Christopher J Sweeney

Harvard Medical School, Boston, Massachusetts, United States

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Publications (165)1118.9 Total impact

  • International journal of radiation oncology, biology, physics 11/2015; 93(3):E199. DOI:10.1016/j.ijrobp.2015.07.1054 · 4.26 Impact Factor

  • International journal of radiation oncology, biology, physics 11/2015; 93(3):E199. DOI:10.1016/j.ijrobp.2015.07.1055 · 4.26 Impact Factor
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    ABSTRACT: Purpose: Recent data suggest that neuroendocrine signaling may influence progression in some cancers. We aimed to determine whether genes within the five major stress-related signaling pathways are differentially expressed in tumor tissue when comparing prostate cancer patients with lethal and non-lethal disease. Experimental design: We measured mRNA expression of 51 selected genes involved in predetermined stress-related signaling pathways (adrenergic, glucocorticoid, dopaminergic, serotoninergic, and muscarinic systems) in tumor tissue and normal prostate tissue collected from prostate cancer patients in the Physicians' Health Study (n=150; n=82 with normal) and the Health Professionals Follow-Up Study (n=254; n=120 with normal). We assessed differences in pathway expression in relation to prostate cancer lethality as the primary outcome, and to biomarkers as secondary outcomes. Results: Differential mRNA expression of genes within the adrenergic (p=0.001), glucocorticoid (p<0.0001), serotoninergic (p=0.0019), and muscarinic (p=0.0045) pathways in tumor tissue was associated with the risk of lethality. The adrenergic pathway was also statistically significant (p=0.001) when comparing against differential expression of genes not involved in the pathways. In adjacent normal prostate tissue, none of the pathways was clearly differentially expressed between lethal and non-lethal prostate cancer. The glucocorticoid and adrenergic pathways were associated with cell proliferation, while the glucocorticoid pathway was additionally associated with angiogenesis and perineural invasion. Conclusions: Our study suggests that stress-related signaling pathways, particularly the adrenergic and glucocorticoid, may be dysregulated in the tumors of men whose prostate cancer proves to be lethal, and motivates further investigation of these pathways in functional studies.
    Clinical Cancer Research 10/2015; DOI:10.1158/1078-0432.CCR-15-0101 · 8.72 Impact Factor
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    ABSTRACT: Purpose: 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. Materials and methods: 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. Results: 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 P<0.001). 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 P<0.01). The likelihood of RP was similar among cT3b vs. cT3a (AOR = 0.95, 0.71-1.26, P = 0.74). Conclusions: 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.
    Urologic Oncology 10/2015; DOI:10.1016/j.urolonc.2015.09.002 · 2.77 Impact Factor
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    ABSTRACT: Purpose: To define characteristics, treatment response, and outcomes of men with brain metastases (BM) from germ cell tumors (GCT). Patients and methods: Data from 523 men with BM from GCT were collected retrospectively from 46 centers in 13 countries by using standardized questionnaires. Clinical features were correlated with overall survival (OS) as the primary end point. Results: BM were present at initial diagnosis in 228 men (group A) and at relapse in 295 men (group B). OS at 3 years (3-year OS) was superior in group A versus group B (48% v 27%; P < .001). Multiple BM and the presence of liver or bone metastasis were independent adverse prognostic factors in both groups; primary mediastinal nonseminoma (group A) and elevations of α-fetoprotein of 100 ng/mL or greater or of human chorionic gonadotropin of 5,000 U/L or greater (group B) were additional independent adverse prognostic factors. Depending on these factors, the 3-year OS ranged from 0% to 70% in group A and from 6% to 52% in group B. In group A, 99% of patients received chemotherapy; multimodality treatment or high-dose chemotherapy was not associated with statistically improved survival in multivariable analysis. In group B, only 54% of patients received chemotherapy; multimodality treatment was associated with improved survival compared with single-modality therapy (hazard ratio, 0.51; 95% CI, 0.36 to 0.73; P < .001), as was high-dose compared with conventional-dose chemotherapy (hazard ratio, 0.41; 95% CI, 0.24 to 0.70; P = .001). Conclusion: Men with BM from GCT have poor OS, particularly if additional risk factors are present. High-dose chemotherapy and multimodality treatment seemed to improve survival probabilities in men with BM at relapse.
    Journal of Clinical Oncology 10/2015; DOI:10.1200/JCO.2015.62.7000 · 18.43 Impact Factor
  • Elizabeth A Guancial · Jonathan E Rosenberg · Christopher J Sweeney ·
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    ABSTRACT: Urothelial carcinoma (UC) is a chemosensitive disease with high response rates to platinum-based combination chemotherapy in locally advanced or advanced disease. However, de novo or emergence of cisplatin-resistance limits the duration of response, patients are frequently ineligible for cisplatin, and therapies tested thus far have minimal activity as second-line therapy. The first wave of clinical trials of novel agents and targeted therapy have modestly advanced the field and laid the foundations for future studies. These trials include the deployment of monoclonal antibodies and tyrosine kinase inhibitors that target mediators of angiogenesis and growth receptors. Novel cytotoxic agents have also been tested as single-agents in the second-line setting and together with the first-line combination of gemcitabine with cisplatin. To date, these novel agents have yet to demonstrate the ability to substantially improve the overall survival of patients with bladder cancer. Comparative trials of chemotherapy with or without a novel agent are ongoing and have the potential to improve upon current standard therapy. Moreover, state-of-the-art technologies have been developed that will likely identify the molecular alterations which drive both UC and platinum-resistance and in turn provide opportunities for drug development. The latter includes an interrogation of microRNAs and the integrated study of genetic mutations in extreme phenotypes of the disease. In essence, this ongoing work paired with physician and patient commitments to clinical trial participation will ultimately lead to advances in the care of patients with urothelial cancer.
    10/2015; 2011:171-176.
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    ABSTRACT: Objectives: To investigate the relationship between microliths and germ cell tumor histologic subtypes and determine whether microliths correlate with tumor stage at diagnosis. Methods: A total of 1249 patients with testicular cancer seen between 1999 and 2013 were evaluated; 346 of 1249 patients (28%) with primary testicular tumors and sonographic imaging of unaffected testicular tissue formed the analytic cohort. Age, ethnicity, tumor histologic subtype, and stage at diagnosis were extracted from the medical record. Two examiners concurrently recorded the highest number of microliths per image of unaffected testicular tissue. Results: A total of 175 of 346 patients (51%) had 1 or more microliths; 69 of 346 (20%) had more than 5 microliths per image. The histologic percentage of seminomas positively correlated with the microlith count (rs = 0.12; P = .036); the histologic percentage of embryonal components negatively correlated with the microlith count (rs = -0.15; P = .007). A higher microlith count was associated with a lower stage at diagnosis (P = .0243). Subgroup analysis of pure seminomas suggested a trend toward a higher microlith count in patients with lower-stage disease at diagnosis (P= .07). No association was found between the tumor stage at diagnosis and microlith count in patients with greater than 50% embryonal components of tumors (P = .55). No association was found between microliths and age, tumor size, and presence of lymphovascular/rete testis invasion (P = .120, .500, .629, and .155, respectively). Conclusions: Patients with testicular cancer who have microliths may be more likely to have a higher percentage of seminomas and a lower percentage of embryonal components in their primary tumors. Microliths also showed an association with earlier stages of disease at diagnosis.
    Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine 09/2015; 34(11). DOI:10.7863/ultra.14.09031 · 1.54 Impact Factor
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    ABSTRACT: Objective: To identify contemporary, clinically low-risk patients with ≥50% cores positive and compare the risk of upgrading at prostatectomy to other low- or intermediate-risk patients. Methods: We studied 14,902 patients with prostate cancer in the Surveillance, Epidemiology, and End Results database in 2010-2011 with prostatectomy. Patients were categorized by NCCN clinical risk-groups, separating low-risk patients by percent positive biopsy cores (PBC). We measured incidence of pathologic high-risk disease, defined as pT3a-T4 or Gleason 8-10, and multivariable logistic regression (MVA) was used to determine if patients with clinical low-risk disease and ≥50% PBC were similar to other low- or intermediate-risk patients. This analysis was repeated with favorable- and unfavorable-intermediate risk. Results: At prostatectomy, 9.2% of clinically low-risk and <50%PBC, 18.6% of clinically low-risk and ≥50%PBC, and 27.6% of clinically intermediate-risk patients had occult, high-risk disease (p<0.001). On MVA low-risk with ≥50%PBC were more likely than low-risk with <50%PBC to have pathologic high-risk disease (Adjusted odds ratio [AOR] 2.28, 95%CI 1.90-2.73, p<0.001), had similar risk to favorable-intermediate disease overall (AOR 1.09, 0.91-1.31, p=0.33), and had higher risk than favorable-intermediate among men over 60 (AOR 1.28, 1.00-1.64, p=0.04). Low-risk and ≥50%PBC had a mean tumor size similar to unfavorable-intermediate risk (21.3 vs. 21.0mm, p=0.82). Conclusion: Nearly one in five clinically low-risk prostate cancer patients with ≥50% positive biopsy cores harbor occult pT3a-T4 or Gleason 8-10, suggesting that national guidelines should not classify low-risk with ≥50% cores positive as "low-risk" and patients should be made aware of this excess risk if considering active surveillance.
    Urology 09/2015; DOI:10.1016/j.urology.2015.08.026 · 2.19 Impact Factor
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    ABSTRACT: During the past 35 years, survival rates for children with extracranial malignant germ cell tumors (GCTs) have increased significantly. Success has been achieved primarily through the application of platinum-based chemotherapy regimens; however, clinical challenges in GCTs remain. Excellent outcomes are not distributed uniformly across the heterogeneous distribution of age, histologic features, and primary tumor site. Despite good outcomes overall, the likelihood of a cure for certain sites and histologic conditions is less than 50%. In addition, there are considerable long-term treatment-related effects for survivors. Even modest cisplatin dosing can cause significant long-term morbidities. A particular challenge in designing new therapies for GCT is that a variety of specialists use different risk stratifications, staging systems, and treatment approaches for three distinct age groups (childhood, adolescence, and young adulthood). Traditionally, pediatric cancer patients younger than 15 years have been treated by pediatric oncologists in collaboration with their surgical specialty colleagues. Adolescents and young adults with GCTs often are treated by medical oncologists, urologists, or gynecologic oncologists. The therapeutic dilemma for all is how to best define disease risk so that therapy and toxicity can be appropriately reduced for some patients and intensified for others. Further clinical and biologic insights can only be achieved through collaborations that do not set limitations by age, sex, and primary tumor site. Therefore, international collaborations, spanning different cooperative groups and disciplines, have been developed to address these challenges. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 08/2015; 33(27). DOI:10.1200/JCO.2014.60.5337 · 18.43 Impact Factor
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    ABSTRACT: Abiraterone improves the overall survival of men with metastatic castration resistance prostate cancer. However, de novo or adaptive resistance to abiraterone limits its activity. Rational combinations of drugs with different mechanisms of action that overcome resistance mechanisms may improve the efficacy of therapy. To that end, we studied the molecular and phenotypic effects of the combination of cabozantinib plus abiraterone. Three prostate cancer cell lines were used to interrogate the in vitro molecular and anti-proliferative effects of the single agents and combination of cabozantinib and abiraterone. The in vivo impact of the combination was assessed using the LAPC4-CR xenograft mouse model. In vitro proliferation studies demonstrated single agent doses between 2 and 10 μM for abiraterone and cabozantinib inhibit prostate cancer cell proliferation in a dose-dependent manner and the anti-cancer activity of abiraterone is enhanced when combined with cabozantinib. In vivo LAPC4-CR xenograft mouse studies also showed that cabozantinib can improve the anti-tumor activity of abiraterone. Cabozantinib, a multiple receptor tyrosine kinase inhibitor, enhances the ability of abiraterone to inhibit AR activity in a cell line dependent manner. In addition our cell line studies demonstrate abiraterone stimulated IGF-1R phosphorylation with downstream activation of MEK1/2 and ERK1/2, and that this potential adaptive resistance mechanism was inhibited by cabozantinib. Cabozantinib can enhance the efficacy of abiraterone by blocking multiple compensatory survival mechanisms including IGF-1R activation and supports the assessment of the combination in a clinical trial. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 08/2015; DOI:10.1158/1078-0432.CCR-15-0824 · 8.72 Impact Factor
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    ABSTRACT: Background: Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone. Methods: We assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone. Results: A total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%. Conclusions: Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. (Funded by the National Cancer Institute and others; number, NCT00309985.).
    New England Journal of Medicine 08/2015; 373(8). DOI:10.1056/NEJMoa1503747 · 55.87 Impact Factor
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    ABSTRACT: Objective: To determine whether very small prostate cancers present in patients who also have lymph node (LN) metastases represent a particularly aggressive disease variant compared with larger LN-positive tumours. Patients and methods: We identified 37 501 patients diagnosed with prostate cancer between 1988 and 2001 treated with radical prostatectomy within the Surveillance, Epidemiology, and End Results database. The primary study variables were tumour size by largest dimension (stratified into: (i) microscopic focus only or 1 mm; (ii) 2-15 mm; (iii) 16-30 mm; (iv) >30 mm), regional LN involvement, and the corresponding interaction term. We evaluated the risk of 10-year prostate cancer-specific mortality (PCSM) using the Fine and Gray model for competing risks after controlling for race, tumour grade, T stage, receipt of radiation, number of dissected LNs, number of positive LNs, year of diagnosis, and age at diagnosis. Results: The median follow-up was 11.8 years. There was a significant interaction between tumour size and LN involvement (P-interaction <0.001). In the absence of LN involvement (36 561 patients), the risk of 10-year PCSM increased monotonically with increasing tumour size. Among patients with LN involvement (940), those with the smallest tumours had increased 10-year PCSM compared with patients with tumours sized 2-15 mm (24.7% vs 11.8%; adjusted hazard ratio [AHR] 2.84, 95% confidence interval [CI] 1.21-6.71; P = 0.017) or 16-30 mm (24.7% vs 15.5%; AHR 3.12, 95% CI 1.51-6.49; P = 0.002), and similar 10-year PCSM as those with tumours >30 mm (24.7% vs 24.9%; P = 0.156). Conclusion: In patients with prostate cancer with LN involvement, very small tumour size may predict for higher PCSM compared with some larger tumours, even after controlling for other prognostic variables. These tumours might be particularly aggressive, beyond what is captured by pathological assessment of tumour grade and stage.
    BJU International 08/2015; DOI:10.1111/bju.13248 · 3.53 Impact Factor
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    ABSTRACT: To determine whether patients with Gleason score 5+3=8 prostate cancer have outcomes more similar to other patients with Gleason 8 disease or to patients with Gleason 9 disease. The SEER database was used to study 40,533 men diagnosed with N0M0 Gleason 8 or 9 prostate cancer from 2004 - 2011. Using Gleason 4+4=8 as the referent, Fine and Gray competing risks regression analyses modeled the association between Gleason score and prostate cancer-specific mortality (PCSM). Five-year PCSM rates for patients with Gleason 4+4=8, Gleason 3+5=8, Gleason 5+3=8, and Gleason 9 disease were 6.3%, 6.6%, 13.5%, and 13.9%, respectively (P<0.001). Patients with Gleason 5+3=8 or Gleason 9 disease had up to a two-fold increased risk for PCSM ([Adjusted Hazard Ratio (AHR) 1.89; 95% CI 1.50 - 2.38; P<0.001] and [AHR 2.17; 95% CI 1.99 - 2.36; P<0.001], respectively) compared to the referent group of patients (Gleason 4+4=8). There was no difference in PCSM between patients with Gleason 5+3=8 versus 9 disease (P=0.25). Gleason 8 disease represents a heterogeneous entity with PCSM outcomes distinguishable by the primary Gleason pattern. The PCSM of Gleason 3+5=8 and Gleason 4+4=8 disease are similar, but patients with Gleason 5+3=8 have a risk of PCSM that is twice as high as other patients with Gleason 8 disease and should be considered to have similar poor prognosis as patients with Gleason 9 disease. Such patients should be allowed onto trials seeking the highest-risk patients in which to test novel aggressive treatment strategies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    BJU International 07/2015; 93(3). DOI:10.1111/bju.13239 · 3.53 Impact Factor

  • International journal of radiation oncology, biology, physics 07/2015; DOI:10.1016/j.ijrobp.2015.07.2281 · 4.26 Impact Factor
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    ABSTRACT: Preclinical xenograft models have contributed to advancing our understanding of the molecular basis of prostate cancer and to the development of targeted therapy. However, traditional preclinical in vivo techniques using caliper measurements and survival analysis evaluate the macroscopic tumor behavior, whereas tissue sampling disrupts the microenvironment and cannot be used for longitudinal studies in the same animal. Herein, we present an in vivo study of [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) designed to evaluate the metabolism within the microenvironment of LAPC4-CR, a unique murine model of castration-resistant prostate cancer. Mice bearing LAPC4-CR subcutaneous tumors were administered [(18)F]-FDG via intravenous injection. After a 60-minute distribution phase, the mice were imaged on a PET/CT scanner with submillimeter resolution; and the fused PET/CT images were analyzed to evaluate tumor size, location, and metabolism across the cohort of mice. The xenograft tumors showed [(18)F]-FDG uptake that was independent of tumor size and was significantly greater than uptake in skeletal muscle and liver in mice (Wilcoxon signed-rank P values of .0002 and .0002, respectively). [(18)F]-FDG metabolism of the LAPC4-CR tumors was 2.1 ± 0.8 ID/cm(3)*wt, with tumor to muscle ratio of 7.4 ± 4.7 and tumor to liver background ratio of 6.7 ± 2.3. Noninvasive molecular imaging techniques such as PET/CT can be used to probe the microenvironment of tumors in vivo. This study showed that [(18)F]-FDG-PET/CT could be used to image and assess glucose metabolism of LAPC4-CR xenografts in vivo. Further work can investigate the use of PET/CT to quantify the metabolic response of LAPC4-CR to novel agents and combination therapies using soft tissue and possibly bone compartment xenograft models. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Translational oncology 06/2015; 63(3). DOI:10.1016/j.tranon.2015.03.004 · 2.88 Impact Factor
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    ABSTRACT: In order to help inform the discussion about the risks versus benefits of prostate cancer screening among older men, we determined whether advanced age is associated with a higher probability of harboring high-grade or high-risk disease. The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 383,039 men diagnosed with prostate cancer in 2004-2011. The percentage of patients diagnosed with low-, intermediate-, or high-risk disease or a Gleason score of 6, 7, or 8 to 10 was calculated by age range. As a secondary analysis, we examined whether this relationship was different in 2010-2011 versus 2007-2008 (before and after the 2009 publication of screening trials). The probability of Gleason score 8 to 10 or high-risk disease increased significantly with increasing age. The percentage of Gleason score 8 to 10 disease among men ages 50 to 54, 70 to 74, and 80 to 84 years was 8.9%, 16.2%, and 28.5%, respectively, and the percentage of high-risk disease was 14.3%, 22.4%, and 38.7% (P < .001). There were similar relationships among men with stage T1c disease. In addition, older men experienced a significant increase in the relative probability of high-risk or high-grade disease from 2007-2008 to 2010-2011. In this large US-based cohort, older men had a much higher probability of high-grade or high-risk prostate cancer. Physicians and patients should take into account the higher risk of more aggressive or advanced disease in older men when discussing the risks and benefits of prostate-specific antigen screening with healthy older men with a substantial life expectancy. Copyright © 2015 Elsevier Inc. All rights reserved.
    Clinical Genitourinary Cancer 06/2015; DOI:10.1016/j.clgc.2015.05.007 · 2.32 Impact Factor
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    ABSTRACT: The first St.Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection.Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with advanced prostate cancer in clinical trials should be encouraged. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
    Annals of Oncology 06/2015; 26(8). DOI:10.1093/annonc/mdv257 · 7.04 Impact Factor
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    ABSTRACT: Long-term androgen deprivation therapy (ADT) was proven in randomized trials to be superior to short-term ADT for radiation-managed patients who have clinical T3 (cT3) disease, but it is unknown whether patients with T3 disease seen only on magnetic resonance imaging require similarly aggressive treatment. We attempted to study this issue by analogy by comparing the long-term post-prostatectomy survival of patients with cT3 disease versus cT1/T2 disease upstaged to pathologic T3 disease. The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 60,165 men diagnosed with prostate adenocarcinoma between 1995 and 2002 who underwent prostatectomy. Prostate cancer-specific mortality (PCSM) was evaluated by stage after adjusting for grade, marital status, race, sex, year of diagnosis, and age. The median follow-up was 10.5 years. Patients with cT1/T2 but pathologic T3a disease had significantly better 10-year PCSM than men with cT3 disease had (3.0% vs. 9.9%, adjusted hazard ratio [AHR] = 0.420, P<0.001), but they had worse PCSM than men with pathologic T2 disease had (3.0% vs. 0.91%, AHR = 2.53, P<0.001). Of patients with occult T3a disease, those with low-grade/intermediate-grade disease (Gleason score 7 or less) had a slightly higher 10-year PCSM when compared with those with pathologic T2 disease (1.34% vs. 0.91%, AHR = 1.69, P<0.001). Patients with cT1/T2 and pathologic T3b disease had similar PCSM as men presenting with cT3 disease (11.0% vs. 9.86%, AHR = 1.14 [0.862, 1.52], P = 0.353). Patients with occult T3a disease had less than half the risk of PCSM as those with cT3 disease, and a subset of those men had similar risk as patients with pathologic T2 disease. Therefore, it is possible that radiation-managed patients with low-grade/intermediate-grade T3a disease by magnetic resonance imaging only might not require long-term ADT. However, patients with occult T3b or high-grade occult T3a disease have similar PCSM as that of those presenting with cT3 disease, so they should be treated as aggressively, including long-course ADT when managed by radiation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Urologic Oncology 05/2015; 33(7). DOI:10.1016/j.urolonc.2015.03.010 · 2.77 Impact Factor
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    ABSTRACT: Importance Statin use has been associated with improved prostate cancer outcomes. Dehydroepiandrosterone sulfate (DHEAS) is a precursor of testosterone and a substrate for SLCO2B1, an organic anionic transporter. We previously demonstrated that genetic variants of SLCO2B1 correlated with time to progression (TTP) during receipt of androgen deprivation therapy (ADT). Statins also use SLCO2B1 to enter cells, and thus we hypothesized that they may compete with DHEAS uptake by the tumor cells.Objective To evaluate whether statin use prolongs TTP during ADT for hormone-sensitive prostate cancer.Design, Setting, and Participants In vitro studies were performed using prostate cancer cell lines at an academic, comprehensive cancer center. Statin use was retrospectively analyzed in 926 patients who had received ADT for biochemical or metastatic recurrence or de novo metastatic prostate cancer between January 1996 and November 2013. Main Outcomes and Measures To determine whether statins interfere with DHEAS uptake, we performed in vitro studies using prostate cancer cell lines. Next, we queried our institutional clinical database to assess for an association between statin use and TTP during ADT using multivariable Cox regression analysis and adjusted for known prognostic factors.Results In vitro, we demonstrated that statins block DHEAS uptake by competitively binding to SLCO2B1. In our ADT cohort of 926 patients, 283 (31%) were taking a statin at ADT initiation. After a median follow-up of 5.8 years, 644 patients (70%) had experienced disease progression while receiving ADT. Median TTP during ADT was 20.3 months (95% CI, 18-24 months). Men taking statins had a longer median TTP during ADT compared with nonusers (27.5 [95% CI, 21.1-37.7] vs 17.4 [95% CI, 14.9-21.1] months; P < .001). The association remained statistically significant after adjusting for predefined prognostic factors (adjusted hazard ratio, 0.83 [95% CI, 0.69-0.99]; P = .04). The positive statin effect was observed for both patients with and without metastases (adjusted hazard ratio, 0.79 [95% CI, 0.58-1.07] for M0 disease and 0.84 [95% CI, 0.67-1.06] for M1 disease; P for interaction = .72).Conclusions and Relevance Statin use at the time of ADT initiation was associated with a significantly longer TTP during ADT even after adjustment for known prognostic factors. Our in vitro finding that statins competitively reduce DHEAS uptake, thus effectively decreasing the available intratumoral androgen pool, affords a plausible mechanism to support the clinical observation of prolonged TTP in statin users.
    05/2015; 1(4). DOI:10.1001/jamaoncol.2015.0829
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    ABSTRACT: Background: Active surveillance is an increasingly accepted approach for managing patients with germ-cell tumors (GCTs) after an orchiectomy. Here we investigate a time-to-relapse stratification scheme for clinical stage 1 (CS1) nonseminoma GCT (NSGCT) patients according to factors associated with relapse and identify a group of patients with a lower frequency and longer time-to-relapse who may require an alternative surveillance strategy. Patients and methods: We analyzed 266 CS1 GCT patients from the IRB-approved DFCI GCT database that exclusively underwent surveillance following orchiectomy from 1997 to 2013. We stratified NSGCT patients according to predominance of embryonal carcinoma (EmbP) and lymphovascular invasion (LVI), using a 0, 1, and 2 scoring system. Cox regression and conditional risk analysis were used to compare each NSGCT group to patients in the seminomatous germ-cell tumor (SGCT) category. Median time-to-relapse values were then calculated among those patients who underwent relapse. Relapse-free survival curves were generated using the Kaplan-Meier method. Results: Fifty (37%) NSGCT and 20 (15%) SGCT patients relapsed. The median time-to-relapse was 11.5 versus 6.3 months for the SGCT and NSGCT groups, respectively. For NSGCT patients, relapse rates were higher and median time-to-relapse faster with increasing number of risk factors (RFs). Relapse rates (%) and median time-to-relapse (months) were 25%/8.5 months, 41%/6.8 months and 78%/3.8 months for RF0, RF1 and RF2, respectively. We found a statistically significant difference between SGCT and patients with one or two RFs (P < 0.001) but not between SGCT and NSGCT RF0 (P = 0.108). Conclusion: NSGCT patients grouped by a risk score system based on EmbP and LVI yielded three groups with distinct relapse patterns -and patients with neither EmbP nor LVI appear to behave similar to SGCT.
    Annals of Oncology 04/2015; 26(7). DOI:10.1093/annonc/mdv180 · 7.04 Impact Factor

Publication Stats

5k Citations
1,118.90 Total Impact Points


  • 2013-2015
    • Harvard Medical School
      • Department of Radiation Oncology
      Boston, Massachusetts, United States
  • 2010-2015
    • Dana-Farber Cancer Institute
      • • Lank Center for Genitourinary Oncology
      • • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 2014
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 2013-2014
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
  • 2010-2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1999-2011
    • Indiana University-Purdue University Indianapolis
      • • Department of Medicine
      • • Department of Surgery
      • • Division of Hematology/Oncology
      Indianapolis, Indiana, United States
  • 2009-2010
    • University of Adelaide
      • Faculty of Health Sciences
      Tarndarnya, South Australia, Australia
  • 2006
    • Indiana University Bloomington
      Bloomington, Indiana, United States
  • 2004
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States