Matthew R Smith

Massachusetts General Hospital, Boston, Massachusetts, United States

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Publications (214)2214.87 Total impact

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    ABSTRACT: Background: The duration of prior hormonal treatment can predict responses to subsequent therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Objective: To determine if prior endocrine therapy duration is an indicator of abiraterone acetate (AA) sensitivity. Design, setting, and participants: Post-hoc exploratory analysis of randomised phase 3 studies examining post-docetaxel (COU-AA-301) or chemotherapy-naïve mCRPC (COU-AA-302) patients receiving AA. The treatment effect on overall survival (OS), radiographic progression-free survival (rPFS), and prostate-specific antigen (PSA) response analysed by quartile duration of prior gonadotropin-releasing hormone agonists (GnRHa) or androgen receptor (AR) antagonist. Intervention: Patients were randomised to AA (1000mg, orally once daily) plus prednisone (5mg, orally twice daily) or placebo plus prednisone. Prior endocrine therapy was GnRHa (COU-AA-301, n=1127 [94%]; COU-AA-302, n=1057 [97%], 45.1 mo or 36.7 mo median duration, respectively) and/or orchiectomy (COU-AA-301, n=78 [7%] COU-AA-302, n=44 [4%]); castrated patients received prior AR antagonists (COU-AA-301, n=1015 [85%]; COU-AA-302, n=1078 [99%], 15.7 mo or 16.1 mo median duration, respectively). Outcome measurements and statistical analysis: Cox model was used to obtain hazard ratio and associated 95% confidence interval with statistical inference by log rank statistic. Results and limitations: Clinical benefit with AA was observed for OS, rPFS, and PSA response for nearly all quartiles with GnRHa or AR antagonists in both COU-AA-301 and COU-AA-302. In COU-AA-301, patients with a longer duration of prior endocrine therapy tended to have greater AA OS, rPFS, and PSA response benefit, with lead-time chemotherapy bias potentially impacting COU-AA-301 results. Time to castration resistance was not captured. This analysis is limited as a post-hoc exploratory analysis. Conclusions: In the COU-AA-301 and COU-AA-302 studies, AA produced clinical benefits regardless of prior endocrine therapy duration in patients with mCRPC. Patient summary: Metastatic castration-resistant prostate cancer patients derived clinical benefits with abiraterone acetate regardless of prior endocrine therapy duration.
    European Urology 10/2015; DOI:10.1016/j.eururo.2015.10.021 · 13.94 Impact Factor
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    ABSTRACT: Prostate cancer is initially responsive to androgen deprivation, but the effectiveness of androgen receptor (AR) inhibitors in recurrent disease is variable. Biopsy of bone metastases is challenging; hence, sampling circulating tumor cells (CTCs) may reveal drug-resistance mechanisms. We established single-cell RNA-sequencing (RNA-Seq) profiles of 77 intact CTCs isolated from 13 patients (mean six CTCs per patient), by using microfluidic enrichment. Single CTCs from each individual display considerable heterogeneity, including expression of AR gene mutations and splicing variants. Retrospective analysis of CTCs from patients progressing under treatment with an AR inhibitor, compared with untreated cases, indicates activation of noncanonical Wnt signaling (P = 0.0064). Ectopic expression of Wnt5a in prostate cancer cells attenuates the antiproliferative effect of AR inhibition, whereas its suppression in drug-resistant cells restores partial sensitivity, a correlation also evident in an established mouse model. Thus, single-cell analysis of prostate CTCs reveals heterogeneity in signaling pathways that could contribute to treatment failure.
    Science 09/2015; 349(6254):1351-6. DOI:10.1126/science.aab0917 · 33.61 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):CT134-CT134. DOI:10.1158/1538-7445.AM2015-CT134 · 9.33 Impact Factor
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    ABSTRACT: Metastatic castration-resistant prostate cancer primarily affects elderly men. In this post hoc analysis we investigated the safety and efficacy of abiraterone acetate in elderly (≥75 years) and younger (<75 years) patient subgroups at the prespecified interim analysis (55% of total overall survival [OS] events) for the COU-AA-302 trial. Patients were stratified and randomized 1:1 to abiraterone acetate 1,000 mg plus prednisone/prednisolone 5 mg bid (abiraterone-prednisone) vs placebo plus prednisone/prednisolone 5 mg bid (prednisone alone). Co-primary end points were radiographic progression-free survival (rPFS) and OS. Median time to event and hazard ratio (HR) were estimated using Kaplan-Meier method and Cox model, respectively. Elderly patients (n=350) treated with abiraterone-prednisone had significant improvements in OS and rPFS vs prednisone alone (HR=0.71 [95% CI 0.53-0.96] and HR=0.63 [95% CI 0.48-0.83], respectively), similar to younger patients (n=738, HR=0.81 [95% CI 0.63-1.03] and HR=0.49 [95% CI 0.40-0.59], respectively). All secondary end points favored the abiraterone-prednisone arm for both age subgroups. Specific adverse events with abiraterone-prednisone were similar between age subgroups. Elderly patients in both treatment arms had higher rates of fluid retention and cardiac disorders than younger patients, although rates of dose reduction or treatment interruptions due to adverse events were low in both age subgroups. Abiraterone acetate demonstrated clinical benefit and was well tolerated in both elderly and younger men with chemotherapy-naïve metastatic castration-resistant prostate cancer, thus supporting it as a treatment option for elderly patients who may not tolerate other therapies with greater toxicity. NCT00887198. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
    The Journal of urology 07/2015; 194(5). DOI:10.1016/j.juro.2015.07.004 · 4.47 Impact Factor
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    ABSTRACT: Skeletal involvement is common in metastatic prostate cancer (PCa) and is associated with skeletal-related events (SREs). The interaction of PCa with the bone microenvironment contributes to self-perpetuating progression of cancer in bone. Bone-targeted agents (BTAs) are available for use in metastatic castration-resistant prostate cancer (mCRPC). To review the biology of bone metastases in PCa and to review the clinical trial data for BTAs in PCa. A literature search was conducted in October 2014. Keywords included clinical trial, prostate cancer, denosumab, bisphosphonates, zoledronic acid, radium-223, bone turnover markers, skeletal-related events, and symptomatic skeletal events. The biology of bone metastases in PCa is summarized. Data supporting the use of BTAs in PCa are reviewed, and issues related to the combination and sequencing of available agents are discussed. The osteoclast-targeted agents zoledronic acid and denosumab decrease SREs in mCRPC, and the α-emitting radiopharmaceutical agent radium-223 improves survival and decreases symptomatic skeletal events. Limited data are available to guide the sequence and combination of BTAs with disease-modifying agents, although data support the use of osteoclast-targeted drugs with chemotherapy, androgen-targeted agents, and radium-223. Zoledronic acid does not reduce SREs when started prior to castration resistance, although osteoclast-targeted agents do improve outcomes when used in patients with asymptomatic to minimally symptomatic chemotherapy-naive mCRPC. The optimal sequence of radium-223 with chemotherapy is uncertain, although data suggest the efficacy and tolerability of radium-223 is similar with either sequence. Clinical trials evaluating the combination of BTAs with other agents are under way. The optimization of sequence and combination strategies will guide the best use of available agents. The literature pertaining to bone metastases in prostate cancer (PCa) was reviewed, and the current understanding of the biology of PCa having spread to bone and the agents available to reduce skeletal complications was discussed. Copyright © 2015. Published by Elsevier B.V.
    European Urology 07/2015; 68(5). DOI:10.1016/j.eururo.2015.06.039 · 13.94 Impact Factor
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    ABSTRACT: To describe the need for treatment and cancer-specific and overall survival in a contemporary active surveillance (AS) cohort. Historical cohort study of men diagnosed with localized prostate cancer between 1997 and 2009 and managed with AS at a tertiary care center. Inclusion criteria were Gleason score≤6 (Gleason score of 7 in select patients),≤3/12 cores positive, and prostate-specific antigen (PSA) level<20ng/ml. Survival analyses were conducted using the Kaplan-Meier method. A total of 469 men with median age at diagnosis of 68.1 years (interquartile range [IQR]: 62.5-73.4) were followed up for a median of 4.8 years (IQR: 3.4-7.3). Median PSA level at diagnosis was 5.1ng/ml (IQR: 4.0-6.9), with 94% of them having PSA level<10ng/ml. Overall, 98.3% (461/469) of patients had a Gleason score of 6 and 1.7% (8/469) had a Gleason score of 3+4 = 7, and 94.0% (441/469) had T1c stage disease. Freedom from treatment was 77% at 5 years and 62% at 10 years. A total of 116 (24.7%) patients received treatment during the course of surveillance. Reasons for treatment included 44.8% (52/116) for pathologic reclassification, 30.2% (35/116) for PSA progression, 12.1% (14/116) for patient preference, 5.2% (6/116) for digital rectal examination progression, and 4.3% (5/116) for metastatic disease. Of the patients treated, 59 (50.1%) received radiation, 26 (22.4%) underwent surgery, 17 (14.7%) received brachytherapy, and 14 (12.1%) received androgen-deprivation therapy. Cancer-specific survival was 100% at 5 and 10 years. Overall survival was 95% at 5 years and 88% at 10 years. In a contemporary cohort of men with low-risk prostate cancer, AS allowed avoidance of treatment most of them. Common reasons for change in management were Gleason upgrading and volume progression on prostate rebiopsy. Copyright © 2015 Elsevier Inc. All rights reserved.
    Urologic Oncology 06/2015; 33(9). DOI:10.1016/j.urolonc.2015.04.015 · 2.77 Impact Factor
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    ABSTRACT: Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy. Investigation of outcomes for concomitant BTT in a post hoc analysis of the COU-AA-302 trial, which demonstrated an overall clinical benefit of abiraterone acetate (AA) plus prednisone over placebo plus prednisone in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients. This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial. Patients were grouped by concomitant BTT use or no BTT use. Radiographic progression-free survival and OS were coprimary end points. This report describes the third interim analysis (prespecified at 55% OS events) and involves patients treated with or without concomitant BTT during the COU-AA-302 study. Median follow-up for OS was 27.1 mo. Median time-to-event variables with 95% confidence intervals (CIs) were estimated using the Kaplan-Meier method. Adjusted hazard ratios (HRs), 95% CIs, and p values for concomitant BTT versus no BTT were obtained via Cox models. While the post hoc nature of the analysis is a limitation, superiority of AA and prednisone versus prednisone alone was demonstrated for clinical outcomes with or without BTT use. Compared with no BTT use, concomitant BTT significantly improved OS (HR 0.75; p=0.01) and increased the time to ECOG deterioration (HR 0.75; p<0.001) and time to opiate use for cancer-related pain (HR 0.80; p=0.036). The safety profile of concomitant BTT with AA was similar to that reported for AA in the overall intent-to-treat population. Osteonecrosis of the jaw (all grade 1/2) with concomitant BTT use was reported in <3% of patients. AA with concomitant BTT was safe and well tolerated in men with chemotherapy-naïve mCRPC. The benefits of AA on clinical outcomes were increased with concomitant BTT. Treatment of advanced prostate cancer often includes bone-targeted therapy. This post hoc analysis showed that in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone in combination with bone-targeted therapy, there was a continued trend in prolongation of life when compared with patients treated with prednisone alone. NCT00887198. Copyright © 2015. Published by Elsevier B.V.
    European Urology 05/2015; 68(4). DOI:10.1016/j.eururo.2015.04.032 · 13.94 Impact Factor
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    The Journal of Urology 04/2015; 193(4):e1088-e1089. DOI:10.1016/j.juro.2015.02.1957 · 4.47 Impact Factor
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    The Journal of Urology 04/2015; 193(4):e1090. DOI:10.1016/j.juro.2015.02.1961 · 4.47 Impact Factor
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    The Journal of Urology 04/2015; 193(4):e933-e934. DOI:10.1016/j.juro.2015.02.2686 · 4.47 Impact Factor
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    ABSTRACT: We constructed a biomarker-survival modeling framework to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients following oral administration of 1,000 mg/d of abiraterone acetate (AA). The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapy-pretreated, n = 1,184) and COU-AA-302 (chemotherapy-naïve, n = 1,081), and included a mixed-effects tumor growth inhibition model and a Cox proportional hazards survival model. The effect of AA on PSA kinetics was significant (P < 0.0001) and comparable between the chemotherapy-naïve and -pretreated patients. PSA kinetics (e.g., PSA nadir, PSA response rate [≥30, 50, and 90%], time to PSA progression, PSA doubling time [PSADT]) were highly associated with OS in both populations. The model-based post-treatment PSADT had the strongest association with OS (hazard ratio ~0.9 in both populations). The models could accurately predict survival outcomes. After adjusting for PSA kinetic end points, the treatment effect of AA on survival was no longer statistically significant in both studies, and the Prentice criteria of surrogacy were met for the PSA kinetic end points. A strong correlation was also observed between PSA and radiographic progression-free survival. The analysis revealed a consistent treatment effect of AA on PSA kinetics and strong associations between PSA kinetics and OS in chemotherapy-pretreated and -naïve patients, thereby providing a rationale to consider PSA kinetics as surrogacy end points to indicate clinical benefit in AA-treated patients with mCRPC regardless of chemotherapy treatment. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 03/2015; 21(14). DOI:10.1158/1078-0432.CCR-14-1549 · 8.72 Impact Factor
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    ABSTRACT: Enzalutamide is an androgen receptor inhibitor with a demonstrated overall survival benefit in metastatic castration-resistant prostate cancer. A phase 2 study of enzalutamide monotherapy in patients with hormone-naïve prostate cancer (HNPC) showed a high response rate for the prespecified primary endpoint (ie, prostate-specific antigen [PSA] response at week 25), regardless of metastases at baseline, and favorable tolerability. To determine the long-term efficacy and safety of enzalutamide monotherapy at 1 and 2 yr. Open-label, single-arm study in patients with HNPC and noncastrate testosterone (≥230 ng/dl). Oral enzalutamide 160mg/d until disease progression or unacceptable toxicity. PSA response (≥80% decline from baseline) assessed at 1 yr (49 wk) and 2 yr (97 wk). The median (range) age was 73 (48-86) yr and 26 patients (39%) presented with metastases at study entry. Of 67 patients enrolled, 45 (67%) remained on enzalutamide at week 97. For patients remaining on therapy, the PSA response rate at week 97 was 100% (95% confidence interval 92-100%). Of 26 patients with metastases at baseline, 13 (50%) had a complete and four (15.4%) had a partial response as best overall tumor response up to 97 wk on treatment. There was overall maintenance of total-body bone mineral density (BMD) and moderate changes in lean and fat body mass at 49 and 97 wk. The most common adverse events were gynecomastia, nipple pain, fatigue, and hot flushes. The study limitations include lack of a control group and of endocrine, glycemic, and lipid data at 97 wk. Long-term enzalutamide monotherapy in men with noncastrate HNPC is associated with large sustained reductions in PSA, signals indicating a favorable tumor response, and favorable safety/tolerability profile, with relatively small negative effects on total-body BMD. In this long-term follow-up of the efficacy and safety of enzalutamide monotherapy in patients with hormone-naïve prostate cancer, enzalutamide maintained long-term reductions in prostate-specific antigen, with a minimal impact on total-body bone mineral density. NCT01302041. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    European Urology 02/2015; 65(5). DOI:10.1016/j.eururo.2015.01.027 · 13.94 Impact Factor
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    ABSTRACT: Outcome measurements and statistical analysis: Co-primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O'Brien-Fleming Lan-DeMets a-spending function was used for OS. Adverse events were summarised descriptively. Results and limitations: With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45-0.61]; p < 0.0001). Abiraterone improved OS (median: 35.3 vs 30.1 mo; HR: 0.79 [95% CI, 0.66-0.95]; p = 0.0151) but did not reach the prespecified statistical efficacy boundary (a-level: 0.0035). A post hoc multivariate analysis for OS using known prognostic factors supported the primary results (HR: 0.74 [95% CI, 0.61-0.89]; p = 0.0017), and all clinically relevant secondary end points and patient-reported outcomes improved. While the post hoc nature of the long-term safety analysis is a limitation, the safety profile with longer treatment exposure was consistent with prior reports.
    European Urology 11/2014; 66(5). DOI:10.1016/j.eururo.2014.02.056 · 13.94 Impact Factor
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    ABSTRACT: Background We retrospectively evaluated the prognostic impact of neutrophil-lymphocyte ratio (NLR) as a marker for inflammatory and immune state in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel. Methods The SUN-1120 phase III trial comparing prednisone combined with sunitinib (n=584) or placebo (n=289) for mCRPC following docetaxel-based chemotherapy was evaluated. The arms were combined for analysis, since no difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression method with forward stepwise selection, stratifying for ECOG PS, progression type (PSA or radiographic) and treatment group. Patients were categorized into risk groups. Results Complete data was evaluable in 784 men for construction of a prognostic model. The factors used in the model that remained individually significant for OS in multivariable analysis were: log-LDH (HR 2.86 [95% CI=2.29, 3.56], P<0.001), hemoglobin (0.80 [0.74, 0.85], P<0.001), >1 organ involved by metastatic disease (1.49 [1.21, 1.84], P<0.001), log-alkaline phosphatase (1.13 [0.99, 1.28], P=0.074), log-number of prior cycles of docetaxel (0.84 [0.71, 0.98], P=0.031), progression on docetaxel (1.35 [1.00, 1.81], P=0.049), log-PSA (1.06 [1.00, 1.12], P=0.075) and log-NLR (1.55 [1.32, 1.83], P<0.001). NLR increased the c-statistic of the prognostic model from 0.703 to 0.715. Conclusion High NLR may be associated with an independent poor prognostic impact in post-docetaxel patients with mCRPC. These data warrant external validation.
    Clinical Genitourinary Cancer 10/2014; 12(5). DOI:10.1016/j.clgc.2014.03.005 · 2.32 Impact Factor
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    Matthew R Smith · Susan Halabi · Eric J Small ·

    Journal of Clinical Oncology 09/2014; 32(32). DOI:10.1200/JCO.2014.57.3808 · 18.43 Impact Factor
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    ABSTRACT: Purpose: Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). Patients and methods: Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ≥ 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. Results: One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. Conclusion: The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.
    Journal of Clinical Oncology 09/2014; 32(30). DOI:10.1200/JCO.2013.54.5954 · 18.43 Impact Factor
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    ABSTRACT: Background and Objectives: Abiraterone acetate, an androgen biosynthesis inhibitor, prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) in the pre- and post-chemotherapy setting as demonstrated by the pivotal phase III studies COU-AA-301 and COU-AA-302. We performed population pharmacokinetic analyses to estimate pharmacokinetic parameters after oral administration of 1,000 mg/day of abiraterone acetate in patients with mCRPC, with or without prior chemotherapy, and after a single 1,000 mg dose in healthy volunteers. The study objectives were to determine consistency between patient populations and to characterize factors that may influence abiraterone pharmacokinetics.
    Clinical Pharmacokinetics 09/2014; 53(12). DOI:10.1007/s40262-014-0178-6 · 5.05 Impact Factor
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    ABSTRACT: Androgen deprivation therapy (ADT) may increase diabetes risk. As benefits of primary ADT (PADT) for localized PCa are controversial, and most PCa survivors are of advanced age with comorbidities, it is important to determine if PADT increases diabetes risk and what are the susceptibility factors. We conducted a retrospective cohort study of 12,191 men diagnosed with incident localized PCa during 1995-2008, aged 35-100 years, and without diabetes or receipt of prostatectomy or radiation one year after diagnosis. Patients were enrolled in one of three managed health plans and followed through 2010. PADT was defined as ADT within 1 year after diagnosis. Incident diabetes was ascertained using inpatient and outpatient diagnosis codes, diabetes medications, and hemoglobin A1c values. We estimated PADT-associated diabetes risk using Cox-proportional hazards models in both conventional and propensity score analyses. 1,203 (9.9%) patients developed diabetes during follow-up (median 4.8 years) with incidence rates of 2.5 and 1.6 events per 100 person-years in the PADT and non-PADT group, respectively. PADT was associated with a 1.61-fold increased diabetes risk (95% C.I. =1.38-1.88). Number-needed-to-harm was 29. The association was stronger in men ≤70 years than in older men (HR=2.25 versus 1.40, p-value for interaction=0.008). PADT may increase diabetes risk by 60% and should be used with caution when managing localized PCa. Because of the consistent association between ADT and greater diabetes risk across disease states, we recommend routine screening and lifestyle interventions to reduce diabetes risk in men receiving ADT. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
    Annals of Epidemiology 09/2014; 24(9):682. DOI:10.1016/j.annepidem.2014.06.009 · 2.00 Impact Factor
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    ABSTRACT: Context Androgen-deprivation therapy (ADT) is a key component of treatment for aggressive and advanced prostate cancer, but it has also been associated with adverse effects on bone, metabolic, cardiovascular, sexual, and cognitive health as well as body composition. Objective To review the current literature on the adverse effects of ADT and strategies for ameliorating harm from ADT. Evidence acquisition The Medline database (through PubMed) was searched from inception to August 1, 2013, for studies documenting the side effects of ADT and for randomized and prospective trials of interventions to mitigate those side effects. Evidence synthesis Adverse effects of ADT include decreases in bone mineral density; metabolic changes such as weight gain, decreased muscle mass, and increased insulin resistance; decreased libido and sexual dysfunction; hot flashes; gynecomastia; reduced testicle size; anemia; and fatigue. Several observational studies suggest an increased risk of diabetes and cardiovascular events, although most published studies report that ADT is not linked to greater cardiovascular mortality. Randomized trials have found value in treatments for some adverse effects including bone loss (bisphosphonates, denosumab, selective estrogen receptor modulators), markers of metabolic syndrome (exercise, diet, metformin), gynecomastia (tamoxifen, prophylactic radiation), muscle loss (resistance and aerobic exercise), and hot flashes (venlafaxine, medroxyprogesterone, cyproterone acetate, gabapentin). Conclusions ADT is often a necessary component of the treatment of aggressive prostate cancer, yet it has known harms that can impair health and quality of life. Clinicians should be aware of interventions that can help mitigate these adverse effects. Patient summary Androgen deprivation therapy is a critical component of the management of aggressive and advanced prostate cancer, but it causes adverse effects including bone loss, metabolic changes, gynecomastia, muscle loss, hot flashes, and possibly increased cardiovascular events. Clinicians should be aware of interventions that can help mitigate these adverse effects.
    European Urology 08/2014; 67(5). DOI:10.1016/j.eururo.2014.07.010 · 13.94 Impact Factor
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    ABSTRACT: Context: Myostatin is a negative regulator of muscle growth. Androgen deprivation (ADT) is associated with muscle loss and increased body fat and currently available therapies have limited efficacy to treat this complication. The anti-myostatin peptibody (AMG 745/Mu-S) markedly attenuated muscle loss and decreased fat accumulation in orchiectomized mice. Objective: The objective was to evaluate safety, pharmacokinetics (PK) and muscle efficacy of AMG 745 in men undergoing ADT for non-metastatic prostate cancer. Methods: This was a randomized, blinded, placebo-controlled multiple dose phase 1 study of AMG 745 given for 28 days. The endpoint of percent change from baseline in lean body mass (LBM) as assessed by dual x-ray absorptiometry (DXA) was pre-specified. Results: Rates of adverse events (AMG 745 versus placebo) were: diarrhea (13% versus 9%), fatigue (13% versus 4%), contusion (10% versus 0%), and injection site bruising (6% versus 4%). Exposure increased linearly from 0.3 mg/kg to 3 mg/kg. AMG 745 significantly increased LBM in the 3 mg/kg versus placebo groups on Day 29 by 2.2% (± 0.8% standard error [SE]), p = 0.008; in exploratory fat mass analysis, a decrease - 2.5% (± 1.0% SE), p = 0.021 was observed. Pharmacodynamic changes in muscle and fat were maintained at follow-up, 1 month after Day 29. Conclusion: Four weekly SC doses of AMG 745 were well tolerated and were associated with increased LBM and decreased fat in the men receiving ADT for non-metastatic prostate cancer. Results support further investigation of AMG 745 in clinical settings with muscle loss and atrophy.
    Journal of Clinical Endocrinology &amp Metabolism 06/2014; 99(10):jc20141271. DOI:10.1210/jc.2014-1271 · 6.21 Impact Factor

Publication Stats

13k Citations
2,214.87 Total Impact Points


  • 1999-2015
    • Massachusetts General Hospital
      • • Department of Radiation Oncology
      • • Department of Psychiatry
      Boston, Massachusetts, United States
  • 2006-2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2010-2013
    • Beverly Hospital, Boston MA
      BVY, Massachusetts, United States
  • 2001-2013
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Health Care Policy
      Boston, Massachusetts, United States
    • Dana-Farber Cancer Institute
      • Lank Center for Genitourinary Oncology
      Boston, Massachusetts, United States
  • 2004-2010
    • University of California, San Francisco
      • Department of Urology
      San Francisco, California, United States
    • Cornell University
      • Department of Medicine
      Итак, New York, United States
  • 2009
    • Pennsylvania State University
      University Park, Maryland, United States
  • 2005-2007
    • University of Waterloo
      • Department of Statistics and Actuarial Science
      Ватерлоо, Ontario, Canada