Cancer Centers of North Carolina

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Cancer Centers of North Carolina

Raleigh, NC, United States

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O'Shaughnessy J.,Baylor Charles mmons Cancer Center | Osborne C.,Baylor Charles mmons Cancer Center | Pippen J.E.,Baylor Charles mmons Cancer Center | Yoffe M.,U.S. Oncology | And 7 more authors.
New England Journal of Medicine | Year: 2011

BACKGROUND: Triple-negative breast cancers have inherent defects in DNA repair, making this cancer a rational target for therapy based on poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition. METHODS: We conducted an open-label, phase 2 study to compare the efficacy and safety of gemcitabine and carboplatin with or without iniparib, a small molecule with PARP-inhibitory activity, in patients with metastatic triple-negative breast cancer. A total of 123 patients were randomly assigned to receive gemcitabine (1000 mg per square meter of body-surface area) and carboplatin (at a dose equivalent to an area under the concentration-time curve of 2) on days 1 and 8 - with or without iniparib (at a dose of 5.6 mg per kilogram of body weight) on days 1, 4, 8, and 11 - every 21 days. Primary end points were the rate of clinical benefit (i.e., the rate of objective response [complete or partial response] plus the rate of stable disease for ≥6 months) and safety. Additional end points included the rate of objective response, progression-free survival, and overall survival. RESULTS: The addition of iniparib to gemcitabine and carboplatin improved the rate of clinical benefit from 34% to 56% (P = 0.01) and the rate of overall response from 32% to 52% (P = 0.02). The addition of iniparib also prolonged the median progression-free survival from 3.6 months to 5.9 months (hazard ratio for progression, 0.59; P = 0.01) and the median overall survival from 7.7 months to 12.3 months (hazard ratio for death, 0.57; P = 0.01). The most frequent grade 3 or 4 adverse events in either treatment group included neutropenia, thrombocytopenia, anemia, fatigue or asthenia, leukopenia, and increased alanine aminotransferase level. No significant difference was seen between the two groups in the rate of adverse events. CONCLUSIONS: The addition of iniparib to chemotherapy improved the clinical benefit and survival of patients with metastatic triple-negative breast cancer without significantly increased toxic effects. On the basis of these results, a phase 3 trial adequately powered to evaluate overall survival and progression-free survival is being conducted. Copyright © 2011 Massachusetts Medical Society. All rights reserved.


Sonpavde G.,Texas Oncology And Us Oncology Research | Matveev V.,Russian Academy of Medical Sciences | Burke J.M.,Rocky Mountain Cancer Centers | Caton J.R.,Willamette Valley Cancer Center | And 9 more authors.
Annals of Oncology | Year: 2012

Background: AT-101 (A), a small molecule oral inhibitor of the Bcl-2 family, has activity alone and in combination with docetaxel (Taxotere) and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC). A randomized, double-blind, placebo-controlled phase II trial compared DP combined with either AT-101 (A) or placebo in chemonaive mCRPC.Patients and methods: Men with progressive mCRPC despite androgen deprivation were eligible and randomized 1 1. Patients received docetaxel (75 mg/m 2 day 1) and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg) or placebo twice daily orally on days 1-3. The primary end point was overall survival (OS).Results: Two hundred and twenty-one patients were randomly assigned. Median OS for AT-101 plus docetaxel-prednisone (ADP) and placebo-DP was 18.1 versus 17.8 months [hazard ratio (HR) 1.07, 95% confidence interval 0.72-1.55, P = 0.63]. Secondary end points were also not statistically different. Grade 3/4 toxic effects for ADP versus placebo-DP were cardiac events (5% versus 2%), lymphopenia (23% versus 16%), neutropenia (47% versus 40%), ileus (2% versus 0%) and pulmonary embolism (6% versus 2%). In a subgroup of high-risk mCRPC (n = 34), outcomes appeared to favor ADP (median OS 19 versus 14 months).Conclusions: AT-101 was tolerable but did not extend OS when combined with DP in mCRPC; a potential benefit was observed in high-risk patients. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Sonpavde G.,U.S. Oncology Research Inc. | Periman P.O.,U.S. Oncology Research Inc. | Bernold D.,U.S. Oncology Research Inc. | Weckstein D.,U.S. Oncology Research Inc. | And 10 more authors.
Annals of Oncology | Year: 2010

Background: Systemic therapy options are limited for metastatic castration-resistant prostate cancer (CRPC) patients who progress following docetaxel (Taxotere). This phase II trial evaluated sunitinib malate in patients with progressing metastatic CRPC following prior docetaxel. Patients and methods: Patients with metastatic CRPC progressing following one to two chemotherapy regimens including docetaxel were included. The primary end point was progression-free survival (PFS) per radiographic and clinical evaluations. Oral sunitinib was administered 50 mg/day 4-weeks on followed by 2-weeks off per cycle up to a maximum of eight cycles or until clinical progression or intolerable toxicity. Results: Thirty-six patients with a median age of 69.5 years were accrued. The median PFS was 19.4 weeks with a 12-week PFS of 75.8%. Four patients (12.1%) had a ≥50% prostate-specific antigen (PSA) decline and seven (21.2%) had a ≥30% PSA decline. Two of 18 patients (11.1%) with measurable disease demonstrated 30% declines by RECIST and eight (44.4%) displayed some shrinkage. A decline in pain score ≥2 points occurred in 13.6% of 22 assessable patients. Drug discontinuation due to toxic effects occurred in 52.8% of patients. Conclusion: Sunitinib malate demonstrated promising activity in metastatic CRPC progressing after prior docetaxel. © The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Regan M.M.,Dana-Farber Cancer Institute | O'Donnell E.K.,Beth Israel Deaconess Medical Center | Kelly W.K.,Yale University | Halabi S.,Duke University | And 5 more authors.
Annals of Oncology | Year: 2010

Background: Docetaxel is associated with prolonged survival in castration-resistant prostate cancer (CRPC). Platinum compounds have modest but distinct single-agent activity. Carboplatin may have greatest potential for benefit when combined with taxanes. We investigated whether there is a subset of patients with CRPC for whom the efficacy of combination taxane-estramustine-carboplatin (TEC) chemotherapy may be greatest. Patients and methods: Individual patient data (n = 310) were obtained from seven trials using TEC chemotherapy. Prostate-specific antigen (PSA) response was defined as ‡50% post-therapy decline from baseline. Overall survival was defined from baseline to death from any cause. Logistic and Cox regression were used to investigate heterogeneity in outcome to TEC by patient and disease characteristics. Predicted survival probabilities were calculated from the Halabi Cancer and Leukemia Group B (CALGB) nomogram. Results: The pooled PSA response proportion was 69% [95% confidence interval (CI) 56% to 80%]. There was no evidence of differential PSA response by disease characteristics. Established prognostic factors were associated with survival. The pooled 12-month survival estimate of 79% (95% CI 71% to 84%) was higher than the median 59% 12-month nomogram-predicted survival. Conclusions: TEC chemotherapy has significant clinical activity in CRPC. A randomized, controlled trial evaluating the addition of carboplatin to taxane-based chemotherapy is needed to elucidate the value of carboplatin in CRPC. © The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Gibbons J.P.,Mary Bird Perkins Cancer Center | Antolak J.A.,Mayo Medical School | Followill D.S.,University of Texas M. D. Anderson Cancer Center | Huq M.S.,University of Pittsburgh | And 6 more authors.
Medical Physics | Year: 2014

A protocol is presented for the calculation of monitor units (MU) for photon and electron beams, delivered with and without beam modifiers, for constant source-surface distance (SSD) and source-axis distance (SAD) setups. This protocol was written by Task Group 71 of the Therapy Physics Committee of the American Association of Physicists in Medicine (AAPM) and has been formally approved by the AAPM for clinical use. The protocol defines the nomenclature for the dosimetric quantities used in these calculations, along with instructions for their determination and measurement. Calculations are made using the dose per MU under normalization conditions, D0', that is determined for each user's photon and electron beams. For electron beams, the depth of normalization is taken to be the depth of maximum dose along the central axis for the same field incident on a water phantom at the same SSD, where D 0' = 1 cGy/MU. For photon beams, this task group recommends that a normalization depth of 10 cm be selected, where an energy-dependent D 0' ≤ 1 cGy/MU is required. This recommendation differs from the more common approach of a normalization depth of dm, with D 0' = 1 cGy/MU, although both systems are acceptable within the current protocol. For photon beams, the formalism includes the use of blocked fields, physical or dynamic wedges, and (static) multileaf collimation. No formalism is provided for intensity modulated radiation therapy calculations, although some general considerations and a review of current calculation techniques are included. For electron beams, the formalism provides for calculations at the standard and extended SSDs using either an effective SSD or an air-gap correction factor. Example tables and problems are included to illustrate the basic concepts within the presented formalism. © 2014 American Association of Physicists in Medicine.


Sonpavde G.,Baylor College of Medicine | Pond G.R.,McMaster University | Berry W.R.,Cancer Centers of North Carolina | De Wit R.,Erasmus Medical Center | And 3 more authors.
Cancer | Year: 2011

Background: In men with metastatic castration-resistant prostate cancer (CRPC), the association of measurable tumor responses with overall survival (OS) is unknown. The authors retrospectively evaluated the TAX327 phase 3 trial to study this relation. Methods: Eligible patients for this analysis included those with World Health Organization (WHO)-defined measurable metastatic disease randomized to receive either docetaxel or mitoxantrone. OS was estimated by using the Kaplan-Meier method, and the prognostic relation of WHO-defined radiologic response with OS was performed by using Cox proportional hazards regression. Landmark analyses evaluated survival from baseline and at 2, 3, 4, and 6 months after baseline. Results: Four hundred twelve patients enrolled on the TAX327 trial had measurable tumors. Thirty-seven patients exhibited a complete or partial objective response (CR/PR, 9.0%), 116 had stable disease (SD, 28.2%), 99 had progressive disease (PD, 24%) and 160 (38.8%) did not have a after-baseline objective assessment. Partial responders demonstrated longer median OS (29.0 months) than patients with SD (22.1 months) or those with PD (10.8 months) or those who were not assessed (12.7 months). These results remained after landmark analysis. The authors found a significant association between ≥30% prostate-specific antigen (PSA) declines and radiologic response, with ≥30% PSA declines occurring in all patients with CR/PR, 79.8% of patients with SD, and 34.4% with PD. Radiologic response remained a significant but modest post-treatment prognostic factor for OS after adjusting for treatment, pain response, and ≥30% PSA decline (P =.009). Conclusions: In men with metastatic CRPC and measurable disease receiving chemotherapy, objective tumor response was prognostic for OS and appeared to complement PSA assessment. © 2011 American Cancer Society.


Ojha R.P.,Dana-Farber Cancer Institute | Ojha R.P.,University of North Texas Health Science Center | Evans E.L.,University of North Texas Health Science Center | Felini M.J.,University of North Texas Health Science Center | And 2 more authors.
BJU International | Year: 2011

OBJECTIVE To evaluate the hypothesis of an association between renal cell carcinoma and multiple myeloma. PATIENTS AND METHODS Data from nine population-based registries in the Surveillance, Epidemiology and End Results programme were used to evaluate two separate cohorts of patients diagnosed between 1973 and 2006: patients diagnosed with renal cell carcinoma as a primary malignancy (n= 57 190) and patients diagnosed with multiple myeloma as a primary malignancy (n= 34 156). We estimated standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CIs) by dividing the number of observed cases of multiple myeloma within the renal cell carcinoma cohort and the number of renal cell carcinoma cases within the multiple myeloma cohort by the number of expected cases for each malignancy in the US general population. RESULTS The renal cell carcinoma cohort yielded 88 multiple myeloma cases during 293 511 person-years of follow up. Patients with renal cell carcinoma had a higher relative risk of multiple myeloma than the general population (SIR = 1.51, 95% CI 1.21-1.85). The multiple myeloma cohort yielded 69 renal cell carcinoma cases during 100 804 person-years of follow up. Patients with multiple myeloma had a higher relative risk of renal cell carcinoma than the general population (SIR = 1.89, 95% CI 1.47-2.40). CONCLUSION Our analyses revealed a bidirectional association between renal cell carcinoma and multiple myeloma, which typically indicates shared risk factors. © 2010 BJU INTERNATIONAL.


Sonpavde G.,Baylor College of Medicine | Pond G.R.,McMaster University | Berry W.R.,Cancer Centers of North Carolina | de Wit R.,Erasmus Medical Center | And 3 more authors.
Urologic Oncology: Seminars and Original Investigations | Year: 2012

Objectives: The association of a change in serum alkaline phosphatase (ALP) with overall survival OS in men with metastatic castration-resistant prostate cancer (CRPC) receiving chemotherapy is unknown. We evaluated the association of changes in ALP within 90 days with OS in men with CRPC and bone metastases treated with docetaxel or mitoxantrone in the TAX327 trial. Materials and methods: Eligible patients included those with bony metastatic disease, baseline ALP ≥ 120 u/L (upper limit of normal) and ≥2 post-therapy measurements of ALP available. Survival was estimated using the Kaplan-Meier method and prognostic potential of change in ALP was evaluated using Cox proportional hazards regression. Surrogacy was calculated by the Likelihood Reduction Factor. Results: 601 patients met the eligibility criteria. By day 90, 159 patients had ALP normalization (<120 u/L) and 442 patients did not normalize. Normalization of ALP remained prognostic for OS after adjusting for PSA decline ≥ 30% by day 90 (HR 0.79, 95% CI = 0.65-0.97, P = 0.022). Increase in ALP remained prognostic for OS when adjusting for PSA increase ≥ 50% by day 90 (HR 1.69, 95% CI = 1.33-2.14, P < 0.001). ALP changes did not meet criteria for surrogacy for OS. Conclusions: For men with CRPC, bone metastasis and high baseline ALP receiving docetaxel or mitoxantrone chemotherapy, normalization of ALP by day 90 was predictive of better survival independent of ≥30% PSA declines. An increase in ALP by day 90 was also predictive of poor survival independent of ≥50% PSA increase. Given the ready availability of ALP, the validation of our data is warranted. © 2012 Elsevier Inc..


Richards A.L.,North Carolina State University | Kleinstreuer C.,North Carolina State University | Kennedy A.S.,Cancer Centers of North Carolina | Childress E.,North Carolina State University | Buckner G.D.,North Carolina State University
IEEE Transactions on Biomedical Engineering | Year: 2012

Recent work employing the computational fluid-particle modeling of the hepatic arteries has identified a correlation between particle release position and downstream branch distribution for direct tumor-targeting in radioembolization procedures. An experimental model has been constructed to evaluate the underlying simulation theory and determine its feasibility for future clinical use. A scaled model of a generalized hepatic system with a single inlet and five outlet branches was fabricated to replicate the fluid dynamics in the hepatic arteries of diseased livers. Assuming steady flow, neutrally buoyant microspheres were released from controlled locations within the inlet of the model and the resulting output distributions were recorded. Fluid and particle transport simulations were conducted with identical parameters. The resulting experimentally and simulation-derived microsphere distributions were compared. The experimental microsphere distribution exhibited a clear dependence on injection location that correlated very strongly with the computationally predicted results. Individual branch targeting was possible for each of the five outputs. The experimental results validate the simulation methodology for achieving targeted microsphere distributions in a known geometry under constant flow conditions. © 2011 IEEE.


Richards A.L.,North Carolina State University | Dickey M.D.,North Carolina State University | Kennedy A.S.,Cancer Centers of North Carolina | Buckner G.D.,North Carolina State University
Journal of Micromechanics and Microengineering | Year: 2012

This paper describes the design and demonstration of a novel, easily fabricated micro-Coulter counter utilizing liquid metal electrodes. Fluid and electrode channels were fabricated simultaneously in a single lithographic patterning step. Eutectic gallium-indium (EGaIn) was injected into the device to form functional electrodes in a cross-channel parallel configuration. Functionality of the device was demonstrated at an ac excitation frequency of 5kHz using a polymer microsphere suspension and simple post-processing techniques. The device successfully detected particles, exhibiting an output response proportional to particle size. EGaIn was demonstrated to be an effective micro-fluidic electrode material and provided a novel approach for the fabrication of a functional micro-Coulter counter. © 2012 IOP Publishing Ltd.

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