Publications by authors named "Mary Lou Affronti"

19 Publications

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Utilizing a Palliative Care Screening Tool in Patients With Glioblastoma.

J Adv Pract Oncol 2020 Sep-Oct;11(7):684-692. Epub 2020 Sep 1.

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

Patients with glioblastoma have poor overall survival and experience significant burden from neurologic decline and adverse treatment effects. Despite the well-known benefits of early palliative care integration with oncology care, utilization of palliative care is low. The purpose of this quality improvement (QI) project is to investigate the feasibility, value, and effectiveness of using an adapted palliative care screening tool to improve outpatient palliative care screening and referral of glioblastoma patients. This QI project was conducted over a 10-week period. A glioma palliative care screening tool was developed and integrated into outpatient visits. Providers were required to use the screening tool during each patient visit. Patients 18 years or older who were diagnosed with a World Health Organization grade IV glioma and returning to the neuro-oncology clinic for a brain MRI evaluation were targeted. Screening, palliative care discussion, and referral rates were evaluated. Among 530 eligible patients who returned to the clinic over a 10-week period, the tool was available for 433 patients. Fifty-six percent (n = 294/530) of the patients were screened. Nine percent (n = 27) of screened patients were identified as candidates for a palliative care referral (score ≥ 5 on the screening tool). Of these 27 patients, the proportion of patients who had a palliative care discussion was 63% (n = 17). Overall, 71% (n = 12) of patients who had a palliative care discussion were referred to a palliative care provider. Integrating a glioma palliative care screening tool with outpatient visits can draw attention to palliative care needs and lead to a referral to palliative care.
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http://dx.doi.org/10.6004/jadpro.2020.11.7.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646633PMC
September 2020

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

Development of a Professional Practice Model for Neuro-oncology Advanced Practitioners at an Academic Medical Center: A Quality Improvement Project.

J Adv Pract Oncol 2018 Jul-Aug;9(5):475-486. Epub 2018 Jul 1.

Duke University School of Nursing, The Preston Robert Tisch Brain Tumor Center, Durham, North Carolina.

In medicine, neuro-oncology practice falls outside the scope of established practice requirements for the specialties of neurology, medical oncology, and neurosurgery, justifying the prerequisite of specialized training to practice neuro-oncology. Neuro-oncology advanced practitioners (AP) also require specialization beyond the scope of population-based generalist training and education. This quality improvement project's primary purpose was to develop a professional practice model (PPM) for APs employed at an academic medical center (AMC) ambulatory neuro-oncology practice. Using the focus, analyze, develop, execute, and evaluate (FADE) quality improvement methodology, the authors (1) reviewed literature and relevant professional organizations to identify possible professional competencies for neuro-oncology APs; (2) analyzed data to develop evidence-based practice domains; (3) used purposive sampling to recruit an interprofessional team of neuro-oncology experts; and (4) conducted a Delphi study with an interprofessional team of experts to gain consensus on practice domains and professional competencies. Twenty-three participants (n = 23) were recruited for the Delphi study, which was executed via electronic transmission using the Web-based software Qualtrics. After two rounds of the Delphi survey, the expert team reached consensus on six domains of practice, with 50 corresponding competency statements. Through interprofessional collaboration and consensus, this quality improvement project successfully created a PPM for an AMC neuro-oncology AP team. The PPM supports neuro-oncology APs by validating the unique set of skills that combines several specialties. The PPM provided the framework to standardize orientation and training, evaluate performance, and support the professional development of an AMC neuro-oncology AP team.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505547PMC
July 2018

Improving Attitudes and Perceptions About End-of-Life Nursing on a Hospital-Based Palliative Care Unit.

J Hosp Palliat Nurs 2019 08;21(4):272-279

Kristine J. Harrington, DNP, RN, AGNP-C, is palliative care nurse practitioner, Providence Cancer Institute Franz Clinic, Providence Portland Medical Center; and adjunct professor, University of Portland School of Nursing, Oregon. Mary Lou Affronti, DNP, RN, MHSc, ANP, is associate professor, Duke University School of Nursing; primary investigator and nurse practitioner, Preston Robert Tisch Brain Tumor Center; and primary investigator and nurse practitioner, Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina. Susan M. Schneider, PhD, RN, AOCN, FAAN, is associate professor, Duke University School of Nursing, Durham, North Carolina; and president, Oncology Nursing Society, Pittsburgh, Pennsylvania. Abdul Rab Razzak, MD, is director of outpatient palliative care, Johns Hopkins Medical Institutions, Baltimore, Maryland. Thomas J. Smith, MD, FACP, FASCO, FAAHPM, is director of palliative care, Johns Hopkins Medical Institutions, Baltimore, Maryland.

Nurses play an integral role in high-quality patient care. Thus, their skills in providing end-of-life care should be assessed and continually enhanced. Education intended to improve end-of-life skills must address the affective/emotional component of nursing care. Evidence demonstrates that emotional engagement and resilience among health care providers are correlated with improved quality outcomes and, conversely, that burnout and stress negatively affect patient safety. Addressing the emotional needs of health care providers is critical to improving quality throughout the health care system. An evidence-based workshop was implemented among direct care staff on a hospital-based palliative care unit, with the goal of fostering emotional engagement to improve staff perceptions and attitudes about caring for patients at or near the end of life. Although perceptions about quality of death were not affected by this intervention, there was a significant improvement in attitudes about end-of-life nursing care. Qualitative feedback also reflected appreciation for small group discussions and opportunities to debrief with peers away from the unit. This intervention reflected the value of emotional engagement in educational efforts to improve end-of-life nursing care.
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http://dx.doi.org/10.1097/NJH.0000000000000523DOI Listing
August 2019

Introduction.

Semin Oncol Nurs 2018 12 14;34(5):417-419. Epub 2018 Nov 14.

Associate Professor, The Duke University School of Nursing, Durham, NC; Primary Investigator, Nurse Practitioner, The Duke Preston Robert Tisch Brain Tumor Center, Division of Medical Neuro-Oncology, Department of Neurosurgery, Duke Cancer Institute, Duke Health, Durham, NC. Electronic address:

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http://dx.doi.org/10.1016/j.soncn.2018.10.003DOI Listing
December 2018

Pilot Study to Describe the Trajectory of Symptoms and Adaptive Strategies of Adults Living with Low-grade Glioma.

Semin Oncol Nurs 2018 12 6;34(5):472-485. Epub 2018 Nov 6.

Objectives: To describe the adaptability to the patterns in symptoms and quality of life (QoL) during 6 months post low-grade glioma diagnosis by valid and reliable tools; to identify through qualitative interviews patient/provider adaptive techniques and strategies; and to assess associations among patient characteristics, symptoms and QoL, and adaptive techniques or strategies.

Data Sources: Demographic, clinical and pathologic data from medical records. Validated instruments that assess QoL, fatigue, depression, and distress were completed at 2, 4, and 6 months post diagnosis. Qualitative interviews identifying the symptoms, challenges, adaptive techniques and strategies were conducted at 4 and 6 months.

Conclusion: The most frequently used adaptive strategies included: obtaining community support (87%), managing expectations (73%) and support systems (67%), and seeking out knowledge about physical (67%) and behavioral symptoms (53%). Seizures were reported with IDH1 (11%) but not IDH1. Patients with either IDH1 or TERT consistently reported lower QoL and higher distress, depression, and fatigue scores. IDH1/TERT may be related to lower QoL because of IDH1-related seizures.

Implications For Nursing Practice: Findings provide a list of adaptive strategies and characteristics to address the problems and symptoms that may improve overall QoL in patients with low-grade glioma.
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http://dx.doi.org/10.1016/j.soncn.2018.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612906PMC
December 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

Chemotherapy-induced nausea and vomiting (CINV) and adherence to antiemetic guidelines: results of a survey of oncology nurses.

Support Care Cancer 2018 02 4;26(2):557-564. Epub 2017 Sep 4.

Rittenberg Oncology Consulting, Metairie, LA, USA.

Purpose: Chemotherapy-induced nausea and vomiting (CINV) can be prevented in most patients with use of guideline-recommended antiemetic regimens. However, studies have suggested that adherence to antiemetic guidelines is suboptimal. Oncology nurses, as part of a multidisciplinary team, can help promote appropriate antiemetic prophylaxis. Therefore, nurses were surveyed to assess antiemetic guideline awareness and practice patterns of antiemetic use, determine adherence to guideline recommendations, and query barriers to adherence.

Methods: In September 2015, 531 US-based oncology nurses participated in an online survey administered and analyzed by ONS:Edge.

Results: Nurses were most familiar with National Comprehensive Cancer Network (73%) and American Society of Clinical Oncology (48%) antiemetic guidelines. While most (77%) felt that antiemetics prescribed were consistent with guideline recommendations, practice patterns of antiemetic use revealed low adherence to those guidelines, particularly during the delayed (25-120 h) phase following highly emetogenic chemotherapy, where only 25% of nurses reported administration of guideline-recommended agents. Overutilization of phenothiazines and benzodiazepines was common. Only 17% of respondents reported that most (> 75%) of their patients have CINV optimally controlled; 39% reported between 6 and 20% of patients have an alteration in their chemotherapy due to CINV, and reports of emergency department/hospital visits due to poorly controlled CINV were high. The predominant barrier interfering guideline-recommended antiemetic prophylaxis was reported as physician preference (71%).

Conclusions: This survey revealed an opportunity to increase awareness of antiemetic guidelines and a critical need to address barriers interfering with utilization of guideline-recommended antiemetic agents in order to optimize CINV control for patients undergoing emetogenic chemotherapy.
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http://dx.doi.org/10.1007/s00520-017-3866-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752733PMC
February 2018

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

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

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

Palonosetron in the management of chemotherapy-induced nausea and vomiting in patients receiving multiple-day chemotherapy.

Cancer Manag Res 2014 5;6:329-37. Epub 2014 Sep 5.

Oregon Health and Science University Hospital and Clinics, Portland, OR, USA.

Prevention of chemotherapy-induced nausea and vomiting (CINV) is a key component of treatment for patients with cancer. Guidelines are available to assist prescribers in the management of CINV associated with single-day chemotherapy regimens. However, currently there are no clear guidelines for management of CINV in patients receiving multiple-day chemotherapy regimens. Serotonin (5-HT3) receptor antagonists are a mainstay in preventing CINV, and palonosetron, given its longer half-life and duration of action relative to other 5-HT3 receptor antagonists, may be a useful option for managing CINV in multiple-day chemotherapy. Here we provide an overview of CINV and CINV treatment options, with a focus on palonosetron. We describe existing challenges in managing CINV, and discuss two patients receiving multiple-day chemotherapy, in whom CINV was managed successfully with palonosetron.
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http://dx.doi.org/10.2147/CMAR.S68102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161526PMC
September 2014

Adherence to antiemetic guidelines in patients with malignant glioma: a quality improvement project to translate evidence into practice.

Support Care Cancer 2014 Jul 26;22(7):1897-905. Epub 2014 Feb 26.

Department of Surgery, Duke University Health System, Durham, NC, 27710, USA,

Purpose: A quality improvement project was implemented to improve adherence to evidence-based antiemetic guidelines for malignant glioma patients treated with moderately emetic chemotherapy (MEC). Poorly controlled chemotherapy-induced nausea and vomiting (CINV) reduce cancer treatment efficacy and significantly impair cancer patients' quality of life (QOL). A review of Duke University Preston Robert Tisch Brain Tumor Center (PRTBTC)'s usual practice demonstrates a high incidence (45%) of CINV, despite premedication with short-acting 5-HT3-serotonin-receptor antagonists (5-HT3-RAs). National Comprehensive Cancer Network (NCCN)'s evidence-based guidelines recommend the combination of the long-acting 5-HT3-RA palonosetron (PAL) and dexamethasone (DEX) for the prevention of acute and delayed CINV with MEC. Low adherence (58%) to antiemetic guidelines may have explained our high CINV incidence.

Methods: One-sample binomial test, quasi-experimental design, evaluated a combination intervention that included a provider education session; implementation of risk-assessment tool with computerized, standardized antiemetic guideline order sets; and a monthly audit-feedback strategy. Post-implementation adherence to evidence-based antiemetic order sets and patient outcomes were measured and compared to baseline and historical data. Primary outcome was the guideline order set adherence rate. Secondary outcomes included nausea/vomiting rates and QOL.

Results: Adherence to ordering MEC guideline antiemetics increased significantly, from 58% to a sustained 90%, with associated improvement in nausea/vomiting. In acute and delayed phases, 75 and 84% of patients, respectively, did not experience CINV. There was no significant change in QOL.

Conclusion: Combination intervention and audit-feedback strategy to translate evidence into oncology practice improved and sustained adherence to antiemetic guidelines. Adherence corresponded with effective nausea/vomiting control and preserved QOL in patients with malignant gliomas.
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http://dx.doi.org/10.1007/s00520-014-2136-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509487PMC
July 2014

Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy.

Cancer 2009 Aug;115(15):3501-11

Department of Surgery, Duke University Medical Center, and The Preston Robert Tisch Brain Tumor Center, South Hospital, Durham, North Carolina. 27710, USA.

Background: Glioblastoma multiforme (GBM), the most lethal type of brain tumor, has a 1-year median survival. The effect of carmustine wafers on the survival of newly diagnosed GBM patients treated with radiotherapy (RT) and concurrent temozolomide (TMZ) plus RT plus rotational chemotherapy was investigated.

Methods: An institutional review board-approved retrospective study was conducted in 85 newly diagnosed GBM patients who received surgical resection with and without carmustine wafers followed by RT and concurrent TMZ plus rotational chemotherapy. Treatment group comparisons were conducted using the log-rank test. Survival experience of the Duke cohort was examined within specific patient subgroups defined by the original Radiation Therapy Oncology Group (RTOG) recursive partition analysis (RPA) class and compared with the European Organization for Research and Treatment of Cancer (Stupp) and RTOG trial.

Results: Overall 1- and 2-year survival for the noncarmustine wafer cohort were 69% and 29%, respectively, with a median survival of 72.7 weeks. One- and 2-year survival for the carmustine wafer cohort were 81% and 47%, with median survival of 89.5 weeks. Carmustine wafer was not an independent predictor (P=.110) of survival after adjustment for RPA class. The proportion of patients in the carmustine wafer cohort who lived longer than predicted based upon Stupp regimen results was significantly greater than 0.5 (P<.006); similar results based upon the RTOG trial data were observed (P<.001).

Conclusions: Carmustine wafer with concurrent TMZ and radiation followed by rotational chemotherapy is a well tolerated, effective therapy, and has a survival benefit compared with radiation alone. Prospective randomized trials are needed to rigorously compare the carmustine wafer regimen to the Stupp and postradiation multimodality regimens.
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http://dx.doi.org/10.1002/cncr.24398DOI Listing
August 2009

Consolidation with high-dose combination alkylating agents with bone marrow transplantation significantly improves disease-free survival in hormone-insensitive metastatic breast cancer in complete remission compared with intensive standard-dose chemotherapy alone.

Biol Blood Marrow Transplant 2006 Feb;12(2):195-203

Duke University Medical Center, Durham, North Carolina 27710, USA.

We conducted this study to determine event-free and overall survival among women with hormone-insensitive or hormone-resistant metastatic breast cancer receiving consolidation with high-dose chemotherapy (HDC) and hematopoietic support versus no further chemotherapy after intensive induction chemotherapy. Eligible patients received induction doxorubicin, 5-fluorouracil, and methotrexate (AFM) for 2 to 4 cycles. Women in complete remission were randomized to immediate HDC with cyclophosphamide, cisplatin, and carmustine followed by autologous hematopoietic support or to no further therapy. Patients on the observation arm of therapy were offered salvage HDC at the time of relapse. Partial responders to AFM were offered immediate HDC. A total of 425 patients were enrolled onto the study. The median event-free survival for women randomized to induction therapy alone was 3.8 months, compared with 9.7 months for women who completed HDC (P < .006). Of the patients randomized to observation, 5 (10%) of 51 remain event free, compared with 13 (26%) of 49 patients who underwent immediate HDC (P = .03). Of women converted to a complete response by salvage HDC after a partial response to AFM, overall survival was similar to that in women randomized to immediate HDC. Follow-up is now in excess of 5 years. The 5-year event-free survival is 15% (95% confidence interval, 12%-18%), and the 5-year overall survival is 20% (95% confidence interval, 17%-25%). Immediate HDC after a complete response to AFM produced some durable long-term responses in hormone-insensitive/-resistant metastatic breast cancer. Salvage HDC converted 30% of partial responders to complete responders with similar survivals. The addition of novel targeted therapies to intensive-dose chemotherapy regimens may further improve survival in metastatic breast cancer.
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http://dx.doi.org/10.1016/j.bbmt.2005.10.009DOI Listing
February 2006

Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma.

Neuro Oncol 2004 Apr;6(2):145-53

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

Irinotecan is a topoisomerase I inhibitor previously shown to be active in the treatment of malignant glioma. We now report the results of a phase 1 trial of irinotecan plus BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, for patients with recurrent or progressive MG. Irinotecan dose escalation occurred independently within 2 strata: patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and patients not receiving EIAEDs. BCNU was administered at a dose of 100 mg/m2 over 1 h every 6 weeks on the same day as the first irinotecan dose was administered. Irinotecan was administered intravenously over 90 min once weekly. Treatment cycles consisted of 4 weekly administrations of irinotecan followed by a 2-week rest with dose escalation in cohorts of 3 to 6 patients. Seventy-three patients were treated, including 49 patients who were on EIAEDs and 24 who were not on EIAEDs. The maximum tolerated dose for patients not on EIAEDs was 125 mg/m2. The maximum tolerated dose for patients on EIAEDs was 225 mg/m2. Dose-limiting toxicity was evenly distributed among the following organ systems: pulmonary, gastrointestinal, cardiovascular, neurologic, infectious, and hematologic, without a clear predominance of toxicity involving any one organ system. There was no evidence of increasing incidence of toxicity involving one organ system as irinotecan dose was escalated. On the basis of these results, we conclude that the recommended doses of irinotecan for a phase 2 clinical trial when given in combination with BCNU (100 mg/m2) are 225 mg/m2 for patients on EIAEDs and 125 mg/m2 for patients not on EIAEDs.
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http://dx.doi.org/10.1215/S1152851703000498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1871988PMC
April 2004

Phase 2 trial of BCNU plus irinotecan in adults with malignant glioma.

Neuro Oncol 2004 Apr;6(2):134-44

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

In preclinical studies, BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, plus CPT-11 (irinotecan) exhibits schedule-dependent, synergistic activity against malignant glioma (MG). We previously established the maximum tolerated dose of CPT-11 when administered for 4 consecutive weeks in combination with BCNU administered on the first day of each 6-week cycle. We now report a phase 2 trial of BCNU plus CPT-11 for patients with MG. In the current study, BCNU (100 mg/m2) was administered on day 1 of each 6-week cycle. CPT-11 was administered on days 1, 8, 15, and 22 at 225 mg/m2 for patients receiving CYP3A1- or CYP3A4-inducing anticonvulsants and at 125 mg/m2 for those not on these medications. Newly diagnosed patients received up to 3 cycles before radiotherapy, while recurrent patients received up to 8 cycles. The primary end point of this study was radiographic response, while time to progression and overall survival were also assessed. Seventy-six patients were treated, including 37 with newly diagnosed tumors and 39 with recurrent disease. Fifty-six had glioblastoma multiforme, 18 had anaplastic astrocytoma, and 2 had anaplastic oligodendroglioma. Toxicities (grade > or =3) included infections (13%), thromboses (12%), diarrhea (10%), and neutropenia (7%). Interstitial pneumonitis developed in 4 patients. Five newly diagnosed patients (14%; 95% CI, 5%-29%) achieved a radiographic response (1 complete response and 4 partial responses). Five patients with recurrent MG also achieved a response (1 complete response and 4 partial responses; 13%; 95% CI, 4%-27%). More than 40% of both newly diagnosed and recurrent patients achieved stable disease. Median time to progression was 11.3 weeks for recurrent glioblastoma multiforme patients and 16.9 weeks for recurrent anaplastic astrocytoma/ anaplastic oligodendroglioma patients. We conclude that the activity of BCNU plus CPT-11 for patients with MG appears comparable to that of CPT-11 alone and may be more toxic.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1871982PMC
http://dx.doi.org/10.1215/s1152851703000413DOI Listing
April 2004

Phase II trial of temozolomide in patients with progressive low-grade glioma.

J Clin Oncol 2003 Feb;21(4):646-51

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

Purpose: Temozolomide (Temodar; Schering-Plough Corp, Kenilworth, NJ) is an imidazole tetrazinone that undergoes chemical conversion to the active methylating agent 5-(3-methyltriazen-1yl)imidazole-4-carboximide under physiologic conditions. Previous studies have confirmed activity of Temodar in the treatment of progressive and newly diagnosed malignant gliomas. We have extended these results, and now we report results of a phase II trial of Temodar for patients with progressive, low-grade glioma.

Patients And Methods: Temodar was administered orally once a day for five consecutive days (in a fasting state) at a starting dose of 200 mg/m(2)/d. Treatment cycles were repeated every 28 days following the first daily dose of Temodar. Response criteria used a combination of magnetic resonance imaging and physical examination to evaluate activity.

Results: Forty-six patients with low-grade glioma have been treated to date. The objective response rate was 61% (24% complete response and 37% partial response), with an additional 35% of patients having stable disease. Median progression-free survival (PFS) was 22 months (95% confidence interval [CI], 15 to infinity months) with a 6-month PFS of 98% (95% CI, 94% to 100%) and a 12-month PFS of 76% (95% CI, 63% to 92%). Toxicity observed during the study was limited to only six patients. Three patients experienced grade 3 neutropenia, with a duration greater than 3 weeks in one patient, and two patients experienced grade 3 thrombocytopenia. One patient experienced > or = grade 4 toxicity, with intracerebral hemorrhage, neutropenia, thrombocytopenia, sepsis, and death.

Conclusion: Initial results indicate that Temodar may be active in the treatment of low-grade glioma, and thus, further evaluation of this agent in the treatment of these tumors is warranted.
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http://dx.doi.org/10.1200/JCO.2003.01.009DOI Listing
February 2003