Toni K Choueiri

Harvard Medical School, Boston, Massachusetts, United States

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Publications (196)1341.26 Total impact

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    ABSTRACT: To identify factors associated with weight gain at 1 year from initiation of androgen deprivation therapy (ADT). A retrospective review assessed weight change among 118 men with nonmetastatic prostate cancer treated with ADT for at least 6 months. Outcome associations were tested using 2-tailed t tests and linear regression. Men in our cohort had significant weight gain (+1.32 kg, P = .0005) in the 1 year after ADT initiation. Three risk factors for weight gain on ADT were identified as follows: age <65 years (2.72 kg gained, P = .001), body mass index (BMI) <30 (1.98 kg gained, P = .00002), and nondiabetic status (1.56 kg gained, P = .0003). Multivariable regression found both age <65 years (beta = 4.01, P = .02) and BMI <30 (beta = 3.57, P = .03) to be independently predictive of weight gain, whereas nondiabetic status was nonsignificantly predictive of weight gain (beta = 2.14, P = .29). Weight change was further stratified by the total number of risk factors present (risk score): scores of 0, 1, 2, and 3 risk factors corresponded to weight changes of -1.10, +0.41, +1.34, and +3.79 kg, respectively (P-trend = .0005). Age <65 years and BMI <30 were both independently associated with weight gain 1 year after starting ADT. Increasing weight gain was also strongly associated with increasing number of baseline risk factors present. Despite traditional concerns about ADT in unhealthy men, these data suggest younger, healthier patients may be at higher risk for gaining weight on ADT and should be counseled accordingly.
    Urology 04/2014; · 2.42 Impact Factor
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    ABSTRACT: Background:Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design.Methods:Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria.Results:In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (P<0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, P<0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months.Conclusions:Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.British Journal of Cancer advance online publication, 1 April 2014; doi:10.1038/bjc.2014.25 www.bjcancer.com.
    British Journal of Cancer 04/2014; · 5.08 Impact Factor
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    ABSTRACT: The role of adjuvant chemotherapy (AC) or neoadjuvant chemotherapy (NC) remains poorly defined for the management of upper tract urothelial carcinoma (UTUC), although some studies suggest a benefit. To update the current evidence on the role of NC and AC for UTUC patients. We searched for all studies investigating NC or AC for UTUC in Medline, Embase, the Cochrane Central Register of Controlled Trials, and abstracts from the American Society of Clinical Oncology meetings prior to February 2014. A systematic review and meta-analysis were performed. No randomized trials investigated the role of AC for UTUC. There was one prospective study (n=36) investigating adjuvant carboplatin-paclitaxel and nine retrospective studies, with a total of 482 patients receiving cisplatin-based or non-cisplatin-based AC after nephroureterectomy (NU) and 1300 patients receiving NU alone. Across three cisplatin-based studies, the pooled hazard ratio (HR) for overall survival (OS) was 0.43 (95% confidence interval [CI], 0.21-0.89; p=0.023) compared with those who received surgery alone. For disease-free survival (DFS), the pooled HR across two studies was 0.49 (95% CI, 0.24-0.99; p=0.048). Benefit was not seen for non-cisplatin-based regimens. For NC, two phase 2 trials demonstrated favorable pathologic downstaging rates, with 3-yr OS and disease-specific survival (DSS) ≤93%. Across two retrospective studies investigating NC, there was a DSS benefit, with a pooled HR of 0.41 (95% CI, 0.22-0.76; p=0.005). There appears to be an OS and DFS benefit for cisplatin-based AC in UTUC. This evidence is limited by the retrospective nature of studies and their relatively small sample size. NC appears to be promising, but more trials are needed to confirm its utility. After a comprehensive search of studies examining the role of chemotherapy for upper tract urothelial cancer, the pooled evidence shows that cisplatin-based adjuvant chemotherapy was beneficial for prolonging survival.
    European Urology 03/2014; · 10.48 Impact Factor
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    ABSTRACT: Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole-exome sequencing of a patient with a 14-month complete response on this trial revealed two concurrent mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biologic mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or "personalized") medicine approaches to screen patients with cancer for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.
    Cancer Discovery 03/2014; · 10.14 Impact Factor
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    ABSTRACT: Multitargeted tyrosine kinase inhibitors (TKIs) have antitumor activity in metastatic renal cell carcinoma (mRCC). Resistance to these agents develops frequently, and their use is often limited by intolerance. Ramucirumab is a recombinant human monoclonal antibody directed against human vascular endothelial growth factor receptor-2. For this study, the authors investigated the clinical efficacy and safety of ramucirumab in patients with TKI-resistant/intolerant mRCC. In this single-arm phase 2 trial, patients received ramucirumab 8 mg/kg every 2 weeks until they developed disease progression or intolerable toxicity. The primary endpoint was the best objective response rate (ORR); additional endpoints included the disease control rate (DCR), progression-free survival (PFS), the median duration of overall response, and safety. Thirty-nine patients with RCC received ramucirumab monotherapy. Prior TKI therapy included sunitinib (59% of patients), sunitinib and sorafenib (30.8% of patients), and sorafenib (10.3% of patients). The ORR was 5.1% (95% confidence interval [CI], 0.6%-17.3%). The 12-week DCR was 64.1% (95% CI, 47.2%-78.8%). The median PFS was 7.1 months (95% CI, 4.1-9.7 months), and the median overall survival was 24.8 months (95% CI, 18.9-32.6 months). Grade 3 or higher adverse events that occurred in ≥5% of patients included grade 3 hypertension (7.7%) and proteinuria (5.1%). There was 1 on-study death from multiorgan failure. Although the study did not meet its primary endpoint of ≥15% ORR, ramucirumab was associated with evidence of antitumor activity in patients with TKI-resistant/intolerant mRCC. Ramucirumab was safe and well tolerated. Cancer 2014. © 2014 American Cancer Society.
    Cancer 02/2014; · 5.20 Impact Factor
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    ABSTRACT: Bone metastases (BMs) are frequently present in patients with metastatic renal cell carcinoma (mRCC) and cause significant morbidity. The purpose of this analysis was to assess the impact of BMs and bisphosphonate therapy (BT) on outcomes in mRCC. We conducted a pooled analysis of patients with mRCC treated from 2003 to 2011 in phase 2 and 3 trials. Statistical analyses were performed using Cox regression and the Kaplan-Meier method. We identified 2749 patients treated with sunitinib (n=1059), sorafenib (n=355), axitinib (n=359), temsirolimus (n=208), temsirolimus plus interferon-α (IFN-α) (n=208), or IFN-α (n=560), with 28% (n=781) having BMs. A total of 285 patients (10.4%) received BT. The presence of BMs in patients was associated with shorter overall survival (OS) when compared with patients without BMs (13.2 vs 20.2 mo, respectively; p<0.0001) and shorter progression-free survival (PFS) (5.1 vs 6.7 mo, respectively; p<0.0008). When stratified by risk groups, the presence of BMs was associated with shorter OS in all risk groups. The use of BT in patients with BMs was not associated with improved OS compared with patients who did not receive BT (13.3 vs 13.1 mo, respectively; p=0.3801) or improved PFS (5.1 vs 4.9 mo, respectively; p=0.1785). Bisphosphonate users with BMs did not have a decreased rate of skeletal-related events (SREs) compared with nonusers (8.6% vs 5.8%, respectively; p=0.191). In addition, BT was associated with increased rates of hypocalcemia, renal insufficiency, and osteonecrosis of the jaw (p<0.0001). Data were analyzed retrospectively. We confirm that the presence of BMs is associated with shorter survival in mRCC. BT did not affect survival or SRE prevention and was associated with increased toxicity. In this analysis, we demonstrate that bone metastases are associated with shorter survival in patients with metastatic renal cell carcinoma. In addition, we call into question the utility of bisphosphonate therapy in this population.
    European Urology 02/2014; · 10.48 Impact Factor
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    ABSTRACT: Gene expression signatures have proven to be useful tools in many cancers to identify distinct subtypes of disease based on molecular features that drive pathogenesis, and to aid in predicting clinical outcomes. However, there are no current signatures for kidney cancer that are applicable in a clinical setting. To generate a signature biomarker for the clear cell renal cell carcinoma (ccRCC) good risk (ccA) and poor risk (ccB) subtype classification that could be readily applied to clinical samples to develop an integrated model for biologically defined risk stratification. A set of 72 ccRCC sample standards was used to develop a 34-gene classifier (ClearCode34) for assigning ccRCC tumors to subtypes. The classifier was applied to RNA-sequencing data from 380 nonmetastatic ccRCC samples from the Cancer Genome Atlas (TCGA), and to 157 formalin-fixed clinical samples collected at the University of North Carolina. Kaplan-Meier analyses were performed on the individual cohorts to calculate recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Training and test sets were randomly selected from the combined cohorts to assemble a risk prediction model for disease recurrence. The subtypes were significantly associated with RFS (p<0.01), CSS (p<0.01), and OS (p<0.01). Hazard ratios for subtype classification were similar to those of stage and grade in association with recurrence risk, and remained significant in multivariate analyses. An integrated molecular/clinical model for RFS to assign patients to risk groups was able to accurately predict CSS above established, clinical risk-prediction algorithms. The ClearCode34-based model provides prognostic stratification that improves upon established algorithms to assess risk for recurrence and death for nonmetastatic ccRCC patients. We developed a 34-gene subtype predictor to classify clear cell renal cell carcinoma tumors according to ccA or ccB subtypes and built a subtype-inclusive model to analyze patient survival outcomes.
    European Urology 02/2014; · 10.48 Impact Factor
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    ABSTRACT: Background:Several reports suggest that vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma (mRCC) may be more toxic in Asian vs non-Asian populations. Comparative efficacy of these agents with respect to ethnicity is not well characterised.Methods:A multicentre, retrospective, cohort study using Asian and non-Asian centres which collected data on ethnicity, dose reductions and outcomes using the International mRCC Database Consortium.Results:This study included 1024 (464 Asian, 560 non-Asian) patients with a 29.4 months median follow-up. The percentage of dose modifications/reductions between non-Asians and Asians was similar (55% vs 61% P=0.1197). When adjusted for risk groups, there was no difference in overall or progression-free survival between non-Asians and Asians. Patients with dose reductions due to toxicity had longer treatment durations and overall survival than those who did not in both non-Asian (10.6 vs 5.0 months, P<0.0001; 22.6 vs 16.1 months, P=0.0016, respectively) and Asian populations (8.9 vs 5.4 months, P=0.0028; 28.0 vs 18.7 months, P=0.0069, respectively).Conclusions:Adjusting for risk groups, there appears to be no difference in outcome between Asian vs non-Asian patients with mRCC treated with VEGF-targeted therapy. Judicious dose reductions may allow for better outcomes in both populations due to longer treatment durations, but direct comparisons are needed.British Journal of Cancer advance online publication, 18 February 2014; doi:10.1038/bjc.2014.28 www.bjcancer.com.
    British Journal of Cancer 02/2014; · 5.08 Impact Factor
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    ABSTRACT: These NCCN Guidelines Insights highlight treatment recommendations and updates specific to the management of patients with advanced non-clear cell carcinoma included in the 2014 version of the NCCN Clinical Practice Guidelines in Oncology for Kidney Cancer.
    Journal of the National Comprehensive Cancer Network: JNCCN 02/2014; 12(2):175-82. · 5.11 Impact Factor
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    ABSTRACT: Metastatic urothelial carcinoma (UC) of the bladder is associated with multiple somatic copy number alterations (SCNAs). We evaluated SCNAs to identify predictors of poor survival in patients with metastatic UC treated with platinum-based chemotherapy. We obtained overall survival (OS) and array DNA copy number data from metastatic UC patients in two cohorts. Associations between recurrent SCNAs and OS were determined by a Cox proportional hazard model adjusting for performance status and visceral disease. mRNA expression was evaluated for potential candidate genes by Nanostring nCounter to identify transcripts from the region that are associated with copy number gain. In addition, expression data from an independent cohort was used to identify candidate genes. Multiple areas of recurrent significant gains and losses were identified. Gain of 1q23.3 was independently associated with a shortened OS in the both cohorts (adjusted HR 2.96; 95% CI, 1.35 to 6.48; P = 0.01 and adjusted HR 5.03; 95% CI 1.43-17.73; P < 0.001). The F11R, PFDN2, PPOX, USP21 and DEDD genes, all located on 1q23.3, were closely associated with poor outcome. 1q23.3 copy number gain displayed association with poor survival in two cohorts of metastatic UC. The identification of the target of this copy number gain is ongoing, and exploration of this finding in other disease states may be useful for the early identification of poor risk UC patients. Prospective validation of the survival association is necessary to demonstrate clinical relevance.
    Clinical Cancer Research 01/2014; · 7.84 Impact Factor
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    ABSTRACT: Androgen deprivation therapy (ADT) might increase the risk of acute kidney injury (AKI) in patients with prostate cancer (PCa). To examine the impact of ADT on AKI in a large contemporary cohort of patients with nonmetastatic PCa representing the US population. Overall, 69 292 patients diagnosed with nonmetastatic PCa between 1995 and 2009 were abstracted from the Surveillance Epidemiology and End Results-Medicare database. Patient in both treatment arms (ADT vs no ADT) were matched using propensity-score methodology. Ten-year AKI rates were estimated. Competing-risks regression analyses tested the association between ADT and AKI, after adjusting for the risk of death during follow-up. Overall, the 10-yr AKI rates were 24.9% versus 30.7% for ADT-naive patients versus those treated with ADT, respectively (p<0.001). When patients were stratified according to the type of ADT, the 10-yr AKI rates were 31.1% versus 26.0% for men treated with gonadotropin-releasing hormone (GnRH) agonists and bilateral orchiectomy, respectively (p<0.001). In multivariable analyses, the administration of GnRH agonists (hazard ratio [HR]: 1.24; 95% confidence interval [CI], 1.18-1.31; p<0.001), but not bilateral orchiectomy (HR: 1.11; 95% CI, 0.96-1.29; p=0.1), was associated with the risk of experiencing AKI. Our study is limited by its retrospective design. ADT is associated with an increased risk of AKI in patients with nonmetastatic PCa. In particular, the administration of GnRH agonists, but not surgical castration, may substantially increase the risk of experiencing AKI. These observations should help provide physicians with better patient selection to reduce the risk of AKI. The administration of gonadotropin-releasing hormone agonists, but not bilateral orchiectomy, increases the risk of acute kidney injury (AKI) in patients with prostate cancer (PCa). These observations should help provide physicians with better patient selection to reduce the risk of AKI in PCa patients.
    European Urology 01/2014; · 10.48 Impact Factor
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    ABSTRACT: Background Approval of the mTOR inhibitors for the treatment of metastatic RCC was based on efficacy in poor risk patients in the first-line setting for temsirolimus and in VEGF inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting. Patients and Methods Retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distributions of progression-free survival (PFS) and overall survival (OS). Results We identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 73% and everolimus in 27%. The main reasons for choice of temsirolimus were poor risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%) whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor risk by IMDC criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus respectively. While limited by small numbers, this study characterizes a real world, international experience with the use of mTOR inhibition in treatment-naïve metastatic RCC patients. Conclusions Poor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Given the different patient populations in which they were administered, direct comparisons of the frontline efficacy of temsirolimus and everolimus cannot be made.
    Clinical Genitourinary Cancer 01/2014; · 1.43 Impact Factor
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    ABSTRACT: Background Patients with metastatic renal cell carcinoma (mRCC) failing first line therapies may have clinical benefit with sequential targeted agents. Limited data is available on the efficacy and toxicity of subsequent therapies after progression on pazopanib. Methods Patients with mRCC who received subsequent systemic treatment after pazopanib failure were identified across 7 institutions. Pazopanib was given as first line therapy in 28 patients and after cytokines in 7 patients. Clinical outcome and toxicity analyses of two sequential treatment options [anti-VEGF or mTOR inhibitors(mTORi)] is presented. Results Subsequent therapy was anti-VEGF in 22 patients and mTORi in 13. One patient receiving bevacizumab+temsirolimus combination was excluded. VEGF-targeted therapies included sorafenib (n=10), sunitinib (n=3), bevacizumab (n=2), cediranib (n=4) and cabozantinib (n=3). Patients treated with mTORi received everolimus. Median progression-free survival (PFS) was 5.6 months from the start of subsequent therapy with anti-VEGF and 2.4 months with mTORi (p=0.009). Overall survival (OS) was not significantly different (p=0.68). Clinical benefit (PR + SD) on subsequent therapy was observed in 64% and 31% of anti-VEGF and everolimus treated patients respectively (p=0.021). Conclusion In this retrospective study, targeting VEGF was an effective strategy after pazopanib progression, although OS was not different among patients treated with VEGF or mTORi.
    Clinical Genitourinary Cancer 01/2014; · 1.43 Impact Factor
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    ABSTRACT: Objective To identify factors associated with weight gain at 1 year from initiation of androgen deprivation therapy (ADT). Methods A retrospective review assessed weight change among 118 men with nonmetastatic prostate cancer treated with ADT for at least 6 months. Outcome associations were tested using 2-tailed t tests and linear regression. Results Men in our cohort had significant weight gain (+1.32 kg, P = .0005) in the 1 year after ADT initiation. Three risk factors for weight gain on ADT were identified as follows: age <65 years (2.72 kg gained, P = .001), body mass index (BMI) <30 (1.98 kg gained, P = .00002), and nondiabetic status (1.56 kg gained, P = .0003). Multivariable regression found both age <65 years (beta = 4.01, P = .02) and BMI <30 (beta = 3.57, P = .03) to be independently predictive of weight gain, whereas nondiabetic status was nonsignificantly predictive of weight gain (beta = 2.14, P = .29). Weight change was further stratified by the total number of risk factors present (risk score): scores of 0, 1, 2, and 3 risk factors corresponded to weight changes of −1.10, +0.41, +1.34, and +3.79 kg, respectively (P-trend = .0005). Conclusion Age <65 years and BMI <30 were both independently associated with weight gain 1 year after starting ADT. Increasing weight gain was also strongly associated with increasing number of baseline risk factors present. Despite traditional concerns about ADT in unhealthy men, these data suggest younger, healthier patients may be at higher risk for gaining weight on ADT and should be counseled accordingly.
    Urology 01/2014; · 2.42 Impact Factor
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    ABSTRACT: Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown. mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3). Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001). The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.
    Annals of Oncology 01/2014; 25(1):149-54. · 7.38 Impact Factor
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    ABSTRACT: Among considerable efforts to improve quality of surgical care, expedited measures such as a selective referral to high-volume institutions have been advocated. Our objective was to examine whether racial, insurance and/or socioeconomic disparities exist in the use of high-volume hospitals for complex surgical oncological procedures within the USA. Patients undergoing colectomy, cystectomy, oesophagectomy, gastrectomy, hysterectomy, lung resection, pancreatectomy or prostatectomy were identified retrospectively, using the Nationwide Inpatient Sample, between years 1999 and 2009. This resulted in a weighted estimate of 2 508 916 patients. Distribution of patients according to race, insurance and income characteristics was examined according to low-volume and high-volume hospitals (highest 20% of patients according to the procedure-specific mean annual volume). Generalised linear regression models for prediction of access to high-volume hospitals were performed. Insurance providers and county income levels varied differently according to patients' race. Most Caucasians resided in wealthier counties, regardless of insurance types (private/Medicare), while most African Americans resided in less wealthy counties (≤$24 999), despite being privately insured. In general, Caucasians, privately insured, and those residing in wealthier counties (≥$45 000) were more likely to receive surgery at high-volume hospitals, even after adjustment for all other patient-specific characteristics. Depending on the procedure, some disparities were more prominent, but the overall trend suggests a collinear effect for race, insurance type and county income levels. Prevailing disparities exist according to several patient and sociodemographic characteristics for utilisation of high-volume hospitals. Efforts should be made to directly reduce such disparities and ensure equal healthcare delivery.
    BMJ Open 01/2014; 4(3):e003921. · 1.58 Impact Factor
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    ABSTRACT: Background Targeted therapy has become the mainstay of treatment for metastatic renal cell carcinoma (mRCC). The efficacy of this therapy in the older population is poorly understood. Patients and methods Data from patients with mRCC treated with first-line anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. Patient characteristics, data on second-line therapy, and outcomes, including treatment duration and overall survival, were evaluated using summary statistics and multivariate analysis. Results and limitations: 1,381 patients were treated with front-line targeted therapy; 144 (10%) were 75-years or older. 4% were favorable risk, 69% intermediate risk, and 27% poor risk as per Heng et al. JCO 2009 prognostic factors. The initial treatment for those ≥75-years was with sunitinib(n=98), sorafenib(n=35), bevacizumab(n=7), and AZD217(n=4). 23% of older patients and 39% of the younger patients went on to receive second-line therapy (p<0.0001). The overall response rate, median treatment duration and overall survival for the older vs. younger group were 18% vs. 25% (p=0.0975), 5.5months vs. 7.5months (p=0.1388) and 16.8months vs. 19.7months (p=0.3321), respectively. When adjusted for poor prognostic factors, age 75-years and above was not found to be associated with poorer overall survival (HR 1.002, 95%CI 0.781-1.285) or shorter treatment duration (HR 1.018, 95%CI 0.827-1.252). The retrospective study design was the primary limitation. Conclusions The use of advanced age as a selection criterion for targeted therapy requires further study, with data suggesting no clinically meaningful differences in overall response rate, treatment duration, and overall survival between older and younger age groups.
    Clinical Genitourinary Cancer 01/2014; · 1.43 Impact Factor
  • Rana R McKay, Mary-Ellen Taplin, Toni K Choueiri
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    ABSTRACT: Maintaining bone health is important in the management of men with prostate cancer. Patients receiving androgen deprivation therapy are at increased risk for treatment-related osteoporosis, and patients with bone metastases are at increased risk for skeletal morbidity related to debilitating skeletal-related events (SREs). Optimizing bone health in these patients includes lifestyle modifications, calcium/vitamin D supplementation, and osteoclast-targeted agents in select high-risk patients. No agent is approved for the prevention of bone metastases. Novel systemic agents have shown a beneficial effect bone by directly affecting tumor growth. Integration of these anticancer agents with osteoclast-targeted agents warrants further investigation.
    Hematology/oncology clinics of North America 12/2013; 27(6):1261-83. · 2.05 Impact Factor
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    ABSTRACT: Alternative response criteria have been proposed in patients with metastatic renal cell carcinoma (mRCC) who are receiving vascular endothelial growth factor (VEGF)-targeted therapy, including 10% tumor shrinkage as an indicator of response/outcome. However, to the authors' knowledge, intraobserver and interobserver measurement variability have not been defined in this setting. The objective of the current study was to determine intraobserver and interobserver agreement of computed tomography (CT) size and attenuation measurements to establish reproducible response indicators. Seventy-one patients with mRCC with 179 target lesions were enrolled in phase 2 and phase 3 trials of VEGF-targeted therapies and retrospectively studied with Institutional Review Board approval. Two radiologists independently measured the long axis diameter and mean attenuation of target lesions at baseline and on follow-up CT. Concordance correlation coefficients and Bland-Altman plots were used to assess intraobserver and interobserver agreement. High concordance correlation coefficients (range, 0.8602-0.9984) were observed in all types of measurements. The 95% limits of agreement for the percentage change of the sum longest diameter was -7.30% to 7.86% for intraobserver variability, indicating that 10% tumor shrinkage represents a true change in tumor size when measured by a single observer. The 95% limits of interobserver variability were -16.3% to 15.4%. On multivariate analysis, the location of the lesion was found to significantly contribute to interobserver variability (P = .048). The 95% limits of intraobserver agreement for the percentage change in CT attenuation were -18.34% to 16.7%. In patients with mRCC who are treated with VEGF inhibitors, 10% tumor shrinkage is a reproducible radiologic response indicator when baseline and follow-up studies are measured by a single radiologist. Lesion location contributes significantly to measurement variability and should be considered when selecting target lesions. Cancer 2013;. © 2013 American Cancer Society.
    Cancer 11/2013; · 5.20 Impact Factor
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    ABSTRACT: Background DNA aptamers represent a novel strategy in anti-cancer medicine. AS1411, a DNA aptamer targeting nucleolin (a protein which is overexpressed in many tumor types), was evaluated in patients with metastatic, clear-cell, renal cell carcinoma (RCC) who had failed treatment with ≥1 prior tyrosine kinase inhibitor. Methods In this phase II, single-arm study, AS1411 was administered at 40 mg/kg/day by continuous intravenous infusion on days 1-4 of a 28-day cycle, for two cycles. Primary endpoint was overall response rate; progression-free survival (PFS) and safety were secondary endpoints. Results 35 patients were enrolled and treated. One patient (2.9 %) had a response to treatment. The response was dramatic (84 % reduction in tumor burden by RECIST 1.0 criteria) and durable (patient remains free of progression 2 years after completing therapy). Whole exome sequencing of this patient's tumor revealed missense mutations in the mTOR and FGFR2 genes which is of interest because nucleolin is known to upregulate mTOR pathway activity by enhancing AKT1 mRNA translation. No other responses were seen. Thirty-four percent of patients had an AS1411-related adverse event, all of which were mild or moderate. Conclusions AS1411 appears to have minimal activity in unselected patients with metastatic RCC. However, rare, dramatic and durable responses can be observed and toxicity is low. One patient in this study had an excellent response and was found to have FGFR2 and mTOR mutations which will be of interest in future efforts to discover and validate predictive biomarkers of response to nucleolin targeted compounds. DNA aptamers represent a novel way to target cancer cells at a molecular level and continue to be developed with a view to improving treatment and imaging in cancer medicine.
    Investigational New Drugs 11/2013; · 3.50 Impact Factor

Publication Stats

2k Citations
352 Downloads
1,341.26 Total Impact Points

Institutions

  • 2008–2014
    • Harvard Medical School
      • Department of Radiation Oncology
      Boston, Massachusetts, United States
    • Dana-Farber Cancer Institute
      • • Lank Center for Genitourinary Oncology
      • • Department of Radiation Oncology
      • • Department of Medical Oncology
      Boston, Massachusetts, United States
    • Nottinghamshire Healthcare NHS Trust
      Nottigham, England, United Kingdom
  • 2013
    • Lancaster General Hospital
      Lancaster, Pennsylvania, United States
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
    • Georgetown University
      • Department of Urology
      Washington, D. C., DC, United States
    • Albert Einstein College of Medicine
      • Department of Medical Oncology
      New York City, NY, United States
    • Memorial Sloan-Kettering Cancer Center
      • Genitourinary Oncology Service
      New York City, New York, United States
  • 2012–2013
    • University of Alabama at Birmingham
      • Department of Medicine
      Birmingham, AL, United States
    • Stanford University
      • Stanford Cancer Institute
      Stanford, CA, United States
    • Seoul National University Hospital
      Sŏul, Seoul, South Korea
  • 2009–2013
    • Harvard University
      • Department of Nutrition
      Cambridge, Massachusetts, United States
    • Tom Baker Cancer Centre
      Calgary, Alberta, Canada
    • Beth Israel Deaconess Medical Center
      • Division of Hematology/Oncology
      Boston, MA, United States
    • Analysis Group
      Boston, Massachusetts, United States
  • 2011–2012
    • Brigham and Women's Hospital
      • • Department of Medicine
      • • Center for Brain Mind Medicine
      Boston, MA, United States
    • The University of Calgary
      Calgary, Alberta, Canada
    • Vancouver Prostate Centre
      Vancouver, British Columbia, Canada
    • Boston Medical Center
      Boston, Massachusetts, United States
  • 2010–2011
    • University of Texas MD Anderson Cancer Center
      • • Department of Urology
      • • Division of Radiation Oncology
      Houston, TX, United States
    • Tulane University
      New Orleans, Louisiana, United States
  • 2006–2008
    • Cleveland Clinic
      • Department of Solid Tumor Oncology
      Cleveland, OH, United States
  • 2007
    • Institut de Cancérologie Gustave Roussy
      Île-de-France, France