Publications by authors named "Frances McSherry"

38 Publications

Adjuvant Radiation in Older Patients With Glioblastoma: A Retrospective Single Institution Analysis.

Front Oncol 2021 25;11:631618. Epub 2021 Feb 25.

Department of Neurosurgery, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, United States.

Objectives: Standard 6-week and hypofractionated 3-week courses of adjuvant radiation therapy (RT) are both options for older patients with glioblastoma (GBM), but deciding the optimal regimen can be challenging. This analysis explores clinical factors associated with selection of RT course, completion of RT, and outcomes following RT.

Materials And Methods: This IRB-approved retrospective analysis identified patients ≥70 years old with GBM who initiated adjuvant RT at our institution between 2004 and 2016. We identified factors associated with standard or hypofractionated RT using the Cochran-Armitage trend test, estimated time-to-event endpoints using the Kaplan-Meier method, and found predictors of overall survival (OS) using Cox proportional hazards models.

Results: Sixty-two patients with a median age of 74 (range 70-90) initiated adjuvant RT, with 43 (69%) receiving standard RT and 19 (31%) receiving hypofractionated RT. Selection of short-course RT was associated with older age (p = 0.04) and poor KPS (p = 0.03). Eight (13%) patients did not complete RT, primarily for hospice care due to worsening symptoms. After a median follow-up of 37 months, median OS was 12.3 months (95% CI 9.0-15.1). Increased age (p < 0.05), poor KPS (p < 0.0001), lack of MGMT methylation (p < 0.05), and lack of RT completion (p < 0.0001) were associated with worse OS on multivariate analysis. In this small cohort, GTV size and receipt of standard or hypofractionated RT were not associated with OS.

Conclusions: In this cohort of older patients with GBM, age and KPS was associated with selection of short-course or standard RT. These regimens had similar OS, though a subset of patients experienced worsening symptoms during RT and discontinued treatment. Further investigation into predictors of RT completion and survival may help guide adjuvant therapies and supportive care for older patients.
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http://dx.doi.org/10.3389/fonc.2021.631618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959812PMC
February 2021

Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.

Nat Commun 2021 01 13;12(1):352. Epub 2021 Jan 13.

Department of Neurosurgery, Duke University Medical Center, Durham, NC, 27710, USA.

Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10-20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.
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http://dx.doi.org/10.1038/s41467-020-20469-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806846PMC
January 2021

Second primary cancers in long-term survivors of glioblastoma.

Neurooncol Pract 2019 Sep 4;6(5):386-391. Epub 2019 Feb 4.

Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.

Background: Overall survival (OS) in glioblastoma (GBM) is poor at an average of 14 to 18 months, and long-term survivors (LTS) of GBM are rare. LTS of GBM, defined as surviving >5 years postdiagnosis, represent only 2% to 10% of all GBM patients. LTS of cancer are at high risk of developing second primary neoplasms. This study looks at occurrences of second primary neoplasms in LTS of GBM.

Methods: Records from adult patients newly diagnosed with GBM between January 1, 1998 and February 8, 2010, were retrospectively reviewed to identify LTS, defined as patients who survived ≥5 years. We focused on the identification of a new diagnosis of cancer occurring at least 2 years after the initial GBM diagnosis.

Results: We identified 155 LTS of GBM, with a median OS of 11.0 years (95% CI: 9.0 to 13.1 years) and a median follow-up of 9.6 years (95% CI: 8.7 to 10.7 years). In this cohort of patients, 13 (8.4%) LTS of GBM developed 17 secondary cancers. Eight could potentially be attributed to previous radiation and chemotherapy (skin cancer in radiation field [n = 4], leukemia [n = 2], low-grade glioma [n = 1], and sarcoma of the scalp [n = 1]). The other 9 cases included melanoma (n = 2), prostate cancer (n = 2), bladder cancer (n = 1), endometrioid adenocarcinoma (n = 1), basal cell carcinoma (n = 1), and renal cell carcinoma (n = 1).

Conclusions: Although second primary cancers are rare in GBM LTS, providers should continue close monitoring with appropriate oncologic care. Moreover, this highlights the need for survivorship care of patients with GBM.
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http://dx.doi.org/10.1093/nop/npz001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753354PMC
September 2019

Randomized open-label phase II trial of 5-day aprepitant plus ondansetron compared to ondansetron alone in the prevention of chemotherapy-induced nausea-vomiting (CINV) in glioma patients receiving adjuvant temozolomide.

Support Care Cancer 2020 May 22;28(5):2229-2238. Epub 2019 Aug 22.

Department of Neurosurgery, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.

Purpose: CINV remains a distressing side effect experienced by glioma patients receiving multi-day temozolomide therapy, in spite of guideline-based antiemetic therapy with selective serotonin-receptor-antagonists. Antiemetic research with aprepitant has routinely excluded glioma patients. In this randomized open-label phase II study, use of a nonstandard 5-day regimen of aprepitant for glioma patients was investigated.

Methods: One hundred thirty-six glioma patients receiving their first cycle of adjuvant temozolomide (150-200 mg/m/day × 5 days every 28 days) were randomized to Arm-A (ondansetron 8 mg days 1-5 with aprepitant day 1: 125 mg, days 2-5: 80 mg) or Arm-B (ondansetron). Randomization was stratified by tumor grade and number of prior chemotherapy regimens. The primary endpoint was the percentage of patients achieving complete control (CC), defined as no emetic episode or antiemetic rescue medication over the 7-day study period. Secondary endpoints included CINV efficacy in the acute phase (≤ 24 h) and delayed phase (days 2-7), as well as safety and quality of life (QoL).

Results: Patients were 61% male, 97% white, 48% with KPS > 90%, 60% non-smokers, mean age 54, 92% with low alcohol use, and 46% with a CINV history. The CC was 58.6% (Arm-A) and 54.5% (Arm-B). Acute-complete response (CR) rates, defined as CC on day 1 in Arm-A and -B, were 97.1% and 87.9%, respectively (p = 0.056). Treatment-related toxicities were mild or moderate in severity.

Conclusions: Aprepitant plus ondansetron may increase acute-CR, may have benefit regarding CINV's effect on QoL, and is safe for 5-day temozolomide compared to ondansetron. This study provides no evidence that aprepitant increases CC rate over ondansetron alone.
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http://dx.doi.org/10.1007/s00520-019-05039-xDOI Listing
May 2020

Complementary and integrative health interventions and their association with health-related quality of life in the primary brain tumor population.

Complement Ther Clin Pract 2019 Aug 18;36:43-48. Epub 2019 May 18.

Department of Neurosurgery, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, DUMC Box 3624, Durham, NC, 27710, USA. Electronic address:

Background And Purpose: Little is known about complementary and integrative health intervention usage in the primary brain tumor population. We aimed to identify the percentage of patients using these practices and explore the impact on quality of life.

Materials And Methods: Clinical records from patients seen in clinic between December 16, 2013 and February 28, 2014 were reviewed retrospectively. The questionnaires used were a modified version of the International Complementary and Alternative Medicine Questionnaire, the Functional Assessment of Cancer Therapy- Brain Cancer and the Functional Assessment of Chronic Illness Therapy- Fatigue.

Results: 76% of patients utilized a complementary and integrative health modality. The most frequently reported modalities used were vitamins, massage, and spiritual healing, prayer, diet and meditation.

Conclusion: These results confirm the usage of complementary and integrative health practices within the primary brain tumor population; however, there was no evidence of association between use and quality of life.
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http://dx.doi.org/10.1016/j.ctcp.2019.05.002DOI Listing
August 2019

Single-institution retrospective review of patients with recurrent glioblastoma treated with bevacizumab in clinical practice.

Health Sci Rep 2019 Apr 13;2(4):e114. Epub 2019 Feb 13.

The Preston Robert Tisch Brain Tumor Center Duke University Medical Center Durham North Carolina.

Background And Aims: This retrospective review of patients with recurrent glioblastoma treated at the Preston Robert Tisch Brain Tumor Center investigated treatment patterns, survival, and safety with bevacizumab in a real-world setting.

Methods: Adult patients with glioblastoma who initiated bevacizumab at disease progression between January 1, 2009, and May 14, 2012, were included. A Kaplan-Meier estimator was used to describe overall survival (OS), progression-free survival (PFS), and time to greater than or equal to 20% reduction in Karnofsky Performance Status (KPS). The effect of baseline demographic and clinical factors on survival was examined using a Cox proportional hazards model. Adverse event (AE) data were collected.

Results: Seventy-four patients, with a median age of 59 years, were included in this cohort. Between bevacizumab initiation and first failure, defined as the first disease progression after bevacizumab initiation, biweekly bevacizumab and bevacizumab/irinotecan were the most frequently prescribed regimens. Median duration of bevacizumab treatment until failure was 6.4 months (range, 0.5-58.7). Median OS and PFS from bevacizumab initiation were 11.1 months (95% confidence interval [CI], 7.3-13.4) and 6.4 months (95% CI, 3.9-8.5), respectively. Median time to greater than or equal to 20% reduction in KPS was 29.3 months (95% CI, 13.8-∞). Lack of corticosteroid usage at the start of bevacizumab therapy was associated with both longer OS and PFS, with a median OS of 13.2 months (95% CI, 8.6-16.6) in patients who did not initially require corticosteroids versus 7.2 months (95% CI, 4.8-12.5) in those who did ( = 0.0382, log-rank), while median PFS values were 8.6 months (95% CI, 4.6-9.7) and 3.7 months (95% CI, 2.7-6.6), respectively ( = 0.0243, log-rank). Treatment failure occurred in 70 patients; 47 of whom received salvage therapy, and most frequently bevacizumab/carboplatin (7/47; 14.9%). Thirteen patients (18%) experienced a grade 3 AE of special interest for bevacizumab.

Conclusions: Treatment patterns and outcomes for patients with recurrent glioblastoma receiving bevacizumab in a real-world setting were comparable with those reported in prospective clinical trials.
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http://dx.doi.org/10.1002/hsr2.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482327PMC
April 2019

Recurrent Glioblastoma Treated with Recombinant Poliovirus.

N Engl J Med 2018 07 26;379(2):150-161. Epub 2018 Jun 26.

From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.).

Background: The prognosis of patients with recurrent World Health Organization (WHO) grade IV malignant glioma is dismal, and there is currently no effective therapy. We conducted a dose-finding and toxicity study in this population of patients, evaluating convection-enhanced, intratumoral delivery of the recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment.

Methods: We enrolled consecutive adult patients who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast-enhancing tumor of ≥1 cm and ≤5.5 cm in the greatest dimension). The study evaluated seven doses, ranging between 10 and 10 50% tissue-culture infectious doses (TCID), first in a dose-escalation phase and then in a dose-expansion phase.

Results: From May 2012 through May 2017, a total of 61 patients were enrolled and received a dose of PVSRIPO. Dose level -1 (5.0×10 TCID) was identified as the phase 2 dose. One dose-limiting toxic effect was observed; a patient in whom dose level 5 (10 TCID) was administered had a grade 4 intracranial hemorrhage immediately after the catheter was removed. To mitigate locoregional inflammation of the infused tumor with prolonged glucocorticoid use, dose level 5 was deescalated to reach the phase 2 dose. In the dose-expansion phase, 19% of the patients had a PVSRIPO-related adverse event of grade 3 or higher. Overall survival among the patients who received PVSRIPO reached a plateau of 21% (95% confidence interval, 11 to 33) at 24 months that was sustained at 36 months.

Conclusions: Intratumoral infusion of PVSRIPO in patients with recurrent WHO grade IV malignant glioma confirmed the absence of neurovirulent potential. The survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls. (Funded by the Brain Tumor Research Charity and others; ClinicalTrials.gov number, NCT01491893 .).
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http://dx.doi.org/10.1056/NEJMoa1716435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065102PMC
July 2018

Phase II Study to Evaluate the Efficacy and Safety of Rilotumumab and Bevacizumab in Subjects with Recurrent Malignant Glioma.

Oncologist 2018 08 17;23(8):889-e98. Epub 2018 Apr 17.

Duke University Medical Center, Durham, North Carolina, USA

Lessons Learned: Due to evolving imaging criteria in brain tumors and variation in magnetic resonance imaging evaluation, it is not ideal to use response rate as a primary objective. Future studies involving antiangiogenic agents should use overall survival.Disease-expected toxicities should be considered when defining the clinical significance of an adverse event. For example, vascular thromboembolic events are common in brain tumor patients and should not be attributed to the study drug in the safety analysis.

Background: Recurrent malignant glioma (rMG) prognosis is poor, with a median patient survival of 3-11 months with bevacizumab (BEV)-containing regimens. BEV in rMG has 6-month progression free survival (PFS-6) of ∼40% and an objective response rate of 21.2%. BEV-containing regimens improve PFS-6 to 42.6%-50.3%, indicating that BEV combination therapies may be superior to single agent. Rilotumumab, a hepatocyte growth factor (HGF) antibody, inhibits angiogenesis and expression of angiogenic autocrine factors (e.g., vascular endothelial growth factor [VEGF]) by c-Met inhibition. Combination of rilotumumab with BEV to block vascular invasion and tumor proliferation may synergistically inhibit tumor growth.

Methods: Thirty-six BEV-naïve rMG subjects received rilotumumab (20 mg/kg and BEV (10 mg/kg) every 2 weeks. Endpoints included objective response rate (using Response Assessment in Neuro-Oncology [RANO] criteria), PFS-6, overall survival (OS), and toxicity.

Results: Median patient follow-up was 65.0 months. Objective response rate was 27.8% (95% confidence interval [CI]: 15.7%-44.1%). Median OS was 11.2 months (95% CI: 7-17.5). PFS-6 was 41.7% (95% CI: 25.6%-57.0%). Most frequent treatment-related grade ≤2 events included weight gain, fatigue, allergic rhinitis, and voice alteration; grade ≥3 events included venous thromboembolism (four patients), including one death from pulmonary embolism.

Conclusion: Rilotumumab with BEV did not significantly improve objective response compared with BEV alone, and toxicity may preclude the use of rilotumumab in combination BEV regimens.
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http://dx.doi.org/10.1634/theoncologist.2018-0149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156179PMC
August 2018

Phase I/II trial of vorinostat, bevacizumab, and daily temozolomide for recurrent malignant gliomas.

J Neurooncol 2018 Apr 21;137(2):349-356. Epub 2017 Dec 21.

Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.

Prognosis of recurrent glioblastoma (GBM) is poor with 6-month progression-free survival (PFS6) ranging from 9 to 48% depending on the treatment regimen and use of anti-angiogenic therapies. We sought to study vorinostat (VOR), a histone deacetylase inhibitor, in combination with bevacizumab (BEV) and daily metronomic temozolomide (TMZ) in a Phase I/II trial in recurrent high-grade gliomas (HGGs). This was a Phase I/II open-label, single-arm study in recurrent HGG patients. Phase I primary endpoint was to determine the maximum tolerated dose (MTD) of VOR with BEV and daily TMZ. Phase II primary endpoint was PFS6. Regimen was BEV 10 mg/kg iv every 2 weeks, TMZ 50 mg/m po daily, and VOR 200 or 400 mg po alternating 7 days on then 7 days off throughout a 28-day cycle. Phase I portion enrolled nine subjects with three receiving VOR 200 mg and 6 receiving VOR 400 mg. With no dose-limiting toxicities (DLTs) at 200 mg and one DLT (thrombocytopenia, Grade 3) at 400 mg, the MTD was 400 mg. Phase II portion enrolled 39 GBM subjects, and PFS6 was 53.8% (95% CI 37.2-67.9%). Of note, 14 subjects had received prior BEV and all had received prior 5-day TMZ. Combination therapy with VOR, BEV, and daily TMZ was well tolerated and safe. While PFS6 was not statistically improved beyond historical controls, it is important to note that this was a heavily pretreated GBM population and further consideration is warranted in a less pretreated group.
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http://dx.doi.org/10.1007/s11060-017-2724-1DOI Listing
April 2018

Surgical Outcomes After Neoadjuvant Chemotherapy and Ipilimumab for Non-Small Cell Lung Cancer.

Ann Thorac Surg 2018 03 16;105(3):924-929. Epub 2017 Dec 16.

Duke University Medical Center, Durham, North Carolina. Electronic address:

Background: The objective of this study was to evaluate the safety and feasibility of using neoadjuvant chemotherapy plus ipilimumab followed by surgery as a treatment strategy for stage II-IIIA non-small cell lung cancer.

Methods: From 2013 to 2017, postoperative data from patients who underwent surgery after neoadjuvant chemotherapy plus ipilimumab in the TOP1201 trial, an open label phase II trial (NCT01820754), were prospectively collected. The surgical outcomes from TOP1201 were compared with outcomes in a historical cohort of patients receiving standard preoperative chemotherapy followed by surgery identified from our institution's prospectively collected thoracic surgery database.

Results: In the TOP1201 trial, 13 patients were treated with preoperative chemotherapy and ipilimumab followed by surgery. In the historical cohort, 42 patients received preoperative chemotherapy by a platinum doublet regimen preoperative chemotherapy by a platinum doublet regimen without ipilimumab followed by lobectomy or pneumonectomy. The 30-day mortality in both groups was 0%. The most frequently occurring perioperative complications in the TOP1201 group were prolonged air leak (n = 2, 15%) and urinary tract infection (n = 2, 15%). The most common perioperative complication in the preoperative chemotherapy alone group was atrial fibrillation (n = 6, 14%). One patient (8%) had atrial fibrillation in the TOP1201 group. There was no apparent increased occurrence of adverse surgical outcomes for patients in the TOP1201 group compared with patients receiving standard of care neoadjuvant chemotherapy alone before surgery for stage II-IIIA non-small cell lung cancer.

Conclusions: This report is the first to demonstrate the safety and feasibility of surgical resection after treatment with ipilimumab and chemotherapy in stage II-IIIA non-small-cell lung cancer.
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http://dx.doi.org/10.1016/j.athoracsur.2017.09.030DOI Listing
March 2018

Single fraction stereotactic radiosurgery for multiple brain metastases.

Adv Radiat Oncol 2017 Oct-Dec;2(4):555-563. Epub 2017 Sep 11.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Introduction: Due to the neurocognitive side effects of whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) is being used with increasing frequency. The use of SRS is expanding for patients with multiple (>4) brain metastases (BM). This study summarizes our institutional experience with single-fraction, linear-accelerator-based SRS for multiple BM.

Methods And Materials: All patients who were treated between January 1, 2013, and September 30, 2015, with single-fraction SRS for ≥4 BM were included in this institutional review board-approved, retrospective, single-institution study. Patients were treated with linear accelerator-based image guided SRS.

Results: A total of 59 patients with ≥4 BM were treated with single-fraction SRS. The median follow-up was 15.2 months, and the median overall survival for the entire cohort was 5.8 months. The median number of treated lesions per patient was 5 (range, 4-23). Per patient, the median planning target volume (PTV) was 4.8 cc (range, 0.7-28.8 cc). The prescribed dose across all 380 BM for the 59 patients ranged from 7 to 20 Gy. The median of the mean dose to the total PTV was 19.5 Gy. Although the number of treated lesions (4-5 vs ≥6) did not influence survival, better survival was noted for a total PTV <10 cc versus ≥10 cc (7.1 vs 4.2 months, respectively;  = .0001). A mean dose of ≥19 Gy to the entire PTV was also associated with increased survival (6.6 vs 5.0 months, respectively;  = .0172). Patients receiving a dose of >12 Gy to ≥10 cc of normal brain had worse survival (5.1 vs 8.6 months, respectively;  = .0028).

Conclusion: In single-fraction SRS for patients with multiple BM, smaller total tumor volume, higher total dose, and lower volume of normal brain receiving >12 Gy were associated with increased survival. These data suggest that using SRS for the treatment of multiple BM is efficacious and that outcomes may be affected more by total tumor volume than by the number of lesions.
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http://dx.doi.org/10.1016/j.adro.2017.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707418PMC
September 2017

Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma.

Oncologist 2018 02 13;23(2):157-e21. Epub 2017 Nov 13.

Duke University Medical Center, Durham, North Carolina, USA

Lessons Learned: Combination regimen with bevacizumab (BEV) and vorinostat is well tolerated in patients with recurrent glioblastoma.Treatment of recurrent glioblastoma remains challenging as this study and others attempt to improve progression-free survival and overall survival with BEV-containing regimens.

Background: Recurrent glioblastoma (GBM; World Health Organization grade 4) continues to have a very poor prognosis. Bevacizumab (BEV) has been shown to improve progression-free survival (PFS) in recurrent GBM and is approved by the U.S. Food and Drug Administration for the treatment of recurrent GBM. Combination regimens have been explored, and in this phase II nonrandomized trial, we evaluated the efficacy of BEV combined with histone deacetylase inhibitor vorinostat (VOR) in recurrent GBM.

Materials And Methods: In this phase II, single-center, nonrandomized study, subjects with recurrent GBM received BEV 10 mg/kg intravenously (IV) every 2 weeks combined with VOR 400 mg p.o. daily for 7 days on, 7 days off, in a 28-day cycle. The primary endpoint was 6-month PFS (PFS6).

Results: Forty patients with recurrent GBM were enrolled and evaluated. PFS6 was 30.0% (95% confidence interval [CI] 16.8%-44.4%). Median overall survival (OS) was 10.4 months (95% CI 7.6-12.8 months). Overall radiographic response rate was 22.5% based on 9 partial responses. The most common grade 2 and above treatment-related adverse events were lymphopenia (55%), leukopenia (45%), neutropenia (35%), and hypertension (33%). Grade 4 adverse events were leukopenia (3%), neutropenia (3%), sinus bradycardia (3%), and venous thromboembolism (3%). Two deaths occurred in this study, with one due to tumor progression and another possibly related as death not otherwise specified.

Conclusion: Combination treatment of BEV and VOR was well tolerated. This combination therapy for this study population did not improve PFS6 or median OS when compared with BEV monotherapy.
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http://dx.doi.org/10.1634/theoncologist.2017-0501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813746PMC
February 2018

Immune Activation in Early-Stage Non-Small Cell Lung Cancer Patients Receiving Neoadjuvant Chemotherapy Plus Ipilimumab.

Clin Cancer Res 2017 Dec 26;23(24):7474-7482. Epub 2017 Sep 26.

Department of Surgery, Duke University Medical Center, Durham, North Carolina.

To determine the immunologic effects of neoadjuvant chemotherapy plus ipilimumab in early-stage non-small cell lung cancer (NSCLC) patients. This is a single-arm chemotherapy plus phased ipilimumab phase II study of 24 treatment-naïve patients with stage IB-IIIA NSCLC. Patients received neoadjuvant therapy consisting of 3 cycles of paclitaxel with either cisplatin or carboplatin and ipilimumab included in the last 2 cycles. Chemotherapy alone had little effect on immune parameters in PBMCs. Profound CD28-dependent activation of both CD4 and CD8 cells was observed following ipilimumab. Significant increases in the frequencies of CD4 cells expressing activation markers ICOS, HLA-DR, CTLA-4, and PD-1 were apparent. Likewise, increased frequencies of CD8 cells expressing the same activation markers, with the exception of PD-1, were observed. We also examined 7 resected tumors and found higher frequencies of activated tumor-infiltrating lymphocytes than those observed in PBMCs. Surprisingly, we found 4 cases of preexisting tumor-associated antigens (TAA) responses against survivin, PRAME, or MAGE-A3 present in PBMC at baseline, but neither increased frequencies nor the appearance of newly detectable responses following ipilimumab therapy. Ipilimumab had little effect on the frequencies of circulating regulatory T cells and MDSCs. This study did not meet the primary endpoint of detecting an increase in blood-based TAA T-cell responses after ipilimumab. Collectively, these results highlight the immune activating properties of ipilimumab in early-stage NSCLC. The immune profiling data for ipilimumab alone can contribute to the interpretation of immunologic data from combined immune checkpoint blockade immunotherapies. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732888PMC
December 2017

A cross sectional analysis from a single institution's experience of psychosocial distress and health-related quality of life in the primary brain tumor population.

J Neurooncol 2017 Sep 1;134(2):363-369. Epub 2017 Jul 1.

Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA.

Primary brain tumor patients experience high levels of distress. The purpose of this cross-sectional, retrospective study is to evaluate the level and different sources of psychosocial distress and how these pertain to health-related quality of life (HRQoL). The Primary and Recurrent Glioma registry at Duke's The Preston Robert Tisch Brain Tumor Center was queried retrospectively for demographic and clinical information on patients seen between December 2013 and February 2014. Data also included the National Comprehensive Cancer Network's Distress Thermometer (NCCN-DT), Functional Assessment of Cancer Therapy-Brain Cancer (FACT-Br), and Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F). 829 subjects completed questionnaires. 54% were male; 96% completed the NCCN-DT; 33.3% had a DT score ≥4 (moderate/severe distress). Women reported DT ≥ 4 more often than men (38.6 vs 29.0%; p = 0.005). Patients within 1 year of diagnosis reported DT ≥ 4 more often than those 1+ years after diagnosis (38.8 vs 30.9%; p = 0.034). 73.0% reported physical problems; the most frequent being fatigue (43.2%) and memory/concentration (40.9%). 42.0% complained of emotional problems with worry (29.4%) and nervousness (22.4%) being the most common. Patients who reported at least one practical, family, emotional or physical problem had significantly lower HRQoL scores (p < 0.001). Primary brain tumor patients experience memory dysfunction, fatigue, nervousness, worry, and financial concerns, which have a negative effect on the patient's HRQoL. By identifying and addressing these stressors, it may be possible to improve patient HRQoL.
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http://dx.doi.org/10.1007/s11060-017-2535-4DOI Listing
September 2017

Biopsy of enlarging lesions after stereotactic radiosurgery for brain metastases frequently reveals radiation necrosis.

Neuro Oncol 2017 Oct;19(10):1391-1397

Breast Cancer Program, Duke Cancer Institute, Clinical Research Training Program, Department of Neurosurgery, The Preston Robert Tisch Brain Tumor Center, Division of Hematology-Oncology, Department of Medicine, Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Division of Neuroradiology, Department of Radiology, Department of Radiation Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.

Background: Stereotactic radiosurgery (SRS) offers excellent local control for brain metastases (BM) with low rates of toxicity. Radiation necrosis (RN) may occur after treatment and is challenging to distinguish from local recurrence (LR). We evaluated enlarging brain lesions following SRS that were subsequently biopsied to differentiate RN versus LR.

Methods: This study reviewed patients receiving SRS for BM between 2008 and 2012 who underwent a biopsy for suspicion of RN versus LR on MRI. Data collection included demographics, radiation parameters, imaging findings, and post-biopsy pathology. Kaplan-Meier methods determined overall survival. Fisher's exact test assessed for association between lesion biopsy result and variables of interest.

Results: Thirty-four patients with 35 biopsied BM were included. Lesions were biopsied a median of 8.8 months after SRS. Most patients had primary lung cancer (11; 31.4%). Eleven (31.4%) biopsies were positive for LR and 24 (68.6%) showed RN only. Median overall survival was longer for patients with RN (31.0 mo) than for patients with LR (14.5 mo; P = 0.135). Time from SRS to biopsy was significantly different between RN and LR groups; 10 lesions (52.5%) biopsied ≤9 months after SRS showed LR, whereas 1 lesion (6.3%) biopsied >9 months after SRS showed LR (P = 0.004). For 16 (65.7%) lesions, management was changed or directed by the biopsy results.

Conclusions: Stereotactic biopsy for accessible enlarging lesions after SRS appears diagnostically valuable in patients with few lesions and changes clinical management. RN should be suspected in patients with an enlarging lesion more than 9 months post-SRS.
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http://dx.doi.org/10.1093/neuonc/nox090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596170PMC
October 2017

A Phase II single-arm trial of palonosetron for the prevention of acute and delayed chemotherapy-induced nausea and vomiting in malignant glioma patients receiving multidose irinotecan in combination with bevacizumab.

Ther Clin Risk Manag 2017 23;13:33-40. Epub 2016 Dec 23.

The Preston Robert Tisch Brain Tumor Center at Duke, South Hospital, Duke University Medical Center; Department of Neurosurgery, Duke University Health System.

Purpose: Given that the prognosis of recurrent malignant glioma (MG) remains poor, improving quality of life (QoL) through symptom management is important. Meta-analyses establishing antiemetic guidelines have demonstrated the superiority of palonosetron (PAL) over older 5-hydroxytryptamine 3-receptor antagonists in chemotherapy-induced nausea and vomiting (CINV) prevention, but excluded patients with gliomas. Irinotecan plus bevacizumab is a treatment frequently used in MG, but is associated with low (55%) CINV complete response (CR; no emesis or use of rescue antiemetic) with commonly prescribed ondansetron. A single-arm Phase II trial was conducted in MG patients to determine the efficacy of intravenous PAL (0.25 mg) and dexamethasone (DEX; 10 mg) received in conjunction with biweekly irinotecan-bevacizumab treatment. The primary end point was the proportion of subjects achieving acute CINV CR (no emesis or antiemetic ≤24 hours postchemotherapy). Secondary end points included delayed CINV CR (days 2-5), overall CINV CR (days 1-5), and QoL, fatigue, and toxicity.

Materials And Methods: A two-stage design of 160 patients was planned to differentiate between CINV CR of 55% and 65% after each dose of PAL-DEX. Validated surveys assessed fatigue and QoL.

Results: A total of 63 patients were enrolled, after which enrollment was terminated due to slow accrual; 52 patients were evaluable for the primary outcome of acute CINV CR. Following PAL-DEX dose administrations 1-3, acute CINV CR rates were 62%, 68%, and 70%; delayed CINV CR rates were 62%, 66%, and 70%, and overall CINV CR rates were 47%, 57%, and 62%, respectively. Compared to baseline, there was a clinically meaningful increase in fatigue during acute and overall phases, but not in the delayed phase. There were no grade ≥3 PAL-DEX treatment-related toxicities.

Conclusion: Data suggest that PAL-DEX is effective in preventing CINV in MG patients, which ultimately maintains the QoL of patients with glioma.
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http://dx.doi.org/10.2147/TCRM.S122480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207433PMC
December 2016

Insomnia and its associations in patients with recurrent glial neoplasms.

Springerplus 2016 21;5(1):823. Epub 2016 Jun 21.

Neurology, Duke University Medical Center, PO Box 3624, Durham, NC 27710 USA.

Background: Patient with neurological disorders and cancer can develop sleep disturbance, in particular insomnia. Etiology of insomnia is multi-factorial in primary brain tumour patients with possible causes including corticosteroids, psychoactive medications, co-morbid psychiatric/medical conditions, and damage to neuronal tissue.

Findings: To understand better insomnia in recurrent glioma patients, a single-center retrospective analysis was performed looking at recurrent glioma patients from January 2004 to May 2009. Data was extracted and included demographics, clinical factors, psychoactive medications, and co-morbid symptoms. Presence and absence of insomnia complaints was evaluated with other co-morbidities using Chi square and Wilcoxon analyses. Records from 340 recurrent glioma patients were evaluated and 46.8 % (n = 159) indicated presence of insomnia with 20 % (n = 66) actively using medications for sleep. Use of corticosteroids were significantly associated with insomnia (p = 0.0003). Age, gender, tumour location, use of stimulants, antipsychotics, and antidepressants were not significantly associated with insomnia in recurrent glioma patients. There was a trend towards a possible significant association with insomnia to fatigue complaints and use of anti-epileptics, p-values of 0.0501 and 0.0725 respectively.

Conclusions: In conclusion, insomnia is commonly encountered in patients with recurrent glial tumors. Corticosteroid use is associated with insomnia in this population. In light of the frequency of insomnia and its associations, future analysis is warranted into sleep complaints in recurrent glioma patients and its impact on quality of life.
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http://dx.doi.org/10.1186/s40064-016-2578-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916119PMC
July 2016

Phase II study to evaluate the safety and efficacy of intravenous palonosetron (PAL) in primary malignant glioma (MG) patients receiving standard radiotherapy (RT) and concomitant temozolomide (TMZ).

Support Care Cancer 2016 10 6;24(10):4365-75. Epub 2016 Jun 6.

Department of Neurosurgery, Duke University Health System, Durham, NC, 27710, USA.

Background: In malignant glioma (MG) patients undergoing radiation therapy (RT) with concomitant temozolomide, chemoradiation-induced nausea and vomiting (cRINV) degrades quality of life (QoL) and reduces treatment adherence, which thereby potentially compromises cancer control.

Methods: We conducted a 6-week phase II single-arm trial of PAL, a second-generation 5-HT3RA antiemetic, for cRINV prevention in MG patients receiving radiation therapy (RT; 54-60 Gy) and concomitant daily temozolomide (TMZ; 75 mg/m(2)/dX42d). Each week before radiation, patients received single-dose palonosetron (PAL) 0.25 mg IV (total = 6 doses). With safety/tolerability as the primary endpoint, the study was designed to differentiate between toxicity rates of 25 % (unacceptable) and 10 % (acceptable) toxicity rates. Secondary endpoints included the percentage of patients achieving cRINV complete response (CR: no emesis or rescue antiemetic) and QoL. Patients reported adverse effects in Common Toxicity Criteria for Adverse Events diaries; recorded vomiting, nausea, and rescue medication use in diaries (which were used to assess cRINV-CR); and reported QoL 4 days/week using the Modified Functional Living Index-Emesis (M-FLIE) and Osoba nausea and vomiting/retching modules.

Results: We enrolled 38 patients (mean age 59 years, 55 % female, 95 % white, 68 % used oral corticosteroids, 76 % reported low alcohol use). Four patients (10.5 %) experienced unacceptable treatment-related toxicity, defined as any grade 3, 4, or 5 non-hematologic toxicity. M-FLIE and Osoba scores showed no evidence of treatment impact on QoL. Overall, cRINV-CR rates for 6 weeks ranged from 67-79 %.

Conclusion: Single-dose weekly PAL is a safe and tolerable antiemetic for cRINV prevention in MG patients receiving standard RT and concomitant TMZ.
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http://dx.doi.org/10.1007/s00520-016-3276-1DOI Listing
October 2016

Phase II Trial of Upfront Bevacizumab, Irinotecan, and Temozolomide for Unresectable Glioblastoma.

Oncologist 2015 Jul 29;20(7):727-8. Epub 2015 May 29.

Division of Medical Oncology, St. Francis Medical Cancer Center, Hartford, Connecticut, USA.

Lessons Learned: Trials focusing on unresectable multifocal glioblastoma are needed because of the extremely poor prognosis and challenges in receiving standard therapy, such as concurrent radiation and chemotherapy.Developing a strategy to chemically debulk tumors before radiation and/or surgery is warranted.

Background: Extent of resection remains a key prognostic factor in glioblastoma (GBM), with gross total resection providing a better prognosis than biopsy or subtotal resection. We conducted a phase II trial of upfront therapy with bevacizumab (BV), irinotecan (CPT-11), and temozolomide (TMZ) prior to chemoradiation in patients with unresectable, subtotally resected, and/or multifocal GBM.

Methods: Patients received up to 4 cycles of TMZ at 200 mg/m(2) per day on days 1-5 (standard dosing) and BV at 10 mg/kg every 2 weeks on a 28-day cycle. CPT-11 was given every 2 weeks on a 28-day cycle at 125 mg/m(2) or 340 mg/m(2) depending on antiepileptic drugs. Magnetic resonance imaging of the brain was done every 4 weeks, and treatment continued as long as there was no tumor progression or unmanageable toxicity. The primary endpoint was tumor response rate, with a goal of 26% or greater.

Results: Forty-one patients were enrolled from December 2009 to November 2010. Radiographic responses were as follows: 9 patients (22.0%) had partial response, 25 (61.0%) had stable disease, and 2 (4.9%) had progression; 5 patients were not assessed. Cumulative response rate was 22%. Median overall survival was 12 months (95% confidence interval: 7.2-13.5 months).

Conclusion: Upfront treatment with BV, TMZ, and CPT-11 is tolerable and can lead to radiographic response in unresectable and/or subtotally resected GBM.
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http://dx.doi.org/10.1634/theoncologist.2015-0135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492239PMC
July 2015

Defining the optimal planning target volume in image-guided stereotactic radiosurgery of brain metastases: results of a randomized trial.

Int J Radiat Oncol Biol Phys 2015 Jan 21;91(1):100-8. Epub 2014 Oct 21.

Department of Radiation Oncology, Duke University, Durham, North Carolina.

Purpose: To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (SRS) of brain metastases, minimizing toxicity and local recurrence.

Methods And Materials: Adult patients with 1 to 3 brain metastases less than 4 cm in greatest dimension, no previous brain radiation therapy, and Karnofsky performance status (KPS) above 70 were eligible for this institutional review board-approved trial. Individual lesions were randomized to 1- or 3- mm uniform expansion of the GTV defined on contrast-enhanced magnetic resonance imaging (MRI). The resulting planning target volume (PTV) was treated to 24, 18, or 15 Gy marginal dose for maximum PTV diameters less than 2, 2 to 2.9, and 3 to 3.9 cm, respectively, using a linear accelerator-based image-guided system. The primary endpoint was local recurrence (LR). Secondary endpoints included neurocognition Mini-Mental State Examination, Trail Making Test Parts A and B, quality of life (Functional Assessment of Cancer Therapy-Brain), radionecrosis (RN), need for salvage radiation therapy, distant failure (DF) in the brain, and overall survival (OS).

Results: Between February 2010 and November 2012, 49 patients with 80 brain metastases were treated. The median age was 61 years, the median KPS was 90, and the predominant histologies were non-small cell lung cancer (25 patients) and melanoma (8). Fifty-five, 19, and 6 lesions were treated to 24, 18, and 15 Gy, respectively. The PTV/GTV ratio, volume receiving 12 Gy or more, and minimum dose to PTV were significantly higher in the 3-mm group (all P<.01), and GTV was similar (P=.76). At a median follow-up time of 32.2 months, 11 patients were alive, with median OS 10.6 months. LR was observed in only 3 lesions (2 in the 1 mm group, P=.51), with 6.7% LR 12 months after SRS. Biopsy-proven RN alone was observed in 6 lesions (5 in the 3-mm group, P=.10). The 12-month DF rate was 45.7%. Three months after SRS, no significant change in neurocognition or quality of life was observed.

Conclusions: SRS was well tolerated, with low rates of LR and RN in both cohorts. However, given the higher potential risk of RN with a 3-mm margin, a 1-mm GTV expansion is more appropriate.
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http://dx.doi.org/10.1016/j.ijrobp.2014.09.004DOI Listing
January 2015

Patterns of failure for stage I ampulla of Vater adenocarcinoma: a single institutional experience.

J Gastrointest Oncol 2014 Dec;5(6):421-7

1 School of Medicine, Duke University, Durham, USA ; 2 Department of Radiation Oncology, 3 Department of Pathology, 4 Duke Cancer Institute, 5 Department of Surgery, 6 Division of Medical Oncology, Department of Internal Medicine, Duke University Medical Center, Durham, NC 27710, USA.

Background: Ampullary adenocarcinoma is a rare malignancy associated with a relatively favorable prognosis. Given high survival rates in stage I patients reported in small series with surgery alone, adjuvant chemoradiotherapy (CRT) has traditionally been recommended only for patients with high risk disease. Recent population-based data have demonstrated inferior outcomes to previous series. We examined disease-related outcomes for stage I tumors treated with pancreaticoduodenectomy, with and without CRT.

Methods: All patients with stage I ampullary adenocarcinoma treated from 1976 to 2011 at Duke University were reviewed. Disease-related endpoints including local control (LC), metastasis-free survival (MFS), disease-free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method.

Results: Forty-four patients were included in this study. Thirty-one patients underwent surgery alone, while 13 also received adjuvant CRT. Five-year LC, MFS, DFS and OS for patients treated with surgery only and surgery with CRT were 56% and 83% (P=0.13), 67% and 83% (P=0.31), 56% and 83% (P=0.13), and 53% and 68% (P=0.09), respectively.

Conclusions: The prognosis for patients diagnosed with stage I ampullary adenocarcinoma may not be as favorable as previously described. Our data suggests a possible benefit of adjuvant CRT delivery.
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http://dx.doi.org/10.3978/j.issn.2078-6891.2014.084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226834PMC
December 2014

Impact of health-related quality of life and fatigue on survival of recurrent high-grade glioma patients.

J Neurooncol 2014 Dec 13;120(3):499-506. Epub 2014 Aug 13.

Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA,

Quality of life (QoL) impairment and fatigue are frequently experienced during treatment for recurrent high-grade glioma (HGG). Fatigue and QoL impairments can be due to primary neurological dysfunction, cytotoxic treatments, mood disturbances, and supportive medications. We now seek to understand how QoL and fatigue impacts survival in recurrent HGG. Using a prospective observational design, 237 patients with recurrent HGG and KPS ≥70 completed a self-administered questionnaire that evaluated QoL and fatigue. QoL was assessed with Functional Assessment of Cancer Therapy-General (FACT-G) and FACT-Brain (FACT-Br) scales while fatigue was assessed using Functional Assessment of Chronic Illness Therapy (FACIT-F) scale. Cox proportional hazard models were utilized to evaluate the association between QoL and fatigue and survival. Seventy-three (31 %) subjects had recurrent WHO grade III gliomas and 164 (69 %) had recurrent WHO grade IV gliomas. Median follow-up analysis was 27.60 months. In univariate Cox analyses, the FACT-Br specific subscale (HR 0.88; CI 95 %, 0.77-1; p = 0.048) and FACIT-F (HR 0.82; CI 95 %, 0.68-0.99; p = 0.045) were both significant predictors of survival. Fatigue added prognostic information beyond that provided by KPS, age, sex, tumor grade, and number of prior progressions (HR 0.80; CI 95 %, 0.68-0.9; p = 0.031). A greater degree of fatigue was associated with poorer survival in recurrent HGG patients. In multivariable analyses, FACT-G and FACT-Br are not independent predictors of prognosis. Fatigue is a strong independent predictor of survival that provides incremental prognostic value to the traditional markers of prognosis in recurrent HGG. Pharmacological or non-pharmacological strategies to treat fatigue warrant investigation.
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http://dx.doi.org/10.1007/s11060-014-1574-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511848PMC
December 2014

Relationship between exercise behavior, cardiorespiratory fitness, and cognitive function in early breast cancer patients treated with doxorubicin-containing chemotherapy: a pilot study.

Appl Physiol Nutr Metab 2014 Jun 3;39(6):724-9. Epub 2013 Dec 3.

a Duke University Medical Center, Durham, NC 27710, USA.

The purpose of this study was to examine the relationship between self-reported exercise behavior, cardiorespiratory fitness (CRF), and cognitive function in early breast cancer patients. Thirty-seven breast cancer patients following completion of chemotherapy (median 16 months) and 14 controls were studied. Cognitive function was assessed using the Central Nervous System (CNS) Vital Signs software (CNS Vital Signs, LLC, Morrisville, N.C., USA), a computerized test battery consisting of 9 cognitive subtests. Exercise behavior was evaluated using the Godin Leisure Time Exercise Questionnaire, and CRF was assessed via a cardiopulmonary exercise test to assess peak oxygen consumption. Patients' mean total exercise was 184 ± 141 min·week(-1) compared with 442 ± 315 min·week(-1) in controls (p < 0.001). Significantly fewer patients (32%) were meeting exercise guidelines (i.e., ≥150 min of moderate-intensity or vigorous exercise per week) compared with 57% of controls (p = 0.014). Patients' peak oxygen consumption averaged 23.5 ± 6.3 mL·kg(-1)·min(-1) compared with 30.6 ± 7.0 mL·kg(-1)·min(-1) in controls (p < 0.01). Scores on the cognitive subdomains were generally lower in patients compared with controls, although only the difference in verbal memory was significant (unadjusted p = 0.041). In patients, weak to moderate correlations were indicated between exercise, peak oxygen consumption, and the majority of cognitive subdomain scores; however, there was a significant positive correlation between exercise and visual memory (r = 0.47, p = 0.004). In conclusion, breast cancer patients following the completion of primary adjuvant chemotherapy exhibit, in general, worse cognitive performance than healthy women from the general population, and such performance may be related to their level of exercise behavior.
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http://dx.doi.org/10.1139/apnm-2013-0380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542053PMC
June 2014

Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: a prospective trial.

Int J Radiat Oncol Biol Phys 2013 Aug 29;86(5):873-9. Epub 2013 May 29.

Department of Radiation Oncology, Duke University, Durham, North Carolina, USA.

Purpose: Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG.

Methods And Materials: Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status.

Results: One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months.

Conclusions: Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach.
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http://dx.doi.org/10.1016/j.ijrobp.2013.04.029DOI Listing
August 2013

Fine-grain analysis of the treatment effect of topiramate on methamphetamine addiction with latent variable analysis.

Drug Alcohol Depend 2013 Jun 9;130(1-3):45-51. Epub 2012 Nov 9.

Department of Public Health Sciences, University of Virginia, PO Box 800717, Charlottesville, VA 22908, USA.

Background: As reported previously, 140 methamphetamine-dependent participants at eight medical centers in the U.S. were assigned randomly to receive topiramate (N=69) or placebo (N=71) in a 13-week clinical trial. The study found that topiramate did not appear to reduce methamphetamine use significantly for the primary outcome (i.e., weekly abstinence from methamphetamine in weeks 6-12). Given that the treatment responses varied considerably among subjects, the objective of this study was to identify the heterogeneous treatment effect of topiramate and determine whether topiramate could reduce methamphetamine use effectively in a subgroup of subjects.

Methods: Latent variable analysis was used for the primary and secondary outcomes during weeks 6-12 and 1-12, adjusting for age, sex, and ethnicity.

Results: Our analysis of the primary outcome identified 30 subjects as responders, who either reduced methamphetamine use consistently over time or achieved abstinence. Moreover, topiramate recipients had a significantly steeper slope in methamphetamine reduction and accelerated to abstinence faster than placebo recipients. For the secondary outcomes in weeks 6-12, we identified 40 subjects as responders (who had significant reductions in methamphetamine use) and 65 as non-responders; topiramate recipients were more than twice as likely as placebo recipients to be responders (odds ratio=2.67; p=0.019). Separate analyses of the outcomes during weeks 1-12 yielded similar results.

Conclusions: Methamphetamine users appear to respond to topiramate treatment differentially. Our findings show an effect of topiramate on the increasing trend of abstinence from methamphetamine, suggesting that a tailored intervention strategy is needed for treating methamphetamine addiction.
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http://dx.doi.org/10.1016/j.drugalcdep.2012.10.009DOI Listing
June 2013

Bevacizumab therapy for adults with recurrent/progressive meningioma: a retrospective series.

J Neurooncol 2012 Aug 26;109(1):63-70. Epub 2012 Apr 26.

Department of Surgery, The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, 27710, USA.

Intracranial meningiomas are often indolent tumors which typically grow over years to decades. Nonetheless, meningiomas that progress after maximum safe resection and radiation therapy pose a significant therapeutic challenge and effective therapies have yet to be identified. Preclinical studies implicate angiogenesis in the pathophysiology of more aggressive meningiomas, suggesting that anti-angiogenic therapies may be of utility in this setting. We performed a retrospective review of fourteen patients with recurrent meningioma treated at Duke University Medical Center with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, administered either alone or in combination with chemotherapy. Most patients were heavily pre-treated. Progression-free survival at 6 months was 86 % and was comparable regardless of meningioma grade and whether bevacizumab was administered as monotherapy or in combination with chemotherapy. Most toxicities were mild however single patients developed CNS hemorrhage (grade 1) and intestinal perforation (grade 4), respectively. Bevacizumab can be administered safely to patients with meningioma and appears to be associated with encouraging anti-tumor effect when administered as either a single agent or in combination with chemotherapy. Phase II trials investigating bevacizumab in patients with progressive/recurrent meningioma are warranted.
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http://dx.doi.org/10.1007/s11060-012-0861-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404217PMC
August 2012

Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma.

J Neurooncol 2012 Jul 10;108(3):499-506. Epub 2012 Mar 10.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of dasatinib, an inhibitor of the Src family kinase proteins, with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, among recurrent malignant glioma patients. Once daily dasatinib was escalated in successive cohorts while erlotinib was administered daily at established doses based on concurrent CYP3A-inducing anticonvulsant (EIAEDS) use. Dasatinib pharmacokinetic analyzes were performed. Forty-seven patients enrolled including 37 (79 %) with grade IV and 10 (21 %) with grade III malignant glioma. Thirty patients (64 %) were at ≥second recurrence, while 27 (57 %) had received prior bevacizumab. The dasatinib MTD was 180 mg when combined with either 150 mg of erlotinib for patients not on EIAEDs, or 450 mg of erlotinib for patients on EIAEDs. The most common DLTs were diarrhea and fatigue, while most adverse events were grade 2. Pharmacokinetic data suggests that dasatinib exposure increased with increased dasatinib dose and concurrent erlotinib administration, while concurrent EIAED use diminished dasatinib exposure. No radiographic responses were observed, and only one patient (2 %) remained progression-free at 6 months. We demonstrate that dasatinib plus erlotinib can be safely co-administered on a continuous, daily dosing schedule with erlotinib, and established the recommended dose level of this combination.
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http://dx.doi.org/10.1007/s11060-012-0848-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690584PMC
July 2012

Topiramate for the treatment of methamphetamine addiction: a multi-center placebo-controlled trial.

Addiction 2012 Jul 28;107(7):1297-306. Epub 2012 Feb 28.

National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892, USA.

Aims:   Topiramate has shown efficacy at facilitating abstinence from alcohol and cocaine abuse. This double-blind, placebo-controlled out-patient trial tested topiramate for treating methamphetamine addiction.

Design:   Participants (n = 140) were randomized to receive topiramate or placebo (13 weeks) in escalating doses from 25 mg/day [DOSAGE ERROR CORRECTED] to the target maintenance of 200 mg/day in weeks 6-12 (tapered in week 13). Medication was combined with weekly brief behavioral compliance enhancement treatment.

Setting:   The trial was conducted at eight medical centers in the United States.

Participants:   One hundred and forty methamphetamine-dependent adults took part in the trial.

Measurements:   The primary outcome was abstinence from methamphetamine during weeks 6-12. Secondary outcomes included use reduction versus baseline, as well as psychosocial variables.

Findings:   In the intent-to-treat analysis, topiramate did not increase abstinence from methamphetamine during weeks 6-12. For secondary outcomes, topiramate reduced weekly median urine methamphetamine levels and observer-rated severity of dependence scores significantly. Subjects with negative urine before randomization (n = 26) had significantly greater abstinence on topiramate versus placebo during study weeks 6-12. Topiramate was safe and well tolerated.

Conclusions:   Topiramate does not appear to promote abstinence in methamphetamine users but can reduce the amount taken and reduce relapse rates in those who are already abstinent.
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http://dx.doi.org/10.1111/j.1360-0443.2011.03771.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3331916PMC
July 2012

Selegiline transdermal system (STS) as an aid for smoking cessation.

Nicotine Tob Res 2012 Mar 16;14(3):377-82. Epub 2011 Aug 16.

Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, Bethesda, MD 20892, USA.

Introduction: This study examined the efficacy and safety of selegiline transdermal system (STS) and brief repeated behavioral intervention (BRBI) for smoking cessation in heavy smokers. We hypothesized that the quit rate of subjects who received STS and BRBI would be significantly greater than that of those who received placebo patch and BRBI.

Methods: This was a double-blind, placebo-controlled parallel-group study in which 246 men and women were randomized to receive either STS (n = 121) or placebo patch (n =125) for 9 weeks. Recruitment targeted heavy smokers, defined as individuals with self-reported use of ≥15 cigarettes/day in the 30 days prior to enrollment, who had smoked cigarettes for the past 5 years, and had an expired CO level ≥9 ppm during screening.

Results: Although STS was well tolerated, the overall results indicated that STS with BRBI was not more effective than placebo plus BRBI for smoking cessation (p = .58).

Conclusions: The results are discussed in relation to interventions for heavy smokers. Although 2 trials using oral selegiline both showed trends toward improved abstinence, these results indicate that STS with BRBI was not an effective aid for smoking cessation at the end of treatment (10 weeks), 14, or 26 weeks.
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http://dx.doi.org/10.1093/ntr/ntr143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281235PMC
March 2012

Modafinil for the treatment of methamphetamine dependence.

Drug Alcohol Depend 2012 Jan 12;120(1-3):135-41. Epub 2011 Aug 12.

Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892-9551, United States.

Aim: Modafinil was tested for efficacy in decreasing use in methamphetamine-dependent participants, compared to placebo.

Methods: This was a randomized, double-blind, placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Eight outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, who all had a DSM-IV diagnosis of methamphetamine dependence; 68 participants to placebo, 72 to modafinil 200mg, and 70 to modafinil 400mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments, urine drug screens, and group psychotherapy. The primary outcome measure was a methamphetamine non-use week, which required all the week's qualitative urine drug screens to be negative for methamphetamine.

Results: Regression analysis showed no significant difference between either modafinil group (200 or 400mg) or placebo in change in weekly percentage having a methamphetamine non-use week over the 12-week treatment period (p=0.53). Similarly, a number of secondary outcomes did not show significant effects of modafinil. However, an ad-hoc analysis of medication compliance, by urinalysis for modafinil and its metabolite, did find a significant difference in maximum duration of abstinence (23 days vs. 10 days, p=0.003), between those having the top quartile of compliance (>85% of urines were positive for modafinil, N=36), and the lower three quartiles of modafinil 200 and 400mg groups (N=106).

Conclusions: Although these data suggest that modafinil, plus group behavioral therapy, was not effective for decreasing methamphetamine use, the study is probably inconclusive because of inadequate compliance with taking medication.
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http://dx.doi.org/10.1016/j.drugalcdep.2011.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227772PMC
January 2012