Publications by authors named "Frances A Collichio"

27 Publications

  • Page 1 of 1

How well do documented goals-of-care discussions for patients with stage IV cancer reflect communication best practices?

BMC Palliat Care 2021 Mar 10;20(1):41. Epub 2021 Mar 10.

Sheps Center for Health Services Research, University of North Carolina, Chapel Hill, USA.

Background: Written clinical communication regarding patients' disease understanding and values may facilitate goal-concordant care, yet little is known about the quality of electronic health record (EHR) documentation. We sought to (1) describe frequency of communication best practices in EHR-documented goals-of-care discussions, and (2) assess whether templated notes improve quality of documentation.

Methods: Researchers pulled text of EHR-documented goals-of-care discussions for hospitalized patients with Stage IV cancer from admission to 60-days follow-up. Text was included when in a single encounter the clinician addressed: (a) prognosis and/or illness understanding; and (b) goals and/or treatment options. Researchers qualitatively coded text based on guidelines for communication best practices, and noted if an EHR template was used.

Results: Forty-two percent (206/492) of patients had EHR-documented goals-of-care discussions. Text frequently described communication of cancer progression (89%), though rarely included prognosis (22%). Text often included patients' goals and values (83%), and at least on specific treatment decision (82%). Communication about treatments was included for 98% of patients; common examples included cancer treatment (62%), hospice (62%), resuscitation (51%), or intensive care (38%). Clinicians documented making recommendations for 40% of patients. Text addressing patient emotional and spiritual concerns was uncommon (15%). Compared to free text, use of a template was associated with increased documentation of goals and values (80% vs. 61%, p < 0.01), but not other best practices.

Conclusion: Insights from the study can be used to guide future training and research to study and improve the quality of documentation about goal of care, and its impact on goal-concordant care.
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http://dx.doi.org/10.1186/s12904-021-00733-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944465PMC
March 2021

Targeting the IL-2 inducible kinase in melanoma; a phase 2 study of ibrutinib in systemic treatment-refractory distant metastatic cutaneous melanoma: preclinical rationale, biology, and clinical activity (NCI9922).

Melanoma Res 2021 04;31(2):162-172

Department of Medicine, The University of North Carolina at Chapel Hill.

Background: IL-2 inducible kinase (ITK) is highly expressed in metastatic melanomas and its inhibition suppresses melanoma cell proliferation. We hypothesize that ibrutinib has a direct antitumor effect in melanoma cell lines and that treatment of metastatic melanomas with ibrutinib induces antitumor responses.

Methods: We assessed the ibrutinib effect on melanoma cell proliferation, apoptosis, and motility. Patients with metastatic melanoma refractory to PD-1 and MAPK inhibitors (if BRAFV600-mutant) were treated with ibrutinib, 840 mg PO QD, as part of a phase II clinical trial (clinicaltrials.gov NCT02581930).

Results: Melanoma cell lines frequently express ITK, YES1, and EGFR. Ibrutinib suppressed cell motility and proliferation in most cell lines. Eighteen patients (13 male; median age 63.5 years, range 37-82; 12 with ipilimumab resistance) were enrolled. The most frequent side effects were fatigue (61%), anorexia (50%), hyponatremia (28%), nausea, and vomiting (22% each). No antitumor responses were seen. At a median follow-up of 6 months (0.3-35.8 months), the median progression-free survival was 1.3 months (range 0.2-5.5 months). Fifteen patients were discontinued from the study due to progression, and 14 patients had died from metastatic melanoma. All archived tumors expressed ITK, 41% had no expression of p16 and PTEN, and 61% had absent tumor-infiltrating lymphocytes (TILs). Ibrutinib significantly suppressed proliferating (Ki67+) CD19+ peripheral blood mononuclear cells and had no significant effect on other lymphocyte subsets.

Conclusion: Ibrutinib did not induce any meaningful clinical benefit. ITK expression may not be clinically relevant. Treatment-refractory metastatic melanomas have other fundamental defects (i.e. absent PTEN and p16 expression, absent TILs) that may contribute to an adverse prognosis.
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http://dx.doi.org/10.1097/CMR.0000000000000726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025369PMC
April 2021

Pre-Post Evaluation of Collaborative Oncology Palliative Care for Patients With Stage IV Cancer.

J Pain Symptom Manage 2021 Feb 27. Epub 2021 Feb 27.

Division of General Internal Medicine, University of Pittsburgh School of Medicine (N.C.E.), Pittsburgh, Pennsylvania, USA.

Context: The Collaborative Care Model improves care processes and outcomes but has never been tested for palliative care.

Objectives: To develop and evaluate a model of collaborative oncology palliative care for Stage IV cancer.

Methods: We conducted a pre-post evaluation of Collaborative Oncology Palliative Care (CO-Pal), enrolling patients with Stage IV lung, breast or genitourinary cancers and acute illness hospitalization. CO-Pal has 4 components: 1) oncologist communication skills training; 2) patient tracking; 3) palliative care needs assessment; and 4) care coordination stratified by high vs. low palliative care need. Health record reviews from hospital admission through 60 days provided data on outcomes - goals-of-care discussions (primary outcome), advance care planning, symptom treatment, specialty palliative care and hospice use, and hospital transfers.

Results: We enrolled 256 patients (n = 114 pre and n = 142 post-intervention); 60-day mortality was 32%. Comparing patients pre vs post-intervention, CO-Pal did not increase overall goals-of-care discussions, but did increase advance care planning (48% vs 63%, P = 0.021) and hospice use (19% vs 31%, P = 0.034). CO-Pal did not impact symptom treatment, overall treatment plans, or 60-day hospital transfers. During the intervention phase, high-need vs low-need patients had more goals-of-care discussions (60% vs. 15%, P < 0.001) and more use of specialty palliative care (64% vs 22%, P < 0.001) and hospice (44% vs 16%, P < 0.001).

Conclusion: Collaborative oncology palliative care is efficient and feasible. While it did not increase overall goals-of-care discussions, it was effective to increase overall advance care planning and hospice use for patients with Stage IV cancer.
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http://dx.doi.org/10.1016/j.jpainsymman.2021.02.032DOI Listing
February 2021

Brain Tumor Microenvironment and Angiogenesis in Melanoma Brain Metastases.

Front Oncol 2020 21;10:604213. Epub 2021 Jan 21.

Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Background: High tumor-infiltrating lymphocytes (TILs) and hemorrhage are important prognostic factors in patients who have undergone craniotomy for melanoma brain metastases (MBM) before 2011 at the University of Pittsburgh Medical Center (UPMC). We have investigated the prognostic or predictive role of these histopathologic factors in a more contemporary craniotomy cohort from the University of North Carolina at Chapel Hill (UNC-CH). We have also sought to understand better how various immune cell subsets, angiogenic factors, and blood vessels may be associated with clinical and radiographic features in MBM.

Methods: Brain tumors from the UPMC and UNC-CH patient cohorts were (re)analyzed by standard histopathology, tumor tissue imaging, and gene expression profiling. Variables were associated with overall survival (OS) and radiographic features.

Results: The patient subgroup with high TILs in craniotomy specimens and subsequent treatment with immune checkpoint inhibitors (ICIs, n=7) trended to have longer OS compared to the subgroup with high TILs and no treatment with ICIs (n=11, p=0.059). Bleeding was significantly associated with tumor volume before craniotomy, high melanoma-specific expression of basic fibroblast growth factor (bFGF), and high density of CD31+αSMA- blood vessels. Brain tumors with high versus low peritumoral edema before craniotomy had low (17%) versus high (41%) incidence of brisk TILs. Melanoma-specific expression of the vascular endothelial growth factor (VEGF) was comparable to VEGF expression by TILs and was not associated with any particular prognostic, radiographic, or histopathologic features. A gene signature associated with gamma delta (gd) T cells was significantly higher in intracranial than same-patient extracranial metastases and primary melanoma. However, gdT cell density in MBM was not prognostic.

Conclusions: ICIs may provide greater clinical benefit in patients with brisk TILs in MBM. Intratumoral hemorrhage in brain metastases, a significant clinical problem, is not merely associated with tumor volume but also with underlying biology. bFGF may be an essential pathway to target. VEGF, a factor principally associated with peritumoral edema, is not only produced by melanoma cells but also by TILs. Therefore, suppressing low-grade peritumoral edema using corticosteroids may harm TIL function in 41% of cases. Ongoing clinical trials targeting VEGF in MBM may predict a lack of unfavorable impacts on TIL density and/or intratumoral hemorrhage.
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http://dx.doi.org/10.3389/fonc.2020.604213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860978PMC
January 2021

Mortality Risk for Patients With Stage IV Cancer and Acute Illness Hospitalization.

J Pain Symptom Manage 2021 Apr 20;61(4):797-804. Epub 2020 Oct 20.

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Context: Cancer prognosis data often come from clinical trials which exclude patients with acute illness.

Objectives: For patients with Stage IV cancer and acute illness hospitalization to 1) describe predictors of 60-day mortality and 2) compare documented decision-making for survivors and decedents.

Methods: Investigators studied a consecutive prospective cohort of patients with Stage IV cancer and acute illness hospitalization. Structured health record and obituary reviews provided data on 60-day mortality (outcome), demographics, health status, and treatment; logistic regression models identified mortality predictors.

Results: Four hundred ninety-two patients with Stage IV cancer and acute illness hospitalization had median age of 60.2 (51% female, 38% minority race/ethnicity); 156 (32%) died within 60 days, and median survival for decedents was 28 days. Nutritional insufficiency (odds rato [OR] 1.83), serum albumin (OR 2.15 per 1.0 g/dL), and hospital days (OR 1.04) were associated with mortality; age, gender, race, cancer, and acute illness type were not predictive. On admission, 79% of patients had orders indicating Full Code. During 60-day follow-up, 42% of patients discussed goals of care. Documented goals of care discussions were more common for decedents than survivors (70% vs. 28%, P < 0.001), as were orders for do not resuscitate/do not intubate (68% vs. 24%, P < 0.001), stopping cancer-directed therapy (29% vs. 10%, P < 0.001), specialty Palliative Care (79% vs. 44%, P < 0.001), and Hospice (68% vs. 14%, P < 0.001).

Conclusion: Acute illness hospitalization is a sentinel event in Stage IV cancer. Short-term mortality is high; nutritional decline increases risk. For patients with Stage IV cancer, acute illness hospitalization should trigger goals of care discussions.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.10.015DOI Listing
April 2021

Development of an Art of Oncology Curriculum to Mitigate Burnout and Foster Solidarity Among Hematology/Oncology Fellows.

JCO Oncol Pract 2020 04 26;16(4):e384-e394. Epub 2020 Feb 26.

UNC Lineberger Comprehensive Cancer Center, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Purpose: Oncologists and fellows in hematology/oncology (HO) training programs report high levels of burnout. The Accreditation Council for Graduate Medical Education requires accredited programs to have a mechanism to foster well-being among fellows.

Methods: Through an iterative process involving a multidisciplinary committee, we created a 3-year longitudinal Art of Oncology (AOO) curriculum intended to address burnout and foster solidary among HO fellows. Sessions used narratives to promote the formation of a shared mental model through discussion of the mutual experience of caring for patients with cancer. We tested the feasibility, acceptability, and initial effectiveness of implementing the curriculum into traditional didactic lectures as a pilot intervention from 2018 to 2019. Eight sessions were completed.

Results: Sixteen fellows participated. Most were married (63%) and planned on pursuing careers in academic medicine (75%). The sample was racially and ethnically diverse (31% minority representation). Thirty-eight percent of fellows reported burnout symptoms. AOO sessions had higher attendance than didactic lectures ( = .04). Of 14 fellows who completed all follow-up assessments (87.5% response rate), 93% (13 of 14 fellows) felt the sessions were very or somewhat helpful and that sessions improved solidarity. Preparedness in managing work-life balance significantly improved (paired test, mean difference, 0.53; = .04). Measured levels of burnout did not significantly improve from baseline (mean difference, -0.133; = .67). Work-life balance was associated with burnout on multivariable analysis (coefficient, 0.40; = .03).

Conclusion: The implementation of a dedicated AOO curriculum is feasible and viewed as helpful by HO fellows. Larger studies are needed to assess the efficacy of this curricular intervention.
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http://dx.doi.org/10.1200/JOP.19.00529DOI Listing
April 2020

Chemotherapy Following PD-1 Inhibitor Blockade in Patients with Unresectable Stage III/Stage IV Metastatic Melanoma: A Single Academic Institution Experience.

Oncology 2020 3;98(3):174-178. Epub 2019 Dec 3.

Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Retrospective case studies in various cancers have shown clinical benefit from chemotherapy following PD-1 inhibitor progression. We asked whether we see a similar clinical benefit with chemotherapy following PD-1 inhibitor progression in metastatic melanoma. We performed a retrospective study in patients with metastatic melanoma, who had received PD-1 inhibitor-based treatments, subsequently progressed, and eventually received chemotherapy. We identified 25 patients (median age 58 years; range 31-77 years; 13 females). Most patients had cutaneous melanoma (72%), were BRAFV600E-negative (75%), and received single-agent temozolomide (84%). At a median follow-up of 21.0 months (range: 4.1-154.2 months), 2 patients had durable response to chemotherapy (progression-free survival is 31.9+ and 21.6+ months, respectively), and 1 patient had a partial, short-term response. We conclude that in this poor prognosis group administration of chemotherapy has a 12% response rate that can be durable. Overall, the clinical benefit is not inferior to that of PD-1 inhibitor-based treatments.
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http://dx.doi.org/10.1159/000504578DOI Listing
March 2020

THYROID DYSFUNCTION, RECOVERY, AND PROGNOSIS IN MELANOMA PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITORS: A RETROSPECTIVE REVIEW.

Endocr Pract 2020 Jan 28;26(1):36-42. Epub 2019 Aug 28.

To describe thyroid dysfunction, factors associated with thyroid recovery, and survival in melanoma patients treated with immune checkpoint inhibitors that developed thyroid immune-related adverse events (irAEs). This was a retrospective study in a tertiary center from 2010-2017. We reviewed the charts of patients with melanoma that developed thyroid dysfunction after checkpoint inhibitor therapy. Cases with thyroid irAEs were grouped by recovery of thyroid function at 1 year. We collected a timeline of thyroid function tests, medication exposure, and survival and compared variables between the groups. We studied survival in comparison to a matched group without thyroid dysfunction. A total of 186 melanoma patients received checkpoint inhibitors, and 17 (9%) had thyroid irAEs. Median time to abnormal thyroid-stimulating hormone was 38 days and followed a pattern of thyroiditis. Seven of 17 had thyroid recovery. In the no-recovery group, free thyroxine (T4) was often above 2 ng/dL (5/10 in no recovery, 0/7 in recovery; = .04). In the recovery group, irAE grade was significantly lower, with 7/7 grade 1 ( = .004). Exposure to glucocorticoids was associated with recovery (3/10 in no recovery, 6/7 in recovery; = .049). There was no difference in overall survival between the thyroid dysfunction group and controls, or between those that received glucocorticoids or not. Certain aspects of thyroid irAEs may correlate with thyroid recovery, including grade 1 thyroid irAEs, exposure to glucocorticoids, and peak free T4 levels less than 2 ng/dL. Thyroid irAEs did not appear to be associated with change in survival nor did exposure to glucocorticoids. = American Society of Clinical Oncology; = cytotoxic T-lymphocyte-associated protein 4; = immune-related adverse event; = programmed cell death protein 1; = thyroxine; = thyroid-stimulating hormone.
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http://dx.doi.org/10.4158/EP-2019-0244DOI Listing
January 2020

The Prognostic Significance of Low-Frequency Somatic Mutations in Metastatic Cutaneous Melanoma.

Front Oncol 2018 4;8:584. Epub 2019 Jan 4.

Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Little is known about the prognostic significance of somatically mutated genes in metastatic melanoma (MM). We have employed a combined clinical and bioinformatics approach on tumor samples from cutaneous melanoma (SKCM) as part of The Cancer Genome Atlas project (TCGA) to identify mutated genes with potential clinical relevance. After limiting our DNA sequencing analysis to MM samples ( = 356) and to the CANCER CENSUS gene list, we filtered out mutations with low functional significance (snpEFF). We performed Cox analysis on 53 genes that were mutated in ≥3% of samples, and had ≥50% difference in incidence of mutations in deceased subjects versus alive subjects. Four genes were potentially prognostic [; false discovery rate (FDR) < 0.2]. We identified 18 additional genes (e.g., ) that were less likely to have prognostic value (FDR < 0.4). Most somatic mutations in these 22 genes were infrequent (< 10%), associated with high somatic mutation burden, and were evenly distributed across all exons, except for and . Mutations in only 9 of these 22 genes were also identified by RNA sequencing in >75% of the samples that exhibited corresponding DNA mutations. The low frequency, UV signature type and RNA expression of the 22 genes in MM samples were confirmed in a separate multi-institution validation cohort ( = 413). An underpowered analysis within a subset of this validation cohort with available patient follow-up ( = 224) showed that somatic mutations in and reached borderline prognostic significance [log-rank favorable ( = 0.09) and adverse ( = 0.07), respectively]. Somatic mutations in , and to a lesser extent , were not associated with definite gene copy number or RNA expression alterations. High (>2+) nuclear plus cytoplasmic expression intensity for SPEN was associated with longer melanoma-specific overall survival (OS) compared to lower (≤ 2+) nuclear intensity ( = 0.048). We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., ), such as and , may have prognostic significance in MM.
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http://dx.doi.org/10.3389/fonc.2018.00584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329304PMC
January 2019

Cutaneous adverse reactions in B-RAF positive metastatic melanoma following sequential treatment with B-RAF/MEK inhibitors and immune checkpoint blockade or vice versa. A single-institutional case-series.

J Immunother Cancer 2019 01 8;7(1). Epub 2019 Jan 8.

Department of Medicine, Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina, 170 Manning Drive, Chapel Hill, NC, 27599, USA.

Background: With the advent of immune-checkpoint inhibitors and targeted treatments (TT), there have been unprecedented response rates and survival in advanced melanoma, but the optimal sequencing of these two treatments modalities is unknown. Combining or sequencing these agents could potentially result in unique toxicities. Cutaneous adverse events (CAE) after sequential exposure to these agents represents one toxicity that needs further description.

Methods: After retrospectively reviewing charts of patients from 2015 to 2018, we identified six patients who experienced CAEs after recent exposure to sequential immunotherapy and TT or vice versa for the treatment for metastatic melanoma at the University of North Carolina, Chapel Hill. Skin biopsies were available in five patients.

Results: Five patients received TT after immunotherapy, and one patient received immunotherapy after TT. TT consisted of vemurafenib/cobimetinib (V/C) in five patients with four patients starting V/C immediately before manifesting with a CAE. In patients receiving V/C after immunotherapy, the median time from beginning V/C to development of CAE was 14.5 days. The clinical presentation of diffuse morbilliform rash, fevers, hypotension, and end-organ damage raised concern for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Histopathological features of lympho-eosinophilic infiltrate were supportive of a drug eruption. Immunotherapy or TT were re-initiated in five patients within 1-8 weeks after resolution of the index CAE. This resulted in two patients re-experiencing the CAE. Both of these patients were off prednisone at the time of therapy re-initiation, whereas none of the patients who were restarted on targeted therapy with a steroid overlap had a rash recurrence.

Conclusions: Sequential treatment using immunotherapy and TT, especially the sequence of V/C after immunotherapy appears to be the most common trigger for CAE with a median time to onset of approximately 2 weeks. Although the clinical presentation of these CAEs can be dramatic, they respond well to prednisone therapy. This unique presentation suggests that it may be reasonably safe to re-challenge certain patients with a steroid overlap after rash resolution.
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http://dx.doi.org/10.1186/s40425-018-0475-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323838PMC
January 2019

A phase 2 study of ontuxizumab, a monoclonal antibody targeting endosialin, in metastatic melanoma.

Invest New Drugs 2018 02 11;36(1):103-113. Epub 2017 Nov 11.

Columbia University Medical Center, 177 Ft Washington Avenue, New York, NY, 10032, USA.

Objectives Ontuxizumab (MORAB-004) is a first-in-class monoclonal antibody that interferes with endosialin function, which is important in tumor stromal cell function, angiogenesis, and tumor growth. This Phase 2 study evaluated the 24-week progression-free survival (PFS) value, pharmacokinetics, and tolerability of 2 doses of ontuxizumab in patients with metastatic melanoma. Patients and methods Patients with metastatic melanoma and disease progression after receiving at least 1 prior systemic treatment were randomized to receive ontuxizumab (2 or 4 mg/kg) weekly, without dose change, until disease progression. Results Seventy-six patients received at least 1 dose of ontuxizumab (40 received 2 mg/kg, 36 received 4 mg/kg). The primary endpoint, 24-week PFS value, was 11.4% (95% Confidence Interval [CI]: 5.3%-19.9%) for all patients (13.5% for 2 mg/kg and 8.9% for 4 mg/kg). The median PFS for all patients was 8.3 weeks (95% CI: 8.1-12.3 weeks). One patient receiving 4 mg/kg had a partial response, as measured by Response Evaluation Criteria in Solid Tumors v1.1. Twenty-seven of 66 response evaluable patients (40.9%) had stable disease. The median overall survival was 31.0 weeks (95% CI: 28.3-44.0 weeks). The most common adverse events overall were headache (55.3%), fatigue (48.7%), chills (42.1%), and nausea (36.8%), mostly grade 1 or 2. Conclusions Ontuxizumab at both doses was well tolerated. The 24-week PFS value was 11.4% among all ontuxizumab-treated patients. The overall response rate was 3.1% at the 4 mg/kg dose, with clinical benefit achieved in 42.4% of response evaluable patients. Efficacy of single-agent ontuxizumab at these doses in melanoma was low.
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http://dx.doi.org/10.1007/s10637-017-0530-4DOI Listing
February 2018

Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials.

J Immunother Cancer 2017 09 19;5(1):72. Epub 2017 Sep 19.

MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.

Background: Traditional response criteria may be insufficient to characterize full clinical benefits of anticancer immunotherapies. Consequently, endpoints such as durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12 months of treatment and lasting ≥6 months) have been employed. There has not, however, been validation that DRR correlates with other more traditional endpoints of clinical benefit such as overall survival.

Methods: We evaluated whether DRR was associated with clinically meaningful measures of benefit (eg, overall survival [OS], quality of life [QoL], or treatment-free interval [TFI]) in a phase 3 clinical trial of an oncolytic virus for melanoma treatment. To evaluate the association between DRR and OS and to mitigate lead time bias, landmark analyses were used. QoL was evaluated using the FACT-BRM questionnaire (comprising the FACT-BRM Physical, Social/Family, Emotional, and Functional well-being domains, the Additional Concerns, Physical and Mental treatment-specific subscales, and the Trial Outcome Index [TOI]). TFI was defined as time from the last study therapy dose to first subsequent therapy dose (including any systemic anticancer therapy for melanoma after study therapy discontinuation).

Results: Four hundred thirty-six patients were included in the intent-to-treat population. Achieving DR was associated with a statistically significant improvement in OS in a landmark analysis at 9 months (HR = 0.07; P = 0.0003), 12 months (HR = 0.05, P < 0.0001), and 18 months (HR = 0.11; P = 0.0002) that persisted after adjusting for disease stage and line of therapy. Achieving a DR was associated with a longer median TFI (HR = 0.33; P = 0.0007) and a higher TOI improvement rate (58.1% versus 30.0%; P = 0.025).

Conclusions: Achieving a DR was associated with clinical benefits such as improved OS and QoL and prolonged TFI, thus supporting the usefulness of DR as a meaningful immunotherapy clinical trial endpoint.

Trial Registration: ClinicalTrials.gov identifier, NCT00769704 ( https://clinicaltrials.gov/ct2/show/NCT00769704 ) October 7, 2008.
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http://dx.doi.org/10.1186/s40425-017-0276-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604502PMC
September 2017

Metastatic melanoma in a 95 years old patient responding to treatment with talimogene laherparepvec followed by nivolumab.

Acta Oncol 2017 10 8;56(10):1327-1330. Epub 2017 May 8.

a Division of Hematology/Oncology , East Carolina University , Greenville , NC , USA.

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http://dx.doi.org/10.1080/0284186X.2017.1324212DOI Listing
October 2017

The incidence of radiation necrosis following stereotactic radiotherapy for melanoma brain metastases: the potential impact of immunotherapy.

Anticancer Drugs 2017 07;28(6):669-675

aUNC Lineberger Comprehensive Cancer Center Departments of bRadiation Oncology cMedicine dNeurosurgery, University of North Carolina, Chapel Hill, North Carolina, USA.

Stereotactic radiotherapy (SRT) is the standard treatment for patients with limited number of brain metastases. In the past few years, newer immunotherapies (immune checkpoint inhibitors) have been proven to prolong survival in patients with metastatic melanoma. The safety of the combination of SRT and immunotherapy for brain metastases is unknown. We retrospectively identified patients with melanoma brain metastases treated with SRT between 2007 and 2015. Patients who did not have at least 3 months of follow-up with imaging after SRT were excluded from the analysis. Outcomes were compared between patients who were treated with or without immunotherapy. A total of 58 patients were included; of these, 29 were treated with SRT and immunotherapy. MAPK inhibitors (BRAF, MEK inhibitors) were used more often in the immunotherapy group (nine vs. two patients). There was a higher incidence of intracranial complications in patients treated with immunotherapy and SRT. Eight patients had radiation necrosis; all occurred in patients who were treated with immunotherapy. Nine patients had hemorrhage, of which seven occurred in patients who were treated with immunotherapy (P=0.08). However, patients treated with immunotherapy and SRT had a significant overall survival advantage compared with SRT without immunotherapy (15 vs. 6 months, P=0.0013). Patients treated with SRT and immunotherapy have a higher incidence/risk of intracranial complications, but a longer overall survival.
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http://dx.doi.org/10.1097/CAD.0000000000000497DOI Listing
July 2017

Use of Susceptibility-Weighted Imaging (SWI) in the Detection of Brain Hemorrhagic Metastases from Breast Cancer and Melanoma.

J Comput Assist Tomogr 2016 Sep-Oct;40(5):803-5

From the *Department of Radiology, New York University Medical Center, New York, NY; and †Division of Hematology and Oncology, Department of Medicine, UNC at Chapel Hill, Chapel Hill, NC; ‡Neuroradiology Section, Department of Radiology, The University of North Carolina School of Medicine, Chapel Hill, NC.

Purpose: Susceptibility-weighted imaging (SWI) has significantly increased our sensitivity in detecting hemorrhagic brain lesions. We sought to explore the prevalence of intratumoral hemorrhage as detected by SWI in brain metastases from melanoma and breast cancer.

Methods: Lesions with a size of 0.1 cm were categorized as micrometastases, whereas larger lesions were categorized as macrometastases. Susceptibility-weighted imaging findings on locations corresponding to enhancing lesions were categorized as either positive or negative based on presence/absence of signal dropout. The percentage of SWI positivity was then estimated as a function of lesion size. Two-tailed Fisher exact test was performed to examine differences in the contingency tables.

Results: Magnetic resonance imaging studies from 73 patients with 1173 brain metastases, which enhanced on postcontrast T1-weighted imaging (T1WI) were selected for analysis. Of these lesions, 952 had SWI data available, and 342 of 952 were micrometastases. Only 10 of the 342 micrometastases and 410 (67.2%) of the 610 macrometastases were SWI positive (P < 0.0001). When examined by tumor type, 76.9% (melanoma) versus 55.6% (breast cancer) were SWI positive (P < 0.0001), regardless of tumor size. All melanoma lesions (8/8) and only 1 of 15 breast cancer lesions larger than 1.5 cm were SWI positive.

Conclusion: With the use of combined SWI and contrast-enhanced high-resolution T1 imaging, we found that presence of intratumoral brain hemorrhage is uncommon in micrometastases but common in metastases greater than 0.1 cm from breast cancer or melanoma. Large metastases commonly harbored hemorrhage, and this occurred more frequently in patients with melanoma than with breast cancer.
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http://dx.doi.org/10.1097/RCT.0000000000000420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027959PMC
January 2017

Medical Knowledge Assessment by Hematology and Medical Oncology In-Training Examinations Are Better Than Program Director Assessments at Predicting Subspecialty Certification Examination Performance.

J Cancer Educ 2017 Sep;32(3):647-654

Division of Hematology/Oncology, University of Michigan Health System and Veterans Affairs Ann Arbor Health System, C345 Med Inn Building/SPC 5848, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA.

The Accreditation Council for Graduate Medical Education's Next Accreditation System requires training programs to demonstrate that fellows are achieving competence in medical knowledge (MK), as part of a global assessment of clinical competency. Passing American Board of Internal Medicine (ABIM) certification examinations is recognized as a metric of MK competency. This study examines several in-training MK assessment approaches and their ability to predict performance on the ABIM Hematology or Medical Oncology Certification Examinations. Results of a Hematology In-Service Examination (ISE) and an Oncology In-Training Examination (ITE), program director (PD) ratings, demographic variables, United States Medical Licensing Examination (USMLE), and ABIM Internal Medicine (IM) Certification Examination were compared. Stepwise multiple regression and logistic regression analyses evaluated these assessment approaches as predictors of performance on the Hematology or Medical Oncology Certification Examinations. Hematology ISE scores were the strongest predictor of Hematology Certification Examination scores (β = 0.41) (passing odds ratio [OR], 1.012; 95 % confidence interval [CI], 1.008-1.015), and the Oncology ITE scores were the strongest predictor of Medical Oncology Certification Examination scores (β = 0.45) (passing OR, 1.013; 95 % CI, 1.011-1.016). PD rating of MK was the weakest predictor of Medical Oncology Certification Examination scores (β = 0.07) and was not significantly predictive of Hematology Certification Examination scores. Hematology and Oncology ITEs are better predictors of certification examination performance than PD ratings of MK, reinforcing the effectiveness of ITEs for competency-based assessment of MK.
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http://dx.doi.org/10.1007/s13187-016-0993-6DOI Listing
September 2017

Unanticipated hospital admissions during or soon after radiation therapy: Incidence and predictive factors.

Pract Radiat Oncol 2015 May-Jun;5(3):e245-e253. Epub 2014 Sep 17.

Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Electronic address:

Purpose: Unplanned hospital admissions in cancer patients undergoing treatment is an understudied area with important implications for both health care costs and patient outcomes. The goal of this retrospective study was to evaluate the rate, reasons for, and predictors of unplanned hospital admissions during or soon after palliative or curative radiation therapy for cancer, with or without chemotherapy.

Methods And Materials: A total of 1116 consecutive patients who received external beam radiation therapy for a malignancy at the University of North Carolina at Chapel Hill from January 1 through December 31, 2010, were studied. The primary outcome was unplanned hospitalization within 90 days of starting radiation therapy (ie, during or soon after). Multivariable logistic regression was used to examine patient and treatment factors associated with admissions.

Results: Twenty percent of patients experienced an unplanned admission, which was especially likely in patients with lung (25% of such patients admitted), head and neck (22%), and gastrointestinal (21%) cancers, as well as those treated with palliative intent (31%). The most common causes for admission were gastrointestinal symptoms, neurologic symptoms, respiratory symptoms, pain, and fever or infection. Forty-seven percent of admitted patients were seen in the clinic within 2 weeks of unplanned hospital admission, and 61% of those patients had a related complaint in the clinic. Multivariate analysis showed that married patients (odds ratio [OR] = 0.58; P < .001), curative intent (OR = 0.38; P < .001), and no concurrent chemotherapy (OR = 0.55; P < .001) were associated with decreased odds for admission.

Conclusions: Unplanned admissions are relatively common during or soon after radiation therapy in our patient series. Additional work is needed to gather data from other centers and to better understand, and hopefully reduce, these unplanned admissions.
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http://dx.doi.org/10.1016/j.prro.2014.08.004DOI Listing
April 2016

Systematic review: surgery for patients with metastatic melanoma during active treatment with ipilimumab.

Am Surg 2014 Aug;80(8):805-10

Division of Surgical Oncology, Department of Surgery, Maine Medical Center, Portland, Maine, USA.

Studies of ipilimumab have shown improved overall survival in patients with metastatic cutaneous melanoma. As a result, use of ipilimumab in patients with Stage IV melanoma is rapidly increasing. Patients with Stage IV melanoma often require urgent operations for complications from metastases, but little is known about the safety of surgical intervention for patients receiving ipilimumab. We performed a systematic review of the literature using PubMed. Our search terms were melanoma and ipilimumab. We excluded foreign language articles, review articles, and those not addressing cutaneous melanoma. We identified 194 publications matching the search criteria. Only six of those met the inclusion criteria. In these six publications, seven patients who had undergone surgical intervention during treatment with ipilimumab were described. There were no documented surgical complications. We reviewed our institutional experience and identified an additional three patients. No postoperative complications could be attributed directly to ipilimumab. There are limited data on the safety of surgical intervention during treatment with ipilimumab. Preliminary reports suggest there is no reason to withhold or delay surgery for patients receiving ipilimumab therapy.
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August 2014

Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin.

J Clin Oncol 2013 Sep 17;31(26):3182-90. Epub 2013 Jun 17.

F. Stephen Hodi, Anita Giobbie-Hurder, Philip Friedlander, Jason J. Luke, Katherine A. Zukotynski, Jeffrey T. Yap, Annick D. Van den Abbeele, and George D. Demetri, Dana-Farber Cancer Institute; Jonathan A. Fletcher, Meijun Zhu, and Adrian Marino-Enriquez, Brigham and Women's Hospital; Donald Lawrence, Keith T. Flaherty, and David E. Fisher, Massachusetts General Hospital, Boston, MA; Christopher L. Corless, Michael C. Heinrich, and Carol Beadling, Portland Veterans Administration Medical Center and Oregon Health & Science University, Portland, OR; Philip Friedlander, Mount Sinai Medical Center, New York, NY; Rene Gonzalez, University of Colorado Cancer Center, Aurora, CO; Jeffrey S. Weber, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Thomas F. Gajewski, University of Chicago, Chicago, IL; Steven J. O'Day, Beverly Hills Cancer Center, Beverly Hills, CA; Kevin B. Kim, The University of Texas MD Anderson Cancer Center, Houston, TX; Frances A. Collichio, The University of North Carolina at Chapel Hill, Chapel Hill, NC; and Marc S. Ernstoff, Geisel School of Medicine and Norris Cotton Cancer Center, Hanover, NH.

Purpose: Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities.

Patients And Methods: We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy.

Results: Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment.

Conclusion: Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.
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http://dx.doi.org/10.1200/JCO.2012.47.7836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878082PMC
September 2013

Phase II study of bortezomib and pegylated liposomal doxorubicin in the treatment of metastatic breast cancer.

Clin Breast Cancer 2010 Dec;10(6):465-70

The Lineberger Comprehensive Cancer Center, and Division of Hematology/Oncology, School of Medicine, University of North Carolina at Chapel Hill, 170 Manning Drive, Chapel Hill, NC 27599, USA.

Background: Based on preclinical studies and a phase I trial of the combination of bortezomib and pegylated liposomal doxorubicin (PLD), which both showed activity in breast cancer, we conducted a phase II study of this regimen in patients with metastatic breast cancer.

Patients And Methods: Patients received bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of an every-21-day cycle, along with PLD 30 mg/m2 on day 4. The primary objective was to evaluate the response rate of this combination, while secondary objectives were to obtain further safety data about this combination, to evaluate the time to disease progression (TTP), and to evaluate response by the breast cancer subtype.

Results: One of 12 evaluable patients had a partial response (8%), while 3 (25%) had stable disease. At 26 months follow-up, the median overall survival was 4.3 months (95% CI, 1.2-26.2) and the median TTP was 1.3 months (95% CI, 0.8-14.0 months). The combination was well tolerated, with the most common events including low-grade nausea and vomiting, neutropenia, and neuropathy, and no cardiac toxicity was seen. Of the 7 tumors subtyped, no association was seen between intrinsic subtype or receptor status and response.

Conclusion: The combination of PLD and bortezomib was well tolerated but has minimal activity in heavily pretreated unselected metastatic breast cancer.
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http://dx.doi.org/10.3816/CBC.2010.n.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830095PMC
December 2010

How to organize a fellowship program: lessons learned and how to include accreditation council for graduate medical education competencies in the curriculum.

J Clin Oncol 2010 Aug 6;28(22):3659-67. Epub 2010 Jul 6.

Division of Hematology Oncology, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA.

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http://dx.doi.org/10.1200/JCO.2010.28.1964DOI Listing
August 2010

Developing an in-training examination for fellows: the experience of the American Society of Clinical Oncology.

J Clin Oncol 2009 Apr 17;27(10):1706-11. Epub 2009 Feb 17.

Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC 27599-7305, USA.

The American Society of Clinical Oncology (ASCO) developed its own test -- the Medical Oncology In-Training Examination (MedOnc ITE) -- as a tool to assess trainees' knowledge of the clinical oncology subspecialty, establish consistency in educational standards across training programs, identify areas of strength and weakness in individual programs, and stimulate intraprogrammatic reading and discussion. The Accreditation Council for Graduate Medical Education Outcome Project provided additional incentive for ASCO to develop an ITE. The examination was developed in 4 years. The concept of the examination and the budget were approved by the ASCO governing board. The National Board of Medical Examiners was selected to work with ASCO. Fellowship programs were contacted to determine if they had the information technology support to hold the examination. A blueprint for the examination was developed. The test format, including the number of questions and the selection of case-based single best answers, was determined. Physician volunteers to write the questions were solicited from among program directors, various ASCO committees, and disease experts. A workshop was held to teach volunteers how to write proper case-based questions. From this pool, a smaller group of physicians was selected to develop the test and review all test questions. The final examination was developed and administered in February 2008, with scores provided to fellows and program directors in April 2008. Feedback received after the examination will be helpful for developing future MedOnc ITEs. The process ASCO went through to develop the MedOnc ITE serves as a model for other subspecialties interested in developing their own ITEs.
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http://dx.doi.org/10.1200/JCO.2008.20.3091DOI Listing
April 2009

Phase I and pharmacokinetic trial of carboplatin and albumin-bound paclitaxel, ABI-007 (Abraxane) on three treatment schedules in patients with solid tumors.

Cancer Chemother Pharmacol 2007 Oct 7;60(5):759-66. Epub 2007 Feb 7.

Department of Hematology/Oncology, Developmental Therapeutics Group Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.

Purpose: Albumin-bound paclitaxel, ABI-007 (Abraxane((R))), has a different toxicity profile than solvent-based paclitaxel, including a lower rate of severe neutropenia. The combination of ABI-007 and carboplatin may have significant activity in a variety of tumor types including non-small and small cell lung cancer, ovarian cancer, and breast cancer. The purpose of this study was to determine the maximum tolerated dose (MTD) of ABI-007, on three different schedules in combination with carboplatin.

Methods: Forty-one patients with solid tumors were enrolled, and received ABI-007 in combination with carboplatin AUC of 6 on day 1. Group A received ABI-007 at doses ranging from 220 to 340 mg/m(2) on day 1 every 21 days; group B received ABI-007 at 100 or 125 mg/m(2) on days 1, 8, and 15 every 28 days; and group C received ABI-007 125 or 150 mg/m(2) on days 1 and 8 every 21 days. Dose-limiting toxicities were assessed after the first cycle. Doses were escalated in cohorts of three to six patients. Fifteen patients participated in a pharmacokinetic study investigating the effects of the sequence of infusion. ABI-007 was infused first followed by carboplatin in cycle 1, and vice versa in cycle 2.

Results: The MTD of ABI-007 in combination with carboplatin was 300, 100, and 125 mg/m(2) in groups A, B, and C, respectively. Myelosuppression was the primary dose limiting toxicity. No unexpected or new toxicities were reported. Sequence of infusion did not affect either the pharmacokinetics of ABI-007 or the degree of neutropenia. Responses were seen in melanoma, lung, bladder, esophageal, pancreatic, breast cancer, and cancer of unknown primary.

Conclusions: The recommended dose for phase II studies of ABI-007 in combination with carboplatin (AUC of 6) is 300, 100, 125 mg/m(2) for the schedules A, B, and C, respectively. The combination of ABI-007 and carboplatin is well tolerated and active in this heavily pretreated patient population.
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http://dx.doi.org/10.1007/s00280-007-0423-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860386PMC
October 2007

Concomitant pregnancy and breast cancer: options for systemic therapy.

Breast Dis 2005-2006;23:95-101

Department of Medicine, Division of Hematology-Oncology, The University of North Carolina School of Medicine, Chapel Hill, 27599, USA.

Breast cancers diagnosed during pregnancy and lactation typically have an aggressive phenotype and an advanced stage at presentation. The timing of treatment modalities in pregnant women is complex and requires multidisciplinary input. Alternatives which are relatively safe for both mother and fetus are available, though unforeseen risks may exist. Chemotherapy is not thought to be safe for a fetus during the first trimester; however, in women with high risk cancers, treatment should not be delayed. Thereafter, anthracycline based chemotherapy has a low incidence of fetal complications. Little evidence beyond case reports exists for taxanes or tamoxifen in pregnancy, and less is available regarding the safety of novel molecularly targeted therapeutics such as trastuzumab. The prognosis of breast cancer diagnosed during pregnancy and lactation is poor, largely because of advanced stage and aggressive phenotype; it is unclear whether pregnancy is an independent prognostic marker for poor outcome.
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http://dx.doi.org/10.3233/bd-2006-23113DOI Listing
August 2006

High-resolution axillary ultrasound is a poor prognostic test for determining pathologic lymph node status in patients undergoing neoadjuvant chemotherapy for locally advanced breast cancer.

Am J Surg 2004 Oct;188(4):386-9

Department of Surgery, University of North Carolina at Chapel Hill, 3010 Old Clinic Bldg., CB No. 7213, Chapel Hill, NC 27599, USA.

Background: The purpose of this study was to evaluate the efficacy of high-resolution axillary ultrasound in detecting axillary lymph node metastases after neoadjuvant chemotherapy in patients with locally advanced breast cancer.

Methods: Fifty-three patients with stage II or III breast cancer undergoing neoadjuvant chemotherapy who had a physical examination, high-resolution axillary ultrasound, and axillary lymph node dissection from January 1999 to September 2003 were included in this study.

Results: The positive predictive value of the postchemotherapy ultrasound for predicting pathologic nodal involvement was 83%, but the negative predictive value was only 52%. Postchemotherapy physical examination was also poor at predicting pathologic nodal involvement with a positive predictive value of 93% and a negative predictive value of only 58%.

Conclusions: A negative post-neoadjuvant chemotherapy high-resolution axillary ultrasound or physical examination does not predict pathologic node status, and this test has limited value in this setting.
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http://dx.doi.org/10.1016/j.amjsurg.2004.06.022DOI Listing
October 2004

Breaking bad news.

Integr Cancer Ther 2003 Mar;2(1):39-62

Institute for Integrative Cancer Research and Education, 1800 Sherman Ave., Suite 515, Evanston, IL 60201, USA.

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http://dx.doi.org/10.1177/1534735403251273DOI Listing
March 2003

Phase II study of low-dose infusional 5-fluorouracil and paclitaxel (Taxol) given every 2 weeks in metastatic breast cancer.

Am J Clin Oncol 2002 Apr;25(2):194-7

University of North Carolina, Chapel Hill, Chapel Hill, North Carolina 27599, USA

Twenty-one patients with recurrent or metastatic breast cancer were treated with paclitaxel (Taxol) as a 1-hour infusion on day 1 only of a 14-day cycle. This treatment was followed by 5-fluorouracil (5-FU) via a portable home pump, through a central venous catheter at 350 mg/m2 per day over 24 hours for a total of 96 hours, on days 1 to 5 and again on days 8 to 12. Based on reported phase I trials in other organ system cancers, the first 5 patients were treated with paclitaxel at 150 mg/m2 every 2 weeks, but this was associated with excessive toxicity. Subsequent patients received paclitaxel at 135 mg/m2. The FACT-B scale was used to assess quality of life for patients on entry of the study and after three cycles. Treatment was well tolerated, with no grade III or IV hematologic toxicities. Grade III nonhematologic toxicities comprised one patient with fatigue, one with mucositis, and one with diarrhea. Grade IV nonhematologic toxicities included 1 hypersensitivity reaction to paclitaxel. Four of the 16 patients (25%) had pump-related problems resulting in disrupted 5-FU dosing in the home setting. The patients had the following responses to the treatment: complete response 0 (0%), partial response 6 (37.5%), stable disease 4 (25%), progression 4 (25%), unassessable 2 (12.5%)-1 anaphylaxis and 1 thrombocytopenia; overall response rate 6 of 16 (0.37; 95% CI, of 0.57). The median duration of survival was 14 months, 95% CI (5.6-18.24). The FACT-B was assessed in 14 patients at baseline and in 8 patients after 3 cycles. Quality of Life improved in 6 patients, no patients remained stable, and worsened in 2 patients. Biweekly paclitaxel with weekly 4-day continuous infusion 5-FU was associated with minimal toxicity but did not meet the target response rate of 60%. This response rate does not justify use of a complex home infusion of 5-FU.
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http://dx.doi.org/10.1097/00000421-200204000-00020DOI Listing
April 2002