = 244), or high-risk disease (n = 215). BT comprised 6.1% of all treatments in 1990-1998 versus 16.6% in 1999-2011 (P .01). The odds of BT use remained increased after adjusting for potential confounders (OR = 3.06; P .001) and was seen among low- (OR = 4.52; P .001), intermediate- (OR = 2.67; P .001), and even high-risk groups (OR = 2.11; P .001).National guidelines did not appear to influence practice patterns, as BT monotherapy use increased relative to other treatments from the 1990-1998 to 1999-2011 periods in unfavorable risk groups including men with high-risk prostate cancer.

To the authors' knowledge, it remains unknown whether race-based differences in cancer outcomes have changed with time. In the current study, the authors assessed whether racial disparities in cancer-specific mortality have improved over the last 20 years.The Surveillance, Epidemiology, and End Results program was used to identify 2,713,474 patients diagnosed between 1988 and 2007 with either lung, breast, prostate, or colorectal cancer (the leading 3 causes of cancer-related mortality among each sex). After exclusions, 1,001,978 patients remained eligible for analysis. The impact of race on cancer-specific mortality was assessed using the regression model of Fine and Gray; an interaction model evaluated trends over time.African Americans presented with a more advanced stage of disease (P.001) and underwent definitive therapy less often (P.001) than whites. After adjustment for demographics and year of diagnosis, African Americans were found to have higher estimates of cancer-specific mortality than whites for all cancers combined (hazards ratio, 1.28; 95% confidence interval, 1.26-1.30 [P.001]) and within each individual cancer (each P.05). These differences did not change significantly between 1988 through 1997 and 1998 through 2007, except among patients with breast cancer, in whom survival disparities increased. These findings remained significant after adjustment for stage of disease at presentation and receipt of definitive therapy (hazards ratio for breast cancer mortality in African Americans vs whites: 1.37 from 1988-1997 and 1.53 from 1998-2007; P for interaction, .001).The survival gap for African Americans has not closed over time. Race-based differences in outcome persist independent of stage of disease and treatment, suggesting that additional strategies beyond screening and improving access to care, such as further research into tumor biologies disproportionately affecting African Americans, are needed to improve survival for African American patients with cancer.

Surgery and radiation therapy represent the only curative options for many patients with solid malignancies. However, despite the recommendations of their physicians, some patients refuse these therapies. This study characterized factors associated with refusal of surgical or radiation therapy as well as the impact of refusal of recommended therapy on patients with localized malignancies.We used the Surveillance, Epidemiology, and End Results program to identify a population-based sample of 925,127 patients who had diagnoses of 1 of 8 common malignancies for which surgery and/or radiation are believed to confer a survival benefit between 1995 and 2008. Refusal of oncologic therapy, as documented in the SEER database, was the primary outcome measure. Multivariable logistic regression was used to investigate factors associated with refusal. The impact of refusal of therapy on cancer-specific mortality was assessed with Fine and Gray's competing risks regression.In total, 2441 of 692,938 patients (0.4%) refused surgery, and 2113 of 232,189 patients (0.9%) refused radiation, despite the recommendations of their physicians. On multivariable analysis, advancing age, decreasing annual income, nonwhite race, and unmarried status were associated with refusal of surgery, whereas advancing age, decreasing annual income, Asian American race, and unmarried status were associated with refusal of radiation (P.001 in all cases). Refusal of surgery and radiation were associated with increased estimates of cancer-specific mortality for all malignancies evaluated (hazard ratio [HR], 2.80, 95% confidence interval [CI], 2.59-3.03; P.001 and HR 1.97 [95% CI, 1.78-2.18]; P.001, respectively).Nonwhite, less affluent, and unmarried patients are more likely to refuse curative surgical and/or radiation-based oncologic therapy, raising concern that socioeconomic factors may drive some patients to forego potentially life-saving care.

Preoperative chemoradiotherapy (preopCRT) for locally advanced rectal cancer is associated with grade 3 or higher acute gastrointestinal (GI) toxicity. This study was conducted to determine whether intensity-modulated radiation therapy (IMRT) significantly reduces acute GI toxicity, compared to 3-dimensional conformal RT (3D-CRT) in preopCRT for rectal cancer.A retrospective analysis was conducted of 48 patients treated between January 2002 and August 2010 with preopCRT for rectal cancer. 3D-CRT or IMRT was administered at a planned dose of 45-50.4 Gy to patients positioned prone on a bowel-displacement device. Data regarding patient and tumor characteristics, treatment, acute toxicity, and tumor response were collected. Comparisons of acute toxicity and treatment response between 3D-CRT and IMRT were performed with the Chi-square or Fisher's exact test.There were no significant differences in radiation dose, median age, race, gender, stage, type of concurrent chemotherapy, pathologic complete response (pCR), or type of surgery (lower anterior or abdominal perineal resection) between 3D-CRT and IMRT. There was a significant reduction in grade 2 or higher GI toxicity (3D-CRT, 60.7%; IMRT, 30%; P = .036) and grade 2 or higher diarrhea (3D-CRT, 42.8%; IMRT, 10%; P = .014). Two patients who underwent 3D-CRT required a treatment break (grade 3 diarrhea and grade 3 dehydration). Radiation duration was significantly less (IMRT, 35 days; 3D-CRT, 39 days; P ≤ .0001). pCR rates were 16.7% for 3D-CRT and 21.4% for IMRT (nonsignificant [NS]); pCR+microscopic residual rates were 57.1% for IMRT and 27.8% for 3D-CRT (P = .093).Maximal bowel displacement with IMRT yields favorable acute GI toxicity and pathologic downstaging profiles, as compared to 3D-CRT in preoperative CRT for rectal cancer and warrants further prospective investigation.

Men receiving radiation for prostate cancer frequently want to know what steps they can take to optimize their chance of cure and reduce their risk of side effects. A variety of modifiable behaviors, medications, and complementary alternative medicine interventions have been investigated in this regard. In this review, we summarize data on tobacco use, exercise, statins and aspirin, and vitamins. There is limited randomized data supporting any of the interventions and additional studies are needed before clinicians can confidently inform their patients regarding what steps to take to improve their outcomes.

Original Article Impact of National Guidelines on Brachytherapy Monotherapy Practice Patterns for Prostate Cancer Yolanda D. Tseng, MD 1 ; Alan T. Paciorek, BS 2 ; Neil E. Martin, MD, MPH 3 ; Anthony V. D’Amico, MD, PhD 3 ; Matthew R. Cooperberg, MD, MPH 2 ; and Paul L. Nguyen, MD 3 BACKGROUND: In 1999 and 2000, 2 national guidelines recommended brachytherapy monotherapy (BT) primarily for treatment of low-risk prostate cancer but not high-risk prostate cancer. This study examined rates of BT use before and after publication of these guidelines, as compared with 4 other treatment options. METHODS: From 1990 to 2011, 8128 men with localized prostate cancer ( T3cN0M0) were treated definitively within the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry with 1 of 5 primary treatments: BT, external beam radiotherapy (EBRT), EBRT with androgen deprivation therapy, EBRT1BT, or radical prostatectomy. Men were categorized into low-, intermediate-, and high-risk groups based on the guidelines’ risk-group definitions. Within each risk group, logistic regression was used to estimate odds ratios (OR) comparing BT with other treatment options between the 1990-1998 and 1999-2011 periods, adjusting for age, disease characteristics, and clinic type. RESULTS: In total, 1117 men received BT alone for low- (n 5 658), intermediate- (n 5 244), or high-risk disease (n 5 215). BT comprised 6.1% of all treatments in 1990-1998 versus 16.6% in 1999-2011 (P

19 Background: Androgen deprivation therapy (ADT) has been associated with cognitive and psychological effects, including depression. ADT may also cause an increased incidence of anxiety; however, most studies have not considered anxiety as an individual outcome. We aimed to determine if receipt of any ADT or longer duration of ADT for prostate cancer is associated with increasing risk of being diagnosed with anxiety. Methods: We identified 78,552 men over 65 with stage I-III prostate cancer using the Surveillance, Epidemiology, and End Results-Medicare linked database from 1992-2006, excluding patients with psychiatric diagnoses within the prior year. Our primary analysis was the association of pharmacologic ADT with the diagnosis of anxiety using Cox-proportional hazard regression with propensity matching. Drug-data for treatment of anxiety was not available. Our secondary analysis was the association of ADT duration with a diagnosis of anxiety. Results: Overall, 43% (33,882) of patients who received ADT and had higher 3-year cumulative incidence of anxiety (4.1% vs. 3.5%) than patients without ADT (p < 0.001). Adjusted cox-analyses with propensity matching demonstrated patients with ADT had a 17% increased risk of anxiety (adjusted hazard ratio [AHR] = 1.17, 95% CI = [1.088-1.263]) compared to patients without ADT (p < 0.0001). The risk of anxiety increased with duration of ADT, from 4.5% with ≤ 6 months, 5.8% with 7-11 months, to 15.7% with ≥ 12 months (p-trend = 0.0123). Conclusions: Pharmacologic ADT is associated with an increased risk of anxiety in this large study of elderly men with localized prostate cancer. This risk increased with longer duration of ADT. Anxiety should be consider among the possible psychiatric effects of ADT and should be discussed along with depression prior to initiating ADT.

18 Background: In 2012, the United States Preventive Services Task Force (USPSTF) recommended against Prostate-Specific Antigen (PSA) screening, despite evidence that Black men are at a higher risk of prostate cancer-specific mortality (PCSM). We evaluated whether Black men of potentially screening-eligible age (55-69) are at a disproportionally high risk of poor outcomes. Methods: The SEER database was used to study 390,259 men diagnosed with prostate cancer in the United States between 2004-2011. Multivariable logistic regression modeled the association between Black race and stage of presentation, while Fine-Gray competing risks regression modeled the association between Black race and PCSM, both as a function of screening eligibility (age 55-69 vs not). Results: Black men were more likely to present with metastatic disease (adjusted odds ratio [AOR] 1.65; 1.58-1.72; P< 0.001) and were at a higher risk of PCSM (adjusted hazard ratio [AHR] 1.36; 1.27-1.46; P< 0.001) compared to Non-Black men. There were significant interactions between race and PSA-screening eligibility such that Black patients experienced more disproportionate rates of metastatic disease (AOR 1.76; 1.65-1.87 vs. 1.55; 1.47-1.65; Pinteraction< 0.001) and PCSM (AHR 1.53; 1.37-1.70 vs. 1.25; 1.14-1.37; Pinteraction= 0.01) in the potentially PSA-screening eligible group than in the group not eligible for screening. Conclusions: Racial disparities in prostate cancer outcome among Black men in are significantly worse in PSA-screening eligible populations. These results raise the possibility that Black men could be disproportionately impacted by recommendations to end PSA screening in the United States and suggest that Black race should inform clinical decisions on PSA screening.

50 Background: Androgen deprivation therapy (ADT) is not recommended for low-risk prostate cancer due to its known harms and lack of benefits. We evaluated the incidence and predictors of ADT use in men with low-risk prostate cancer. Methods: We identified 197,980 patients in the National Cancer Database (NCDB) with low-risk prostate cancer (Gleason 3+3 = 6, PSA < 10ng/mL, and cT1-T2a) diagnosed from 2004 to 2012 with complete demographic and treatment information. We determined the incidence of ADT use and utilized multiple logistic regression to evaluate predictors of ADT use. Results: ADT use in low-risk prostate cancer patients declined steadily from 2004 to 2012 (17.6% vs. 3.5%). 80.6% of these patients underwent radiation, and 10.0% received ADT as primary therapy. Among 82,354 low-risk disease patients treated with radiation, demographic and treatment factors associated with increased likelihood of ADT use include older age (adjusted odds ratio [AOR] 1.04 per year, p < 0.001); Hispanic vs. non-Hispanic white ethnicity (18.9% vs. 17.8%, AOR 1.26, p < 0.001); having Medicare at age < 65 (15.3%, AOR 1.14, p = 0.008) or Medicare at age ≥ 65 (21.5%, AOR 1.11, p < 0.001) vs. private insurance (13.9%); having bottom quartile vs. top quartile income (19.4% vs. 16.3%, AOR 1.26, p < 0.001); being treated in a community cancer program (22.0%, AOR 1.60, p < 0.001) or a comprehensive community cancer program (18.7%, AOR 1.38, p < 0.001) vs. an academic/research cancer program (13.9%); and receiving brachytherapy vs. external beam radiation therapy (19.3% vs. 15.5%, AOR 1.32, p < 0.001). Increasing distance from the treatment facility was associated with decreased likelihood of receiving ADT (AOR 0.97 for every 100 miles, p = 0.001). Conclusions: Among men with low-risk prostate cancer, increasing age, Hispanic ethnicity, Medicare insurance, lower income level, treatment in a non-academic/research cancer program, and brachytherapy use were all associated with increased odds of receiving ADT. Given the lack of evidence supporting ADT use in low-risk disease and increasing evidence of its many side-effects, it is critical to understand why low-risk prostate cancer patients are still receiving ADT so that this practice may be reduced.

Purpose: To study associations between single nucleotide polymorphisms (SNP) in Ribonuclease L (RNASEL), a gene implicated in inflammation and prostate cancer risk, and outcomes after radiation therapy. Experimental Design: We followed participants in the prospective US Health Professionals Follow-Up Study treated with radiation therapy for early-stage prostate cancer. Three SNPs were genotyped based on previously determined functional and biological significance. We used multivariable Cox proportional hazards models to assess per-allele associations with the primary outcome defined as time to a composite endpoint including development of lethal prostate cancer or biochemical recurrence. Results: We followed 434 patients treated with radiation therapy for a median of 9 years. On multivariate analysis, the rs12757998 variant allele was associated with significantly decreased risk of the composite endpoint [HR: 0.65; 95% confidence interval (CI), 0.45–0.94%; P = 0.02] driven by decreased biochemical recurrence (HR: 0.60; 95% CI, 0.40–0.89%; P = 0.01) and men treated with external beam (HR: 0.58; 95% CI, 0.36–0.93%; P = 0.02). In contrast, in 516 men from the same cohort treated with radical prostatectomy, we found no significant impact of this variant on outcome. Furthermore, the rs12757998 variant allele significantly modified the association between androgen deprivation therapy and outcomes after radiation therapy (p-interaction = 0.02). Conclusion: We show an association between RNASEL SNP rs12757998 and outcome after radiation therapy for prostate cancer. This SNP is associated with increased circulating C-reactive protein and interleukin-6, suggesting a potential role for inflammation in the response to radiation. If validated, genetic predictors of outcome may help inform prostate cancer management. Clin Cancer Res; 19(6); 1612–9. ©2013 AACR.

To characterize prostate swelling and dosimetry in patients with small prostate volumes (PVs) undergoing brachytherapy.We studied 25 patients with PV25 cc (range, 15.1-24.8) and 65 patients with PV ≥25 cc (range, 25.0-66.2) based on three-dimensional ultrasound contours who underwent brachytherapy monotherapy with intraoperative planning. Postoperative Days 1 and 30 dosimetry was done by CT-MRI fusion.Small PVs had greater Day 1 swelling than large PVs (32.5% increase in volume vs. 23.7%, p = 0.04), but by Day 30, swelling was minimal and not significantly different (p = 0.44). Small PVs had greater seed and needle densities at implant (p0.001). Rectal and urethral doses were nearly identical by Day 30 (small PV rectum receiving 100% of the prescription dose [145 Gy] [V100] = 0.32 cc; large PV rectum V100 = 0.33 cc, p = 0.99; small PV urethra receiving 150% of the prescription dose [145 Gy] [V150] = 0.20, large PV urethra V150 = 0.20, p = 0.91). Swelling at Day 1 created some cool implants (rate dose that covers 90% of the prostate volume [D90140 Gy = 12.0% and 9.4% for the small and large PV groups, respectively, p = 0.71), but Day 30 planning target volume coverage was excellent (rate D90140 Gy = 0% for both groups).Although smaller prostates have greater Day 1 swelling, good Day 30 dosimetry can be achieved, making them excellent candidates for (125)I seeds (half-life [t½] = 60 days). Smaller prostates may be suboptimal for shorter t½ sources such as (131)Cs (t½ = 9.7 days), in which the majority of the dose may be delivered to an edematous gland, unless the planning is adjusted to anticipate the edema.

Prostate cancer patients who are overweight have greater risk of disease recurrence and cancer-specific mortality (1,2). In the United States, 238590 men will be diagnosed with prostate cancer in 2013, and two-thirds of the adult male population is overweight or obese (3,4). Thus, understanding the mechanisms linking excess bodyweight with worse prostate cancer outcomes has important public health implications. Obesity deregulates multiple pathways that could influence disease outcomes. For example, circulating levels of insulin, free insulin growth factor 1 (IGF-1), adiponectin, and sex hormones are altered in obese vs normal-weight men (5,6). The common gene fusion TMPRSS2:ERG is present in half of prostate cancers (7,8). TMPRSS2 is regulated by androgens and possibly estrogens (9), and the oncogene ERG is a member of the ETS transcription factor family. Its discovery in 2005 was notable both because it was the first identification of a common gene fusion in a common solid tumor and because it represents a model of hormonal regulation of an oncogene. Based on experimental and clinical data, TMPRSS2:ERG-positive tumors may define a distinct subgroup of prostate cancers (8). Gene fusions involving ETS transcription factors are also present in other cancers. Notably, the ETS fusion EWS/FLI-1 occurs in 90% of Ewing sarcomas and is linked with increased IGF-1 receptor (IGF-1R) activity (10,11). Given its influence on several hormonal pathways (5,6), obesity could potentially interact with TMPRSS2:ERG to differentially impact prostate cancer outcomes. In this study, we examined in a cohort of 1243 US men with prostate cancer whether the associations of body mass index (BMI; kg/m2) and waist circumference with prostate cancer recurrence and death differ among men whose tumors overexpressed ERG [a marker of TMPRSS2:ERG (12)] compared with men whose tumors did not. We also explored whether tumor expression of key metabolic proteins IGF-1R, insulin receptor (IR), adiponectin receptor 2 (AdipoR2), and fatty acid synthase (FASN) differs in ERG-positive vs ERG-negative tumors.

Background: Loss of PTEN has been shown to be associated with aggressive behavior of prostate cancer. It is less clear that loss of PTEN also increases the risk of cancer mortality. We investigated the association between PTEN expression and prostate cancer mortality and the potential effect modification by IGF-IR, a direct activator of the phosphoinositide-3-kinase (PI3K) pathway. Methods: Protein expression in tumor was evaluated using tumor tissues obtained from 805 participants of the Physicians' Health and the Health Professionals Follow-up studies who were diagnosed with prostate cancer and underwent radical prostatectomy. Proportional hazard models were used to assess PTEN expression and its interaction with IGF-IR, in relation to lethal prostate cancer (cancer-specific death or distant metastases). Results: Low PTEN expression was associated with an increased risk of lethal prostate cancer [HR, 1.7; 95% confidence interval (CI), 0.98–3.2; Ptrend = 0.04]. The association was attenuated after adjustment for Gleason grade, tumor stage, and prostate-specific antigen (PSA) at diagnosis. A significant negative interaction between PTEN and IGF-IR was found (Pinteraction = 0.03). Either reduction in PTEN or increase in IGF-IR expression was sufficient to worsen prognosis. Models including PTEN and IGF-IR expression offer additional predicting power to prostate cancer survival, compared to those only including demographic and clinical factors. Conclusions: Low PTEN protein expression significantly increases the risk of lethal prostate cancer, particularly when the IGF-IR expression remains at normal level. Impact: PTEN and IGF-IR expression in tumor are promising candidates for independent prognostic factors to predict lethal prostate cancer. Cancer Epidemiol Biomarkers Prev; 22(11); 1984–93. ©2013 AACR.

170 Background: Clinical pathways increase compliance with treatment guidelines and reduce in-hospital complications. Evidence around treatment of complicated bone metastases is increasingly nuanced and although ASTRO/ACR recommend single fraction radiation therapy for uncomplicated bone metastases, implementation is variable. We sought to determine the effects of a bone metastases-focused clinical pathway on the practice patterns of our institution’s palliative radiation oncology service (SPRO), which sees 600 patients yearly and on a rotating basis, involves 23 physicians, 28 residents, 2 nurse practitioners, and 1 fellow. We hypothesized that pathway implementation would augment data-driven use of palliative radiation for bone metastases, including use of 8 Gy x 1 for uncomplicated metastases. It would also enhance physician efficiency and confidence. Methods: Using published literature, clinical guidelines, and expert input, we designed a comprehensive clinical pathway for bone metastases radiation. This was translated to a secure electronic interface as a decision support tool and integrated into daily SPRO workflows. Providers were surveyed pre and post implementation to assess expectations and elicit feedback. Rates of pathway compliance and reasons for non-compliance were assessed. Rates of 8 Gy x 1 use for uncomplicated metastases were compared pre and post implementation. Our aim was for approximately 70-80% on-pathway rates. Results: The final pathway, which includes twenty endpoints, integrates several validated scoring systems, including assessments of life expectancy, spinal stability, and appropriateness of surgical management. The pathway has been well received on the SPRO service, with addition of extra steps to workflows being the main cause of resistance to use. Data on rates of pathway adherence will be reported, and rates of 8 Gy x 1 use will be compared to the baseline of 22%. Conclusions: Our experience suggests the utility of pathways-based decision support for bone metastases radiation on a palliation consult service. Next steps include assessing the pathway’s effects on guideline-concordant care and calculating associated cost savings.

97 Background: We sought to implement patient reported outcomes (PRO) surveys to measure the acute and late effects of radiation treatment at a multisite academic medical center. Methods: Over the course of 18 months we addressed survey identification and implementation hurdles. Many existing validated instruments were designed for clinical research and are not ideally suited for either routine care or for the tracking of acute toxicities of radiation therapy. A physician and a nurse champion for each disease site identified or created situation- and site-specific tools based on validated questionnaires form the literature. Our aim was for questionnaires to be no longer than 20 - 30 questions. Using iPads, we deployed an institutionally-developed survey platform integrated with scheduling within the clinic. We surveyed physicians, nurses, and residents 3 months following the implementation of PROMs to assess their general response to the initiative. Results: Thirty-seven PRO measures comprised of 640 questions were implemented for all disease sites in adult patients at 6 departmental locations treating a total of 350 patients daily. Following implementation in January of 2015, > 13,000 surveys have been completed through the end of September 2015. Each question took on average approximately 14 seconds to complete and common surveys took approximately 10 minutes. Of 36 departmental provider respondents (50% response rate overall), 47% stated that they use the PROMs in their daily practice. The majority of respondents felt that the PROs were valuable (67%) and relevant (75%) either usually, most of the time or always. Only 33% felt the quality of their care was enhanced usually or most of the time while 53% felt the PROs engaged patients in a better understanding of their own care. Conclusions: We successfully implemented disease site- and context-specific PROs across a large, academic radiation oncology department. Although we have achieved widespread adoption and some subjective impression of care improvement among providers, further work is necessary to reduce barriers to their clinical use and to leverage them for systematic improvements in care.

Given the clinical heterogeneity and increasing stage migration to lower-risk disease with PSA screening, there is a pressing need for reliable prognostic factors in prostate cancer. An increased understanding of the molecular pathogenesis of the disease has resulted in the identification of a variety of molecular markers representing many of the hallmarks of cancer. Current markers which hold promise include cell cycle control molecules, pro-growth signals, and markers for invasion and metastasis. Evolving technologies such as circulating tumor cells also hold great promise. This chapter summarizes markers from the tumor, urine, and blood which may help better characterize an individual patient’s clinical course.

Purpose: To investigate clinical and pathologic factors significant in predicting local response and time to further treatment after low-dose involved-field radiation therapy (LD-IFRT) for non-Hodgkin lymphoma (NHL). Methods and Materials: Records of NHL patients treated at a single institution between April 2004 and September 2011 were retrospectively reviewed. Low-dose involved-field radiation therapy was given as 4 Gy in 2 fractions over 2 consecutive days. Treatment response and disease control were determined by radiographic studies and/or physical examination. A generalized estimating equation model was used to assess the effect of tumor and patient characteristics on disease response. A Cox proportional hazards regression model was used to assess time to further treatment. Results: We treated a total of 187 sites in 127 patients with LD-IFRT. Histologies included 66% follicular, 9% chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma, 10% marginal zone, 6% mantle cell lymphoma (MCL), and 8% other. Median follow-up time was 23.4 months (range, 0.03-92.2 months). The complete response, partial response, and overall response rates were 57%, 25%, and 82%, respectively. A CLL histology was associated with a lower response rate (odds ratio 0.2, 95% confidence interval 0.1-0.5, P=.02). Tumor size, site, age at diagnosis, and prior systemic therapy were not associatedmore » with response. The median time to first recurrence was 13.6 months. Those with CLL and age ≤50 years at diagnosis had a shorter time to further treatment for local failures (hazard ratio [HR] 3.63, P=.01 and HR 5.50, P=.02, respectively). Those with CLL and MCL had a shorter time to further treatment for distant failures (HR 11.1 and 16.3, respectively, P

Study Type - Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? The return of testosterone to normal levels following short-course androgen blockade in prostate cancer is variable. Factors associated with a longer time to recovery include older age and lower baseline testosterone level. In this study, we found that among men treated with 6 months of combined androgen blockade and radiation therapy, higher biopsy Gleason grade was associated with a shorter time to testosterone normalization.• To determine whether the biopsy Gleason score is associated with duration of testosterone suppression following 6 months of combined androgen blockade (CAB) and radiation therapy (RT) in men with prostate cancer (PCa).• The study cohort consisted of 221 men with PCa treated with RT and 6 months of CAB between 1996 and 2005. • We defined the duration of testosterone suppression as the time between the last day of CAB and the date the testosterone returned to ≥ 252 ng/dL. We used Cox regression multivariable analysis to relate biopsy Gleason score to duration of testosterone suppression following cessation of CAB.• A biopsy Gleason score of 8-10 had an adjusted hazard ratio (AHR) of 1.56 (95% confidence interval [CI] 1.04, 2.34; P= 0.03) for a shorter time to testosterone normalization relative to Gleason 6. Specifically, the 51 men with biopsy Gleason score of 8-10 had a median time to testosterone normalization of 17.0 months compared with 22.1 months and 23.8 months for those with biopsy Gleason ≤ 6 and 7, respectively. • Increasing age was significantly associated with a longer duration of testosterone suppression (AHR of 0.95 [95% CI 0.92, 0.97; P0.001]) as was a higher baseline PSA (AHR 0.82 [95% CI 0.69, 0.97; P= 0.02]).• A biopsy Gleason score of 8-10 was associated with a shorter period of testosterone suppression following 6 months of CAB and RT. These data are consistent with the hypothesis that a factor released from high-grade PCa cells may impact on testosterone production.

BACKGROUND: Automated scanning devices and image analysis software provide a means to overcome the limitations of manual semiquantitative scoring of immunohistochemistry. Common drawbacks to automated imaging systems include an inability to classify tissue type and an inability to segregate cytoplasmic and nuclear staining. METHODS: Immunohistochemistry for the membranous marker α-catenin, the cytoplasmic marker stathmin and the nuclear marker Ki-67 was performed on tissue microarrays (TMA) of archival formalin-fixed paraffin-embedded tissue comprising 471 (α-catenin and stathmin) and 511 (Ki-67) cases of prostate adenocarcinoma. These TMA were quantitatively analysed using two commercially available automated image analysers, the Ariol SL-50 system and the Nuance system from CRi. Both systems use brightfield microscopy for automated, unbiased and standardised quantification of immunohistochemistry, while the Nuance system has spectral deconvolution capabilities. RESULTS: Overall concordance between scores from both systems was excellent (r=0.90; 0.83-0.95). The software associated with the multispectral imager allowed accurate automated classification of tissue type into epithelial glandular structures and stroma, and a single-step segmentation of staining into cytoplasmic or nuclear compartments allowing independent evaluation of these areas. The Nuance system, however, was not able to distinguish reliably between tumour and non-tumour tissue. In addition, variance in the labour and time required for analysis between the two systems was also noted. CONCLUSION: Despite limitations, this study suggests some beneficial role for the use of a multispectral imaging system in automated analysis of immunohistochemistry.

Background: Whether the genomic rearrangement transmembrane protease, serine 2 (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (ERG) has prognostic value in prostate cancer is unclear. Methods: Among men with prostate cancer in the prospective Physicians' Health and Health Professionals Follow-Up Studies, we identified rearrangement status by immunohistochemical assessment of ERG protein expression. We used Cox models to examine associations of ERG overexpression with biochemical recurrence and lethal disease (distant metastases or cancer-specific mortality). In a meta-analysis including 47 additional studies, we used random-effects models to estimate associations between rearrangement status and outcomes. Results: The cohort consisted of 1,180 men treated with radical prostatectomy between 1983 and 2005. During a median follow-up of 12.6 years, 266 men experienced recurrence and 85 men developed lethal disease. We found no significant association between ERG overexpression and biochemical recurrence [hazard ratio (HR), 0.99; 95% confidence interval (CI), 0.78–1.26] or lethal disease (HR, 0.93; 95% CI, 0.61–1.43). The meta-analysis of prostatectomy series included 5,074 men followed for biochemical recurrence (1,623 events), and 2,049 men followed for lethal disease (131 events). TMPRSS2:ERG was associated with stage at diagnosis [risk ratio (RR)≥T3 vs. T2, 1.23; 95% CI, 1.16–1.30) but not with biochemical recurrence (RR, 1.00; 95% CI, 0.86–1.17) or lethal disease (RR, 0.99; 95% CI, 0.47–2.09). Conclusions: These results suggest that TMPRSS2:ERG, or ERG overexpression, is associated with tumor stage but does not strongly predict recurrence or mortality among men treated with radical prostatectomy. Impact: This is the largest prospective cohort study to examine associations of ERG overexpression and lethal prostate cancer among men treated with radical prostatectomy. Cancer Epidemiol Biomarkers Prev; 21(9); 1497–509. ©2012 AACR.

Purpose Conflicting reports remain regarding the association between vasectomy, a common form of male contraception in the United States, and prostate cancer risk. We examined prospectively this association with extended follow-up and an emphasis on advanced and lethal disease. Patients and Methods Among 49,405 US men in the Health Professionals Follow-Up Study, age 40 to 75 years at baseline in 1986, 6,023 patients with prostate cancer were diagnosed during the follow-up to 2010, including 811 lethal cases. In total, 12,321 men (25%) had vasectomies. We used Cox proportional hazards models to estimate the relative risk (RR) and 95% CIs of total, advanced, high-grade, and lethal disease, with adjustment for a variety of possible confounders. Results Vasectomy was associated with a small increased risk of prostate cancer overall (RR, 1.10; 95% CI, 1.04 to 1.17). Risk was elevated for high-grade (Gleason score 8 to 10; RR, 1.22; 95% CI, 1.03 to 1.45) and lethal disease (death or distant metastasis; RR, 1.19; 95% CI, 1.00 to 1.43). Among a subcohort of men receiving regular prostate-specific antigen screening, the association with lethal cancer was stronger (RR, 1.56; 95% CI, 1.03 to 2.36). Vasectomy was not associated with the risk of low-grade or localized disease. Additional analyses suggested that the associations were not driven by differences in sex hormone levels, sexually transmitted infections, or cancer treatment. Conclusion Our data support the hypothesis that vasectomy is associated with a modest increased incidence of lethal prostate cancer. The results do not appear to be due to detection bias, and confounding by infections or cancer treatment is unlikely.

Clinical outcomes in prostate cancer are heterogeneous, and given the high prevalence of the disease, there is a pressing need to identify clinically useful markers of prognosis. Many clinical, pathological, molecular, and genetic factors have been investigated in this capacity, although relatively few are routinely used. With a growing understanding of the molecular pathogenesis of prostate cancer, there is the potential that the next generation of makers will prove sufficiently robust to guide the optimal management of men with prostate cancer. Here, we review the various clinical and molecular prognostic determinants in prostate cancer.

We investigated whether the prostate specific antigen nadir predicts prostate cancer specific and all cause mortality in men treated in a randomized trial of radiation with or without 6 months of androgen deprivation therapy.The study included 204 men with cT1b-T2bN0M0 prostate adenocarcinoma and at least 1 unfavorable factor, including prostate specific antigen less than 10 to 40 ng/ml, Gleason 7 or greater, or T3 on magnetic resonance imaging. We performed Fine and Gray regression, and Cox multivariable analysis to determine whether an increasing prostate specific antigen nadir was associated with prostate cancer specific and all cause mortality, adjusting for treatment, age, Adult Comorbidity Evaluation 27 score and cancer prognostic factors.At a 6.9-year median followup median prostate specific antigen nadir was 0.7 ng/ml for radiation alone and 0.1 ng/ml for radiation plus androgen deprivation therapy. The prostate specific antigen nadir (adjusted HR 1.18/ng/ml increase, 95% CI 1.07-1.31, p=0.001) and Gleason 8 or greater (adjusted HR 8.05, 95% CI 1.01-64.05, p=0.049) significantly predicted increased prostate cancer specific mortality. Moderate/severe comorbidity carried a decreased risk (adjusted HR 0.13, 95% CI 0.02-0.96, p=0.045). Higher prostate specific antigen nadir (adjusted HR 1.10/ng/ml increase, 95% CI 1.04-1.17), older age (adjusted HR 1.10/year, 95% CI 1.04-1.15) and interaction between comorbidity score and randomization arm (each p0.001) increased the all cause mortality risk. Men who achieved a prostate specific antigen nadir of the median value or less had lower estimated prostate cancer specific and all cause mortality at 7 years (3.7% vs 18.3%, p=0.0005 and 31.5% vs 55.0%, p=0.002).Posttreatment prostate specific antigen nadir is significantly associated with the risk of prostate cancer specific and all cause mortality after radiation with or without androgen deprivation therapy. A suboptimal prostate specific antigen nadir may identify candidates for earlier intervention to prolong survival.

Purpose To determine the incidence and predictors of clinician-scored gynecomastia induced by 6 months of combined androgen blockade (CAB) in a randomized trial. Methods We studied 94 men with intermediate or high-risk prostate cancer randomized to radiation plus 6 months of neoadjuvant CAB consisting of a gonadotropin-releasing hormone agonist and antiandrogen (flutamide). Patients were assessed for breast symptoms monthly as per protocol. Patients reporting breast tenderness or enlargement were then examined shirtless. Results Median age at entry was 72.1 years. While 52 patients (55.3%) reported either breast tenderness or enlargement, only 9 patients (9.6%) were scored as having gynecomastia when examined shirtless by a single clinician. Four patients received radiation for self-reported breast tenderness or enlargement without clinician-scored gynecomastia. If these 4 had not been radiated, the total incidence of clinician-scored gynecomastia may have been as high as 13 of 94 (13.8%). No patient variable, such as age, body-mass index, and Adult Comorbidity Evaluation-27 score, or discontinuation of the antiandrogen, was associated with the development of gynecomastia. Conclusions While many patients self-reported breast tenderness or enlargement with short-course CAB, the incidence of breast enlargement noticeable to an examiner when the patient was shirtless was less than 15%, which is much lower than the 60% to 80% rates typically reported with antiandrogen monotherapy. Given that the long-term risks of prophylactic breast irradiation are not well characterized, these data suggest that prophylactic breast irradiation may not be as necessary in men receiving short-course CAB.

Purpose Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis. Patients and Methods Using the complementary DNA–mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason ≤ 6 to those with Gleason ≥ 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases. Results We built a 157-gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006). Conclusion Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment.

Purpose It is unknown whether the excess risk of all-cause mortality (ACM) observed when androgen deprivation therapy (ADT) is added to radiation for men with prostate cancer and a history of congestive heart failure (CHF) or myocardial infarction (MI) also applies to those with high-risk disease. Methods and Materials Of 14,594 men with cT1c–T3aN0M0 prostate cancer treated with brachytherapy-based radiation from 1991 through 2006, 1,378 (9.4%) with a history of CHF or MI comprised the study cohort. Of these, 22.6% received supplemental external beam radiation, and 42.9% received a median of 4 months of neoadjuvant ADT. Median age was 71.8 years. Median follow-up was 4.3 years. Cox multivariable analysis tested for an association between ADT use and ACM within risk groups, after adjusting for treatment factors, prognostic factors, and propensity score for ADT. Results ADT was associated with significantly increased ACM (adjusted hazard ratio [AHR] = 1.76; 95% confidence interval [CI], 1.32–2.34; p = 0.0001), with 5-year estimates of 22.71% with ADT and 11.62% without ADT. The impact of ADT on ACM by risk group was as follows: high-risk AHR = 2.57; 95% CI, 1.17–5.67; p = 0.019; intermediate-risk AHR = 1.75; 95% CI, 1.13–2.73; p = 0.012; low-risk AHR = 1.52; 95% CI, 0.96–2.43; p = 0.075). Conclusions Among patients with a history of CHF or MI treated with brachytherapy-based radiation, ADT was associated with increased all-cause mortality, even for patients with high-risk disease. Although ADT has been shown in Phase III studies to improve overall survival in high-risk disease, the small subgroup of high-risk patients with a history of CHF or MI, who represented about 9% of the patients, may be harmed by ADT.

BRCA1 functions as a tumor suppressor; recent work suggests that BRCA1 may also induce cell cycle arrest to allow for DNA repair. We hypothesized that BRCA1 expression in prostate tumor tissue may be associated with prostate cancer progression through regulation of the cell cycle. We used immunohistochemistry to evaluate BRCA1 protein expression in archival tumor samples from 393 prostate cancer cases in the Physicians' Health Study. The men were followed prospectively from diagnosis to development of metastases and mortality. Fifteen percent of tumors stained positive for BRCA1. BRCA1-positive tumors had substantially increased tumor proliferation index compared with negative tumors (47.0 Ki67-positive nuclei versus 10.3, P = 0.0016) and were more likely to develop lethal cancer compared with BRCA1-negative tumors (hazard ratio, 4.6; 95% confidence interval, 2.4–8.7). These findings strengthen the hypothesis that BRCA1 plays a role in cell cycle control and show that BRCA1 is a marker of clinical prostate cancer prognosis. Cancer Res; 70(8); 3136–9. ©2010 AACR.

Numerous management options are available to patients with advanced-stage or relapsed/refractory indolent non-Hodgkin lymphomas (NHLs). These include observation in patients with low-volume disease, systemic therapy including radioimmunotherapy, and high-dose therapy with stem cell transplant. In selected patients with localized symptomatic disease, local radiation therapy to sites of involvement can offer effective palliation. However, systemic therapy and standard-dose radiation therapy can be associated with significant toxicities. Over the past 15 years, several groups have investigated the role of low-dose radiation therapy--typically 4 Gy in two fractions--to an involved-field as an option for palliation in patients with NHL. Overall response rates of more than 80% have been consistently reported with local control maintained for 2 years. In this review, we outline the clinical experience with this approach in NHL of various histologies.

556 Background: Approximately 7000 cases of anal squamous cell carcinoma (ASCC) are diagnosed annually in the US, and the incidence is increasing. Combination chemoradiotherapy (CRT) is the standard of care for locally-advanced ASCC, and the 5-year survival rate is approximately 70%. Unlike many other tumor types, no large-scale genomic studies have been reported for anal cancer. In order to characterize the mutational landscape of ASCC and identify potential therapeutic targets, we perform comprehensive genomic analysis of a pilot cohort of ASCC cases. Methods: We performed whole exome sequencing of tumor and matched germline DNA from a pilot cohort of twelve patients with locally advanced (Stage II-IVA) ASCC cases treated at Dana-Farber Cancer Institute. All patients received concurrent chemoradiotherapy (CRT): seven ‘responders’ had complete response and no evidence of recurrence with a minimum of one year follow-up, while five ‘non-responders’ had residual or recurrent disease following CRT. For non-responders, both primary and residual/recurrent tumors were analyzed. Results: The overall mutation rate was 3.7 mutations per megabase (Mb). Recurrent mutations in several known cancer genes were observed. Five of twelve cases had a hotspot mutation in FBXW7, including 3 of the 5 non-responders. Known oncogenic mutations were also observed in PIK3CA (3 tumors) and NFE2L2/KEAP1 (3 tumors). Analysis of paired primary and recurrent samples revealed surprising examples of distinct driver mutations in clonally-related tumors. Copy number analysis revealed focal amplifications of chromosome 3q. Conclusions: This study represents one of the first genome-scale analyses in ASCC. The overall mutation rate was similar to other HPV-associated squamous cell carcinomas, and recurrent mutations in several known cancer genes were observed. Analysis of paired primary and residual/recurrent tumors revealed surprising heterogeneity. To extend our findings, we are currently performing a similar analysis in a larger extension cohort of ASCC tumors.

We aimed to describe changes in treatment patterns for clinical T3 prostate cancer (PCa) from 1998 to 2012, specifically investigating what factors influence receipt of prostatectomy or radiation.Using the Surveillance, Epidemiology, and End Results database, we studied 11,604 men with clinical T3N0M0 PCa from 1998 to 2012, with treatment categorized as radiation, radical prostatectomy (RP), or no curative therapy. We calculated rate of treatment type by year of diagnosis to investigate trends in treatment patterns, further stratifying by clinical T3a, defined as unilateral and bilateral extracapsular extension (n = 3,842), vs. T3b (defined as extension to seminal vesicles (n = 3,665). Finally, a multivariable logistic regression analysis measured association of demographic and clinical variables with type of treatment received for years 2010 to 2011.Rates of prostatectomy increased significantly from 1998 to 2012 (12.5% vs. 44.4%), radiation decreased significantly (55.8% vs. 38.4%), and receipt of no treatment also decreased (31.7% vs. 17.2%, all P0.001). These trends were similar for clinical T3a and T3b. Rates of prostatectomy surpassed radiation by 2008 in clinical T3a, reaching 49.8% vs. 37.1%, respectively, in 2012 (P = 0.002), and were statistically similar to radiation in 2012 for clinical T3b, reaching 41.6% vs. 42.1% (P = 0.92). Multivariable logistic regression analysis demonstrated that patients were less likely to receive prostatectomy than radiation if biopsy Gleason scores of 8 to 10 (adjusted odds ratio [AOR] = 0.41, 0.32-0.53), higher initial prostate-specific antigen (AOR = 0.97, 0.97-0.98), and older age (AOR = 0.92, 0.90-0.03, all P0.01). The likelihood of RP was similar among cT3b vs. cT3a (AOR = 0.95, 0.71-1.26, P = 0.74).Since 1998, there has been a significant increase in the use of RP for clinical T3 PCa and a significant decrease in the use of radiation such that in 2012, the use of prostatectomy exceeded the use of radiation.

494 Background: Re-irradiation (re-RT) with external beam RT following prior pelvic RT has not been reported, given both an absence of guidelines and concerns for toxicity. We sought to characterize bladder and bowel toxicities among patients treated with high-dose palliative re-RT for genitourinary secondary malignant neoplasms (SMN) or local recurrence (LR) following prior RT for pelvic cancer and to assess the response to re-RT with regard to palliation of symptoms. Methods: With IRB approval, the records of 28 consecutive patients with advanced pelvic malignancies given palliative re-RT between 2008-2014 were retrospectively analyzed. Descriptive analyses focused on toxicities and symptom control; responses were evaluated by two independent observers. Results: The cohort contained 27 males and 1 female. Initial cancers included 19 prostate, 4 ureteral, 2 bladder, 2 rectal and 1 penile carcinoma and 1 large cell lymphoma. Median initial RT dose was 63.5 Gy (range, 30-75.6 Gy; 8 unknown). The median time between initial RT and re-RT was 9.5 years (range, 0.2-32 years). At re-RT, there were 16 LRs and 12 SMNs including 14 bladder, 11 prostate, 3 ureteral and 1 penile cancers. Indications for re-RT were most commonly pain and bleeding. Given the severity of symptoms and bulk of disease at the time of re-RT, hypofractionated higher-dose RT was given. Median re-RT dose was 50 Gy (range, 27.5-66 Gy). For patients who received < 60 Gy, the median daily re-RT dose was 250 cGy. Re-RT was well-tolerated; there were no grade 2-4 toxicities. After treatment, 24 patients (92%) had complete resolution of their symptoms. Relief was durable in 67% of patients. Median overall survival was 5.8 months (range, 0.3-38.9 months) and 89% of patients were followed until death. Median follow-up was 5.2 months (range, 0.23-30.2 months). Conclusions: This institutional series suggests that moderate- to high-dose re-RT with median cumulative doses ≥ 100 Gy may achieve successful palliation of pelvic symptoms without undue toxicity in patients previously treated with high-dose RT. These results require validation in a larger prospective cohort.

54 Background: Current National Comprehensive Cancer Network (NCCN) guidelines uniformly recommend long-term androgen deprivation therapy (ADT) for all men with high-risk prostate cancer. We sought to determine whether the use of long-term ADT varied by the subcategory of disease, including the recently-defined subcategories of high-risk disease (favorable, other, and very-high) versus intermediate-risk disease. Methods: We identified 5,836 patients with NCCN intermediate-, high-, or very high-risk prostate cancer diagnosed between 2004 and 2007 and managed with external beam radiation therapy (EBRT) using the Surveillance, Epidemiology, and End Results database linked to Medicare claims data. Patients were stratified by risk group: intermediate-risk, favorable high-risk (previously defined and validated as T1c, Gleason 4+4=8, PSA < 10 ng/mL or T1c, Gleason 6, PSA > 20 ng/mL), other high-risk, or very high-risk. We used competing risks regression to estimate the rates of long-term (≥ 2 years) ADT in each of these groups. Differences were compared using multivariable regression modeling, adjusting for year of diagnosis, race, marital status, income level, age, and comorbidity. Results: Men with favorable high-risk prostate cancer were significantly less likely to receive 2 years of ADT than others with high-risk disease (21.9% vs. 29.3%, adjusted hazard ratio [AHR] 0.78, 95% confidence interval [CI] 0.67-0.90, p = 0.001), and similarly likely as those with intermediate-risk disease (AHR 1.08, 95% CI 0.94-1.25, p = 0.288). Others with high-risk disease were less likely to receive 2 years of ADT than those with very high-risk cancer (29.3% vs 36.4%, AHR 0.84, 95% CI 0.74-0.96, p = 0.010). Conclusions: Patients with EBRT-managed high-risk prostate cancer received significantly different rates of long-course ADT based on subclassification. Despite NCCN guidelines recommending long-term ADT for all high-risk or very high-risk prostate cancer, our results might reflect the view that these patients represent a heterogeneous group, with favorable high-risk cancer possibly warranting less aggressive therapy than other high-risk or very high-risk disease.

52 Background: A randomized trial has recently reported improved 5-year biochemical recurrence-free survival with brachytherapy (BT) boost compared with external beam radiation therapy (EBRT) boost in intermediate- to high-risk prostate cancer. Recent retrospective data suggest that BT boost may also confer a cancer-specific survival benefit in the high-risk subgroup. We sought to determine whether this survival benefit would extend to the recently defined favorable high-risk subgroup of prostate cancer patients (T1c, Gleason 4+4 = 8, PSA < 10 ng/mL or T1c, Gleason 6, PSA > 20 ng/mL). Methods: We identified 45,078 patients in the Surveillance, Epidemiology, and End Results database with cT1c-T3aN0M0 intermediate- to high-risk prostate cancer diagnosed 2004-2011 treated with EBRT or EBRT plus BT. We used multivariable competing risks regression to determine differences in the rate of prostate cancer-specific mortality (PCSM) after EBRT+BT or EBRT alone in patients with intermediate-risk, favorable high-risk, or other high-risk disease after adjusting for demographic and clinical factors. Results: BT boost was not associated with an improvement in 5-year PCSM compared with EBRT alone among patients with favorable high-risk disease (1.6% vs 1.9%; adjusted hazard ratio [AHR] 0.56; 95% confidence interval [CI], 0.21 to 1.52, P = 0.258) and intermediate-risk disease (0.7% vs 0.9%; AHR 0.83; 95% CI, 0.59 to 1.16; P = 0.270). Others with high-risk disease had significantly lower 5-year PCSM when treated with BT boost compared with EBRT alone (3.9% vs 5.0%; AHR 0.73; 95% CI, 0.55 to 0.95; P = 0.022). Conclusions: Brachytherapy boost is associated with a decreased rate of PCSM in men with high-risk prostate cancer, but this benefit was not seen among patients with favorable high-risk disease. This suggests that the recently-defined “favorable high-risk” category may be used to personalize therapy for men with high risk disease.

Background: Obese men are at higher risk of advanced prostate cancer and have higher rates of cancer-specific mortality after diagnosis. The biological mechanisms explaining this association are unknown. Using mRNA expression profiles of tissue from prostate cancer patients, we aimed to identify pathways that are differentially altered among overweight/obese men compared to healthy weight men. Methods: The study includes men with prostate cancer in the Health Professionals Follow-up Study and the Physicians' Health Study, for whom archival tissue and long-term follow-up is available. Whole genome mRNA expression profiling was performed on tumor (N=402) and adjacent normal (N=200) tissue using the Affymetrix GeneChip Human Gene 1.0 ST Array. Body mass index (BMI) was taken from questionnaires before diagnosis. Among 402 men in the study, 113 lethal events (metastasis or death) were recorded. We identified top Gene Ontology biological processes differentially expressed by obesity status using Gene Set Enrichment Analysis (GSEA). Pathway scores were computed for each tumor by averaging the normalized signal intensities of all member genes. Odds ratios for lethal disease were estimated using logistic regression. Results: 48% of men were healthy weight (BMI 18.5 to To look further into the role of chromatin remodeling, we calculated a pathway score based on 35 chromatin-related leading edge genes from the obesity GSEA. As expected, the score was significantly associated with BMI. In addition, the score was positively associated with pathologic stage and Gleason grade. After adjustment for age and year at diagnosis, the score was associated with lethal progression, with an odds ratio of 6.78 (95% CI: 3.42, 14.16) for lethal outcome comparing extreme quartiles. After further adjusting for stage and Gleason grade the odds ratio decreased slightly but remained significant. In a mediation analysis, we found that 36% of the BMI effect on lethal outcome was mediated by the score. Conclusion: Genes involved in chromatin regulation were enriched in tumor tissue of obese men. Tumors with high expression of these genes were found to have worse clinical characteristics and poorer outcomes. Our findings support a role for epigenetic regulation in the obesity-lethal prostate cancer relationship. Citation Format: Ericka M. Ebot, Travis Gerke, Svitlana Tyekucheva, David P. Labbé, Giorgia Zadra, Rachel S. Kelly, Michaela Bowden, Jennifer R. Rider, M Kathryn Wilson, Neil E. Martin, Myles Brown, Matthew G. Vander Heiden, Edward L. Giovannucci, Massimo Loda, Lorelei A. Mucci. Identifying obesity-linked gene expression changes in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B67.

Background: Recent evidence suggests that dysregulation of tumor metabolism is a key feature in the progression of normal prostate epithelium to cancer, and that it may also reflect disease aggressiveness and metastatic potential. Identifying and understanding the biologic differences between lethal and non-lethal prostate cancer tumors and illuminating the key mechanisms underlying the progression to a lethal phenotype is critical to the study of this common malignancy. Methods: mRNA was extracted from the tumors of 404 participants of the Health Professionals Follow-up Study and the Physicians' Health Study diagnosed with incident prostate cancer (113 lethal (prostate cancer death or metastases) and 291 non-lethal), and from adjacent histologically normal tissue available for 202 of these cases. mRNA expression was analyzed for 401 metabolic genes encoding enzymes involved in several metabolic pathways: Fatty Acid metabolism, Glycolysis/Gluconeogenesis, Oxidative Phosphorylation, Pentose Phosphate, Purine metabolism, Pyrimidine metabolism and the TCA cycle. Gene and pathway-level differences in expression between lethal and non-lethal tumors were assessed, and the findings compared to the expression patterns in adjacent normal tissue. Potential confounders and effect modifiers including cohort, age, year of diagnosis, BMI at diagnosis, subtype heterogeneity, clinical tumor stage, and Gleason grade were explored and multiple testing was accounted for. Results: Two thirds (93/123) of the genes significantly (p Conclusions: In this large prostate cancer study, we demonstrate alterations in key metabolic pathways within the prostate during carcinogenesis, and offer evidence that these changes differ in lethal compared to non-lethal tumors. We additionally identify novel associations with the expression of certain metabolic genes. There was no evidence for a strong role of the tumor microenvironment in this study. Our results were robust to confounding and independent of Gleason grade. A better comprehension of the dysregulation in the genes and pathways involved in lethality may offer novel therapeutic targets for the treatment of prostate cancer. Citation Format: Rachel S. Kelly, Jennifer A. Sinnott, Jennifer R. Rider, Ericka Ebot, Travis Gerke, Kathryn L. Penney, Michaela Bowden, Andreas Pettersson, Massimo Loda, Meir Stampfer, Philip Kantoff, Neil E. Martin, Edward L. Giovannucci, Svitlana Tyekucheva, Matthew Vander Heiden, Lorelei A. Mucci. Tumor metabolism as a driver of lethal prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A25.

Lymph Node Retrieval Following Neoadjuvant Therapy in Patients With Rectal Cancer R.N. Dagoglu, P.J. Catalano, A. Mahadevan, N.E. Martin, T.S. Hong, J.Y. Wo, E.A. Nedea, A.C. Kimmelman, and H.J. Mamon; Istanbul Medical Faculty, Radiation Oncology Department, Istanbul, Turkey, Beth Israel Deaconess Medical Center, Boston, MA, Dana-Farber Cancer Institute, Boston, MA, Massachusetts General Hospital, Harvard Medical School, Boston, MA

BACKGROUND: Recent evidence suggests that dysregulation of tumor metabolism is a key feature in the progression of normal prostate epithelium to cancer, and may also reflect disease aggressiveness and metastatic potential. Identifying the altered metabolic processes driving prostate cancer progression is of particular importance in understanding the biology of this disease. METHODS: mRNA was extracted from the tumors of 404 participants of the Health Professionals Follow-up Study and the Physicians’ Health Study diagnosed with incident prostate cancer (113 lethal (prostate cancer death or metastases) and 291 non-lethal cases), and from adjacent histologically normal tissue available for 202 of these cases. mRNA expression was analyzed for 426 metabolic genes encoding enzymes involved in seven metabolic pathways: Fatty Acid metabolism, Glycolysis/Gluconeogenesis, Oxidative Phosphorylation, Pentose Phosphate, Purine metabolism, Pyrimidine metabolism and the TCA cycle. Gene and pathway-level differences in expression between lethal and non-lethal tumors were assessed, and the findings compared to the expression patterns in adjacent normal tissue. Potential confounders and effect modifiers including cohort, age, year of diagnosis, BMI at diagnosis, clinical tumor stage and Gleason grade were explored and multiple testing was accounted for. RESULTS: Two thirds (99/130) of the genes significantly (p CONCLUSIONS: These results support the hypothesis that metabolic changes in tumors may have utility in predicting and understanding lethality. A better comprehension of the dysregulation in specific metabolic genes and pathways may offer novel therapeutic targets for the treatment of prostate cancer. Citation Format: Rachel S. Kelly, Jennifer A. Sinnott, Jennifer R. Rider, Ericka Ebot, Travis Gerke, Kathryn Penney, Michaela Bowden, Massimo Loda, Philip W. Kantoff, Neil E. Martin, Edward L. Giovannucci, Andreas Pettersson Pettersson, Svitlana Tyekucheva, Kathryn M. Wilson, Matthew Vander Heiden, Lorelei A. Mucci. Tumor metabolism as a driver of lethal prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5168. doi:10.1158/1538-7445.AM2015-5168