Toni K Choueiri

Dana-Farber Cancer Institute, Boston, Massachusetts, United States

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Publications (278)1904.38 Total impact

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    ABSTRACT: Adrenocortical carcinoma (ACC) is a rare tumor in which prognostic factors are still not well established. Programmed Death Ligand-1 (PD-L1) expression in ACC and its association with clinico-pathological features and survival outcomes are unknown. Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 28 patients with ACC. PD-L1 expression was evaluated by immunohistochemistry (IHC) in both tumor cell membrane and tumor infiltrating mononuclear cells (TIMC). PD-L1 positivity on tumor cells was defined as ≥5% tumor cell membrane staining. TIMC were evaluated by IHC using a CD45 monoclonal antibody. For PD-L1 expression in TIMC, a combined score based on the extent of infiltrates and percentage of positive cells was developed. Any score greater that zero was considered PD-L1 positive. Baseline clinico-pathological characteristics and follow up data were retrospectively collected. Comparisons between PD-L1 expression and clinico-pathological features were evaluated using unpaired t-test and Fisher's exact test. Kaplan-Meier method and log-rank test were used to assess association between PD-L1 expression and 5-year overall survival (OS). Among 28 patients with surgically treated ACC, 3 (10.7%) were considered PD-L1 positive on tumor cell membrane. On the other hand, PD-L1 expression in TIMC was performed in 27 specimens and PD-L1 positive staining was observed in 19 (70.4%) patients. PD-L1 positivity in either tumor cell membrane or TIMC was not significantly associated with higher stage at diagnosis, higher tumor grade, excessive hormone secretion, or OS. PD-L1 expression can exist in ACC in both tumor cell membrane and TIMC with no relationship to clinico-pathologic parameters or survival.
    12/2015; 3(1). DOI:10.1186/s40425-015-0047-3
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    ABSTRACT: Racial disparities in cancer survival outcomes have been primarily attributed to underlying biologic mechanisms and the quality of cancer care received. Because prior literature shows little difference exists in the socioeconomic status of non-Hispanic whites and Asian Americans, any difference in cancer survival is less likely to be attributable to inequalities of care. We sought to examine differences in cancer-specific survival between whites and Asian Americans. The Surveillance, Epidemiology, and End Results Program was used to identify patients with lung (n = 130 852 [16.9%]), breast (n = 313 977 [40.4%]), prostate (n = 166 529 [21.4%]), or colorectal (n = 165 140 [21.3%]) cancer (the three leading causes of cancer-related mortality within each sex) diagnosed between 1991 and 2007. Fine and Gray's competing risks regression compared the cancer-specific mortality (CSM) of eight Asian American groups (Chinese, Filipino, Hawaiian/Pacific Islander, Japanese, Korean, other Asian, South Asian [Indian/Pakistani], and Vietnamese) to non-Hispanic white patients. All P values were two-sided. In competing risks regression, the receipt of definitive treatment was an independent predictor of CSM (hazard ratio [HR] = 0.37, 95% confidence interval [CI] = 0.35 to 0.40; HR = 0.55, 95% CI = 0.53 to 0.58; HR = 0.61, 95% CI = 0.60 to 0.62; and HR = 0.27, 95% CI = 0.25 to 0.29) for prostate, breast, lung, and colorectal cancers respectively, all P < .001). In adjusted analyses, most Asian subgroups (except Hawaiians and Koreans) had lower CSM relative to white patients, with hazard ratios ranging from 0.54 (95% CI = 0.38 to 0.78) to 0.88 (95% CI = 0.84 to 0.93) for Japanese patients with prostate and Chinese patients with lung cancer, respectively. Despite adjustment for potential confounders, including the receipt of definitive treatment and tumor characteristics, most Asian subgroups had better CSM than non-Hispanic white patients. These findings suggest that underlying genetic/biological differences, along with potential cultural variations, may impact survival in Asian American cancer patients. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    CancerSpectrum Knowledge Environment 06/2015; 107(6). DOI:10.1093/jnci/djv054 · 15.16 Impact Factor
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    ABSTRACT: A trial-level meta-analysis of randomized phase II/III controlled trials in renal cell carcinoma (RCC) and other malignancies was conducted to systematically determine the relative risk (RR) of fatigue, a common side effect associated with single agent therapy with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) and mammalian target of rapamycin inhibitors (mTORi). The RR of all grade fatigue and high grade fatigue in 7,304 patients from 19 trials was 1.35 (95% CI 1.22-1.49, p <0.001) and 1.33 (95% CI 0.97-1.82, p = 0.08), respectively in patients receiving VEGFR TKIs or mTORi. The summary incidence of all grade and high grade fatigue in the drug arm was 38.2% (95% CI 31.8-45.1) and 4.0% (95% CI 2.8-5.7), respectively. The type of drug (VEGFR TKI vs. mTORi), line of therapy, age, type of tumor (RCC vs others) and median duration of therapy did not affect the risk of all-grade fatigue.
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    ABSTRACT: Objectives To describe outcomes of patients with prostate cancer (PCa) diagnosed after another malignancy and identify factors associated with PCa death in this population, as little is known about the clinical significance of PCa as a subsequent malignancy.Patients and methodsWe studied 18,225 men diagnosed with PCa after another malignancy from 1973 to 2006. We compared demographic and clinical variables and proportion of death from PCa versus prior malignancy with T-test and chi-squared analyses. Fine and Gray's regression was used to consider the effect of treatment on PCa death. We then studied a second cohort of 88,013 men with PCa as a first or second malignancy to describe current diagnostic and treatment patterns.ResultsOne in seven men died from PCa in our first cohort. More died from PCa following colorectal cancer (16.8 vs. 13.7%), melanoma (13.4 vs. 7.56%), and oral cancer (19.1 vs. 4.04%), but fewer following bladder, kidney, lung, leukemia and non-Hodgkin's lymphoma (all p<0.001). PCa treatment was associated with a nearly 50% lower-risk of death when high-grade or high-stage PCa (AHR 0.55; 0.47-0.64). Patients who died from PCa had higher-grade and stage disease and received less treatment than patients who died of prior malignancy. The second cohort showed subsequent PCa had more high-risk disease (36.3 vs. 22.2%,p<0.001) and less PCa treatment (AOR 0.872, 0.818-0.930) than primary PCa.ConclusionsPCa remains a significant cause of mortality when diagnosed as a subsequent cancer. These results suggest PCa treatment should be seriously considered in patients with prior malignancies, especially those with high-grade or locally-advanced PCa.This article is protected by copyright. All rights reserved.
    BJU International 04/2015; DOI:10.1111/bju.13144 · 3.13 Impact Factor
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    ABSTRACT: Blockade of the programmed death-1 inhibitory cell-surface molecule on immune cells using the fully human immunoglobulin G4 antibody nivolumab mediates tumor regression in a portion of patients with advanced treatment-refractory solid tumors. We report clinical activity, survival, and long-term safety in patients with advanced renal cell carcinoma (RCC) treated with nivolumab in a phase I study with expansion cohorts. A total of 34 patients with previously treated advanced RCC, enrolled between 2008 and 2012, received intravenous nivolumab (1 or 10 mg/kg) in an outpatient setting twice per week for up to 96 weeks and were observed for survival and duration of response after treatment discontinuation. Ten patients (29%) achieved objective responses (according to RECIST [version 1.0]), with median response duration of 12.9 months; nine additional patients (27%) demonstrated stable disease lasting > 24 weeks. Three of five patients who stopped treatment while in response continued to respond for ≥ 45 weeks. Median overall survival in all patients (71% with two to five prior systemic therapies) was 22.4 months; 1-, 2-, and 3-year survival rates were 71%, 48%, and 44%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 18% of patients; all were reversible. Patients with advanced treatment-refractory RCC treated with nivolumab demonstrated durable responses that in some responders persisted after drug discontinuation. Overall survival is encouraging, and toxicities were generally manageable. Ongoing randomized clinical trials will further assess the impact of nivolumab on overall survival in patients with advanced RCC. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 03/2015; DOI:10.1200/JCO.2014.58.1041 · 17.88 Impact Factor
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    ABSTRACT: Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma. In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00924989. Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days [95% CI 256-507] vs 356 days [249-556]; hazard ratio 0·94 [95% CI 0·61-1·44]; p=0·77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three [3%] patients vs no patients in the placebo group), nausea (two [2%] vs none), and hyperglycaemia (two [2%] vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related. Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma. Astellas. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 03/2015; DOI:10.1016/S1470-2045(15)70081-1 · 24.73 Impact Factor
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    ABSTRACT: OBJECTIVE. Response Evaluation Criteria in Solid Tumors (RECIST) is the most widely accepted method to objectively assess response to therapy in renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF)-targeted therapy. Both RECIST 1.0 and 1.1 have been used to assess response to VEGF-targeted therapies; however, systematic comparisons are lacking. MATERIALS AND METHODS. Sixty-two patients with metastatic RCC treated with VEGF-targeted therapies were retrospectively studied. Tumor measurements and response assessment according to RECIST 1.1 and RECIST 1.0 were compared, including the number of target lesions, baseline measurements, response at each follow-up, best overall response, and time to progression (TTP). Morphologic changes and new enhancement were also assessed over the course of treatment, and TTP was evaluated using morphologic change criteria in combination with RECIST 1.1. RESULTS. The number of target lesions according to RECIST 1.1 was significantly fewer than by RECIST 1.0 (median, 2 vs 4; p < 0.0001). At first imaging follow-up, the percentage change of the sums of the diameter measurements by RECIST 1.1 and RECIST 1.0 were highly concordant (R = 0.857; mean shrinkage, 12.1% by RECIST 1.1 vs 10.8% by RECIST 1.0). Best response assessment was highly concordant between the two criteria (weighted κ = 0.819). There was no evidence of a difference in TTP by the two criteria, with a median TTP of 8.9 months (95% CI for the median, 5.5-13.9) by RECIST 1.1 and 8.9 months (95% CI for the median, 5.8-13.6) by RECIST 1.0. The median TTP by RECIST 1.1 alone was 8.9 months compared with 5.6 months for RECIST 1.1 and morphologic changes combined. CONCLUSION. RECIST 1.1 and RECIST 1.0 response assessments were overall highly concordant in patients with RCC treated with VEGF-targeted therapy, with fewer target lesions according to RECIST 1.1 but no difference in TTP.
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    ABSTRACT: Purpose: The renin-angiotensin system may play a role in carcinogenesis. The purpose of this study was to evaluate the impact of angiotensin system inhibitors (ASIs) on outcomes in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era. Methods: We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. Results: 4,736 patients were included, of whom 1,487 received ASIs and 783 received other anti-hypertensive agents. Overall, ASI users demonstrated improved overall survival (OS) compared to users of other anti-hypertensive agents (adjusted HR 0.838, p=0.0105, 26.68 versus 18.07 months) and individuals receiving no anti-hypertensive therapy (adjusted HR 0.810, p=0.0026, 26.68 versus 16.72 months). When stratified by therapy type, a benefit in OS was demonstrated in ASI users compared to non-users in individuals receiving vascular endothelial growth factor targeted therapy (adjusted HR 0.737, p<0.0001, 31.12 versus 21.94 months) but not temsirolimus or interferon-alpha. An in vitro cell viability assay demonstrated that sunitinib in combination with an ASI significantly decreased RCC cell viability compared to control at physiologically relevant doses. This effect was not observed with either agent alone or with other non-ASI anti-hypertensives or temsirolimus. Conclusions: In the largest analysis to date, we demonstrate that ASI use improved survival in mRCC patients treated in the targeted therapy era. Further studies are warranted to investigate the mechanism underlying this interaction and verify our observations to inform clinical practice. Copyright © 2015, American Association for Cancer Research.
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    ABSTRACT: We evaluated primary tumors from two cohorts, Spain (N = 111) and Greece (N = 102), for patients who were treated with platinum-based chemotherapy. Patients were tested for HER2 status (IHC score of 3+ or FISH ratio of ≥2.2) by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), DNA copy number, mRNA expression, and mutation status in patients with metastatic urothelial carcinoma (UC), and its impact on survival. ERBB2 mutation was determined by hotspot sequencing. mRNA expression was assessed using NanoString counting. Association of overall survival (OS) and HER2 status was assessed by a Cox regression model. NIH-3T3 cells containing HER2 V777L were assessed for growth, invasion, and HER2 kinase activation. In all, 22% of Spanish and 4% of Greek cohorts had 3+ HER2 staining by IHC. FISH amplification was identified in 20% of Spanish and 4% of Greek cohorts. Kappa coefficient between FISH and IHC was 0.47. HER2 status was not associated with OS in univariate (Spanish P = 0.34; Greek P = 0.11) or multivariate (Spanish P = 0.49; Greek P = 0.12) analysis. HER2-positive tumors expressed higher levels of HER2 mRNA than HER2-negative tumors (P < 0.001). HER2 mutations (V777L and L755S) were identified in two (2%) patients. In vitro analysis of V777L results in transformation of NIH-3T3 cells, leading to increased growth, invasion on soft agar, and HER2 kinase constitutive activation. In summary, HER2 overexpression or amplification in the primary tumor did not predict OS in patients with metastatic UC. HER2 positivity rates can differ between different populations. Further trials in genomically screened patients are needed to assess HER2-targeted therapies in UC. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
    Cancer Medicine 02/2015; DOI:10.1002/cam4.432
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    ABSTRACT: Background:We evaluated germline single nucleotide polymorphisms (SNPs) for association with overall survival (OS) in pazopanib- or sunitinib-treated patients with advanced renal cell carcinoma (aRCC).Methods:The discovery analysis tested 27 SNPs within 13 genes from a phase III pazopanib trial (N=241, study 1). Suggestive associations were then pursued in two independent datasets: a phase III trial (COMPARZ) comparing pazopanib vs sunitinib (N=729, study 2) and an observational study of sunitinib-treated patients (N=89, study 3).Results:In study 1, four SNPs showed nominally significant association (P≤0.05) with OS; two of these SNPs (rs1126647, rs4073) in IL8 were associated (P≤0.05) with OS in study 2. Because rs1126647 and rs4073 were highly correlated, only rs1126647 was evaluated in study 3, which also showed association (P≤0.05). In the combined data, rs1126647 was associated with OS after conservative multiple-test adjustment (P=8.8 × 10(-5); variant vs reference allele hazard ratio 1.32, 95% confidence interval: 1.15-1.52), without evidence for heterogeneity of effects between studies or between pazopanib- and sunitinib-treated patients.Conclusions:Variant alleles of IL8 polymorphisms are associated with poorer survival outcomes in pazopanib- or sunitinib-treated patients with aRCC. These findings provide insight in aRCC prognosis and may advance our thinking in development of new therapies.British Journal of Cancer advance online publication, 19 February 2015; doi:10.1038/bjc.2015.64 www.bjcancer.com.
    British Journal of Cancer 02/2015; DOI:10.1038/bjc.2015.64 · 4.82 Impact Factor
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    ABSTRACT: Previous prognostic models for second-line systemic therapy in patients with metastatic renal cell carcinoma have not been studied in the setting of targeted therapy. We sought to validate the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model in patients with metastatic renal cell carcinoma receiving next-line targeted therapy after progression on first-line targeted therapy. In this population-based study, we analysed patients who received second-line targeted therapy for metastatic renal cell carcinoma at 19 centres in Canada, USA, Greece, Japan, Singapore, South Korea, and Denmark. The primary endpoint was overall survival since the initiation of second-line therapy. We compared the prognostic performance of the IMDC model with the three-factor MSKCC model used for previously treated patients for overall survival since the start of second-line targeted therapy. Between Jan 1, 2005, and Nov 30, 2012, we included 1021 patients treated with second-line targeted therapy. Median overall survival since the start of second-line targeted therapy was 12·5 months (95% CI 11·3-14·3). Five of six predefined factors in the IMDC model (anaemia, thrombocytosis, neutrophilia, Karnofsky performance status [KPS] <80, and <1 year from diagnosis to first-line targeted therapy) were independent predictors of poor overall survival on multivariable analysis. The concordance index using all six prognostic factors (ie, also including hypercalcaemia) was 0·70 (95% CI 0·67-0·72) with the IMDC model and was 0·66 (95% CI 0·64-0·68) with the three-factor MSKCC model. When patients were divided into three risk categories using IMDC criteria, median overall survival was 35·3 months (95% CI 28·3-47·8) in the favourable risk group (n=76), 16·6 months (14·9-17·9) in the intermediate risk group (n=529), and 5·4 months (4·7-6·8) in the poor risk group (n=261). The IMDC prognostic model can be applied to patients previously treated with targeted therapy, in addition to previously validated populations in first-line targeted therapy. The IMDC prognostic model in the second-line targeted therapy setting has an improved prognostic performance and is applicable to a more contemporary patient cohort than that of the three-factor MSKCC model. DF/HCC Kidney Cancer SPORE P50 CA101942-01, Kidney Cancer Research Network of Canada, Canadian Institute for Health Research, Trust Family, Loker Pinard, Michael Brigham, and Gerald DeWulf. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 02/2015; DOI:10.1016/S1470-2045(14)71222-7 · 24.73 Impact Factor
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    ABSTRACT: To determine the incidence of pathologic upgrading and upstaging for contemporary, clinically low-risk patients and identify predictors of having occult, advanced disease to inform selection of patients for active surveillance. We studied 10,273 patients in the Surveillance, Epidemiology, and End Results database diagnosed with clinically low-risk disease (cT1c/T2a, Prostate specific antigen(PSA)<10ng/mL, Gleason 3+3=6) in 2010-2011 and treated with prostatectomy. The primary outcome was the incidence of upgrading to pathologic Gleason score 7-10 or upstaging to pathologic T3-T4/N1 disease. Multivariable logistic regression of men with complete biopsy data (n=5,581) identified significant predictors of upgrading or upstaging, which were then used to create a risk-stratification table. At prostatectomy, 44% of patients were upgraded and 9.7% were upstaged. Multivariable analysis of 5,581 patients showed age, PSA, and percent positive cores (all p<0.001), but not race, were associated with occult, advanced disease. With these variables dichotomized at the median, age >60 (Adjusted Odds Ratio[AOR]1.39), PSA>5.0 (AOR1.28), and >25% positive cores (AOR1.76) were significantly associated with upgrading (all p<0.001). Similarly, age>60 (AOR1.42), PSA>5.0 (AOR1.44), and >25% positive cores (AOR2.26) were associated with upstaging (all p<0.001). Sixty percent of 5,581 low-risk patients with PSA 7.5-9.9 and >25% positive cores were upgraded. This study is limited by possible bias introduced by only using patients selected for prostatectomy. Nearly half of clinically low-risk patients harbor Gleason ≥7 or ≥pT3 disease and should be risk-stratified by PSA and percent positive cores for consideration of further testing before deciding on active surveillance. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
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    ABSTRACT: The receptor tyrosine kinase c-Met is over-expressed in renal cancer cells and can play major role in the growth and survival of tumor. We investigated how the c-Met-mediated signaling through binding to its ligand hepatocyte growth factor (HGF) can modulate the apoptosis and immune escape mechanism(s) of renal cancer cells by the regulations of novel molecules heme oxygenase-1 (HO-1) and programmed cell death 1 ligand (PD-L1). We found that HGF/c-Met-mediated signaling activated the Ras/Raf pathway and down-regulated cancer cell apoptosis; and it was associated with the over-expression of cytoprotective HO-1 and anti-apoptotic Bcl-2/Bcl-xL. c-Met-induced HO-1 over-expression was regulated at the transcriptional level. Next, we observed that c-Met induction markedly up-regulated the expression of the negative co-stimulatory molecule PD-L1, and this can be prevented following treatment of the cells with pharmacological inhibitors of c-Met. Interestingly, HGF/c-Met-mediated signaling could not induce PD-L1 at the optimum level when either Ras or HO-1 was knocked down. To study the functional significance of c-Met-induced PD-L1 expression, we performed a co-culture assay using mouse splenocytes (expressing PD-L1 receptor PD-1) and murine renal cancer cells (RENCA, expressing high PD-L1). We observed that the splenocyte-mediated apoptosis of cancer cells during co-culture was markedly increased in the presence of either c-Met inhibitor or PD-L1 neutralizing antibody. Finally, we found that both c-Met and PD-L1 are significantly up-regulated and co-localized in human renal cancer tissues. Together, our study suggests a novel mechanism(s) by which c-Met can promote increased survival of renal cancer cells through the regulation of HO-1 and PD-L1. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 02/2015; DOI:10.1074/jbc.M114.612689 · 4.60 Impact Factor
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    ABSTRACT: The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These NCCN Guidelines Insights highlight the recent updates/changes in these guidelines, and updates include axitinib as first-line treatment option for patients with clear cell renal carcinoma, new data to support pazopanib as subsequent therapy for patients with clear cell carcinoma after first-line treatment with another tyrosine kinase inhibitor, and guidelines for follow-up of patients with renal cell carcinoma. Copyright © 2015 by the National Comprehensive Cancer Network.
    Journal of the National Comprehensive Cancer Network: JNCCN 02/2015; 13(2):151-9. · 4.24 Impact Factor
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    ABSTRACT: To examine the rates of hospitalization in patients with metastatic prostate cancer (mCaP), as well as the effect of hospice utilization on the cost patterns of mCaP. Over the past decade, dramatic changes in the management of advanced prostate cancer have proceeded alongside changes in end-of-life care. But, the impact of these contemporary advances in management of mCaP and its implications on US health care expenditure remains unknown. Patients hospitalized with mCaP from 1998 to 2010 were extracted from the Nationwide Inpatient Sample (n = 100,220). Temporal trends in incidence and charges were assessed by linear regression. Complex samples logistic regression models were used to identify the predictors of in-hospital mortality, elevated hospital charges beyond the 75th percentile and hospice utilization. Between 1998 and 2010, admissions for mCaP decreased at a rate of -5.95% per year (P <.001), whereas per-incident charges increased at the rate of 6.1% (P <.001) annually; the national economic burden of care was stable. Over the study period, hospice use increased 488.0% per year (P <.001) but was significantly lower among black (odds ratio [OR], 0.73; P = .01) and Hispanic (OR, 0.65; P = .03) patients. In multivariable analyses, hospice utilization was associated with decreased odds of elevated hospital charges beyond the 75th percentile (OR, 0.84; P = .02). Despite a decline in hospitalizations for mCaP, the economic burden of care has remained stable. Increasing use of hospice services has moderated the effect of rising per-incident hospital charges, highlighting the importance of promoting access to hospice in the right clinical setting. These findings have important policy implications, particularly as advances in treatment are expected to further increase expenditures related to the inpatient management of mCaP. Copyright © 2015 Elsevier Inc. All rights reserved.
    Urology 02/2015; 85(2):343-50. DOI:10.1016/j.urology.2014.09.053 · 2.13 Impact Factor
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    ABSTRACT: The long-term prostate cancer-specific survival for patients initially managed with active surveillance for low-risk prostate cancer ranges from 97-100%. We characterized factors that are associated with aggressive treatment with either radical prostatectomy or radiation for indolent prostate cancer (defined as screening-detected, low-risk disease). The Surveillance, Epidemiology and End Results Program was used to extract a cohort of 39,803 men diagnosed with PSA-detected, low-risk prostate cancer (clinical category T1c, Gleason score<6, and PSA<10) from 2004 - 2010. After socioeconomic profiles were generated from county-linked education and income data, multivariable logistic regression was used to determine whether there were any factors associated with high rates of aggressive treatment. The rate of aggressive treatment among all men with indolent prostate cancer was 64.3%. Greater rates of aggressive treatment were experienced by high socioeconomic status, Caucasian, and married men (P<0.001 for all cases). The increased adjusted odds for receipt of aggressive therapy was 1.25 (95% CI 1.17-1.32; P<0.001), 1.26 (95% CI 1.21-1.32; P<0.001), and 1.88 (95% CI 1.80-1.97; P<0.001) for high socioeconomic status, Caucasian, and married men, respectively, compared to low socioeconomic status, non-Caucasian, and unmarried men, respectively. While high socioeconomic status, Caucasian, and married men often receive the highest quality health care and have the best outcomes for many cancers, it appears that they are most at risk for the avoidable potential harms of aggressive treatment of indolent prostate cancer. Future policy should encourage more stringent guidelines for deferred treatment and culturally and sociodemographically competent counseling of active surveillance. Copyright © 2015 Elsevier Inc. All rights reserved.
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    ABSTRACT: Programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) pathway negatively regulates T cell-mediated responses. The prognostic impact of PD-L1 expression needs to be defined in urothelial carcinoma (UC). Formalin-fixed paraffin embedded tumor samples from 160 patients with UC were retrieved. PD-L1 expression was evaluated by immunohistochemistry (IHC) using a mouse monoclonal anti-PD-L1 antibody (405.9A11). PD-L1 positivity on tumor cell membrane was defined as ≥5% of tumor cell membrane staining. The extent of tumor infiltrating mononuclear cells (TIMCs) as well as PD-L1 expression on TIMCs was scored from 0 to 4. A score of 2, 3, or 4 was considered PD-L1 positive. Clinico-pathological variables were documented. Cox regression model was used to assess the association of PD-L1 expression with overall survival (OS) in patients who developed metastases. TIMCs were present in 143 of the 160 patient samples. Out of 160 samples, 32 (20%) had positive PD-L1 expression in tumor cell membrane. Out of 143 samples with TIMCs, 58(40%) had positive PD-L1 expression in TIMC. Smoking history, prior BCG use and chromosome 9 loss did not correlate with PD-L1 expression in either tumor cell membrane or TIMCs. PD-L1 positivity was not different between non-invasive or invasive UC. In patients who developed metastases (M1) and were treated with systemic therapy (n=100), PD-L1 positivity on tumor cell membrane was seen in 14% of patients and did not correlate with OS (p=0.45). Out of 89 M1 patients who had evaluable PD-L1 on TIMCs, PD-L1 expression was seen in 33% of patients and was significantly associated with longer OS on multivariate analysis (p=0.0007). PD-L1 is widely expressed in tumor cell membrane and TIMCs in UC. PD-L1 in tumor cells was not predictive of OS. However, positive PD-L1 expression in TIMCs was significantly associated with longer survival in those patients who developed metastases. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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    ABSTRACT: Response remains an important endpoint in clinical cancer trials. However, the prognostic utility of best tumor response in metastatic renal cell carcinoma (mRCC) remains vague. To define the prognostic relevance of the depth of remission in mRCC. Pooled data from the Pfizer database for 2749 patients from phase 2 and 3 clinical trials in mRCC were analyzed. Tumor shrinkage was categorized according to the best percentage change in the sum of the largest diameter of target lesions. Outcome was computed using Kaplan-Meier curves and correlation was assessed via Cox regression, including a 6-mo landmark. Sunitinib, sorafenib, axitinib, temsirolimus, or temsirolimus and interferon-α. Categorized tumor shrinkage, overall survival (OS), progression free survival (PFS). Major tumor shrinkage of 60% or more occurred in approximately 10% of patients and was associated with median OS of 54.5 mo. OS expectations steadily decreased with depth of remission (26.4, 16.6, 10.4, and 7.3 mo). The association was maintained when stratified by type of therapy, line of therapy, and performance status. Cox proportional regression analyses for the 6-mo landmark confirmed the prognostic relevance of major tumor shrinkage (hazard ratio 0.29, 95% confidence interval 0.22-0.39; p<0.001). The major limitation of our study is the variability of imaging intervals among studies. This is the first and largest analysis of best tumor response in mRCC. We demonstrate that depth of remission is an independent prognostic factor in mRCC. It remains unknown whether tumor shrinkage during therapy is needed to achieve clinical activity in metastatic renal cell carcinoma. Our analysis shows that the magnitude of tumor shrinkage correlates with better survival in patients. This observation may be used as a clinical research tool in future trials. NCT00054886, NCT00077974, NCT00267748, NCT00338884, NCT00137423, NCT00083889, NCT00065468, NCT00678392. Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    European Urology 01/2015; DOI:10.1016/j.eururo.2014.12.036 · 12.48 Impact Factor
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    ABSTRACT: Evidence-based consensus guidelines recommend only observation for men with low-risk prostate cancer and life expectancy less than 10 years. This report describes the incidence, drivers, cost, and morbidity of overtreatment of low-risk prostate cancer within the United States. The SEER-Medicare Program was used to identify 11,744 men aged 66 years or older diagnosed with low-risk prostate cancer in 2004 through 2007. Overtreatment of prostate cancer was defined as definitive treatment of a patient with a life expectancy of less than 10 years. Expected survival was estimated using NCCN methodology. Costs were the amount paid by Medicare in years after minus year before diagnosis. Toxicities were relevant Medicare diagnoses/interventions. P values are 2-sided. Of 3001 men with low-risk prostate cancer and a life expectancy of less than 10 years, 2011 men (67%) were overtreated. On multivariable logistic regression, overtreated men were more likely to be married (odds ratio [OR], 1.29; 95% CI, 1.05-1.59; P=.02), reside in affluent regions (P<.001), and harbor more advanced disease at diagnosis (P<.001). Two-year toxicity was greater in overtreated patients (P<.001). Relative to active surveillance/watchful waiting/observation, the median additional cost per definitive treatment was $18,827 over 5 years; the cumulative annual cost attributable to overtreatment in the United States was $58.7 million. The ability to avoid treating the 80% of men with low-grade disease who will never die of prostate cancer would save $1.32 billion per year nationally. Overtreatment of low-risk prostate cancer is partially driven by sociodemographic factors and occurs frequently, with marked impact on patient quality of life and health-related costs. Copyright © 2015 by the National Comprehensive Cancer Network.
    Journal of the National Comprehensive Cancer Network: JNCCN 01/2015; 13(1):61-8. · 4.24 Impact Factor
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    ABSTRACT: Ror2 is a Wnt ligand receptor that is overexpressed in a variety of tumors including clear cell renal cell carcinoma (ccRCC). Here we demonstrate that expression of wild type Ror2 results in increased tumorigenic properties in in vitro cell culture and in vivo xenograft models. In addition, Ror2 expression produced positive changes in both cell migration and invasion, which were dependent on matrix metalloprotease 2 (MMP2) activity. Mutations in key regions of the kinase domain of Ror2 resulted in the abrogation of increased tumor growth, cell migration, and cell invasion observed with expression of wild-type Ror2. Finally, we examined Ror2 expression as a prognostic biomarker for ccRCC utilizing the TCGA ccRCC dataset. High expression of Ror2 showed a significant correlation with higher clinical stage, nuclear grade, and tumor stage. Furthermore, high expression of Ror2 in ccRCC patients correlated with significant lower overall survival, cancer specific survival, and recurrence free survival. Together, these findings suggest that Ror2 plays a central role in influencing the ccRCC phenotype, and can be considered as a negative prognostic biomarker and potential therapeutic target in this cancer.
    PLoS ONE 12/2014; 9(12):e116101. DOI:10.1371/journal.pone.0116101 · 3.53 Impact Factor

Publication Stats

4k Citations
1,904.38 Total Impact Points

Institutions

  • 2008–2015
    • Dana-Farber Cancer Institute
      • • Department of Medical Oncology
      • • Lank Center for Genitourinary Oncology
      Boston, Massachusetts, United States
    • Harvard Medical School
      • Department of Radiation Oncology
      Boston, Massachusetts, United States
  • 2014
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2010–2014
    • Brigham and Women's Hospital
      • Lank Center for Genitourinary Oncology
      Boston, Massachusetts, United States
    • Beverly Hospital, Boston MA
      BVY, Massachusetts, United States
  • 2008–2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2013
    • University of Connecticut
      • Department of Statistics
      Storrs, Connecticut, United States
  • 2011
    • Boston Medical Center
      Boston, Massachusetts, United States
  • 2009–2010
    • Tom Baker Cancer Centre
      Calgary, Alberta, Canada
  • 2007
    • Wojskowy Instytut Medyczny
      Warszawa, Masovian Voivodeship, Poland
  • 2006–2007
    • Cleveland Clinic
      • Department of Solid Tumor Oncology
      Cleveland, Ohio, United States