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ABSTRACT: Recurrent head and neck squamous cell carcinoma (HNSCC) remains a difficult cancer to treat. Here, we describe a patient with HNSCC who had complete response to methotrexate (MTX) after progressing on multiple cytotoxic agents, cetuximab, and AMG-479 (monoclonal antibody against insulin-like growth factor-1 receptor [IGF-1R]).
The clinical information was collected by a retrospective medical record review under an Institutional Review Board-approved protocol. From 4 tumors and 2 normal mucosal epithelia, global gene expression, and IGF-1R and dihydrofolate reductase (DHFR) protein levels were determined.
Effective target inhibition in the tumor was confirmed by the decreased protein levels of total and phospho-IGF-1R after treatment with AMG-479. Decreased level of DHFR and conversion of a gene expression profile associated with cetuximab-resistance to cetuximab-sensitivity were also observed.
This suggests that the combination of AMG-479 and MTX or cetuximab may be a promising therapeutic approach in refractory HNSCC.
Head & Neck 12/2011; 33(12):1804-8. · 2.40 Impact Factor
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ABSTRACT: Treatment of the truncal lymphatics prior to treatment of the lymphedematous arm is an accepted, although not empirically tested, therapeutic intervention delivered during decongestive lymphatic therapy (DLT). Breast cancer survivors with arm lymphedema are encouraged to use these techniques when performing simple lymphatic drainage as part of their life-long lymphedema self-care. Self-massage is at times difficult and pneumatic compression devices are used by many patients to assist with self-care. One such device, the Flexitouch(®) System, replicates the techniques used during DLT; however, the need for application of pneumatic compression in unaffected truncal areas to improve self-care outcomes in arm only lymphedema is not established. The objective of this study was to compare the therapeutic benefit of truncal/chest/arm advanced pneumatic compression therapy (experimental group) verses arm only pneumatic compression (control group) in self-care for arm lymphedema without truncal involvement using the Flexitouch(®) System. Outcomes of interest were self-reported symptoms, function, arm impedance ratios, circumference, volume, and trunk circumference. Forty-two breast cancer survivors, (21 per group), with Stage II lymphedema completed 30 days of home self-care using the Flexitouch(®) System. Findings revealed a statistically significant reduction in both the number of symptoms and overall symptom burden within each group; however, there were no statistically significant differences in these outcomes between the groups. There was no statistically significant overall change or differential pattern of change between the groups in function. A statistically significant reduction in bioelectrical impedance and arm circumference within both of the groups was achieved; however, there was no statistically significant difference in reduction between groups. These findings indicate that both configurations are effective, but that there may be no added benefit to advanced pneumatic treatment of the truncal lymphatics prior to arm massage when the trunk is not also affected. Further research is indicated in a larger sample.
Breast Cancer Research and Treatment 09/2011; 131(1):147-58. · 4.43 Impact Factor
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ABSTRACT: This phase 2 trial evaluated the tolerability and clinical efficacy of the combination of oxaliplatin and pemetrexed as an induction chemotherapy regimen in locally advanced head and neck squamous cell carcinoma (HNSCC).
Forty-two patients were enrolled in the study. Patients received pemetrexed 300 mg/m(2) intravenously (IV) and oxaliplatin 85 mg/m(2) IV every 14 days for a total of 4 cycles. A subset of patients consented to correlative studies including tumor tissue for human papillomavirus (HPV) detection and expression of DNA repair genes that may be predictive of response or resistance to oxaliplatin or pemetrexed.
Response data were available for 40 patients. Eighteen had a partial response, and 1 had a complete response, for a response rate of 47.5%. Patients with HPV(+) disease demonstrated superior response rates, progression-free survival, and overall survival. The regimen was well tolerated, with predominantly grade 1 or 2 alanine aminotransferase/aspartate aminotransferase elevation. One patient had grade 5 toxicity with neutropenia and sepsis. The authors did not identify genes predictive of response or toxicity, although HPV(+) tumors demonstrated a unique gene expression signature.
Although the response rate of oxaliplatin and pemetrexed proved less than anticipated, the combination remains an active induction regimen in HNSCC. This regimen should be evaluated further in combination with targeted agents, such as cetuximab, especially in the HPV(+) patient population.
Cancer 07/2011; 118(4):1007-13. · 4.77 Impact Factor
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ABSTRACT: The purpose of this study was to conduct a preliminary, post-market, home study of the Flexitouch(®) system to examine the potential efficacy of the device as a component of self-care in breast cancer survivors with truncal lymphedema.
A quasi-experimental, pre-treatment, post-treatment design was used. Twelve participants received a total of ten self-administered, consecutive, one hour per day treatments. Treatments one and two were observed by study staff and the remaining eight were unobserved. Assessments were conducted at baseline, after the first two treatments, mid-way through therapy, and at the end-of-study. Logs revealed 100% compliance with the eight prescribed unobserved home treatments. Symptoms were assessed by self-report symptom surveys. Signs, objectively observed physical phenomenon, were assessed by staff-initiated skin examination and circumferential truncal measurements. Statistically significant improvement in truncal symptoms and sleep were found. Changes in function and girth were not statistically significant in this initial study.
Breast cancer survivors with truncal lymphedema may benefit from using an advanced pneumatic compression devices with truncal treatment as part of their self-care program. Participants were highly compliant in device use. Further research of this intervention is warranted. To facilitate future research, clinically meaningful reductions in truncal girth should be defined.
Lymphatic Research and Biology 12/2010; 8(4):209-15.
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ABSTRACT: Good cancer pain control requires appropriate assessment and treatment. The purpose of this study was to examine the relationships among physician, nurse practitioner, and nurse knowledge, documentation of assessment, treatment, and pain reduction in cancer patients seen in ambulatory settings.
The study method included an assessment of pain knowledge of providers (physicians, nurse practitioners, and nurses) who worked in cancer clinics and a retrospective review of patients' records treated for cancer-related pain in their clinics. Fifty-eight providers from eight cancer clinics completed the knowledge questionnaire; 56 patient records were reviewed for assessment, treatment, and outcome data. Pain relief, the outcome, was obtained from documentation at the next clinic visit.
Of the 54 patient records that documented pain relief at the next clinic visit, 61.9% reported no relief. Chi square analysis revealed clinics with a higher level of pain knowledge documented a greater number of elements of an ideal pain assessment (p = 0.03) but was unrelated to treatment and pain relief reported. Assessment and treatment were unrelated to reported pain relief at the next clinic visit.
These data suggest that providers' pain knowledge is related to pain assessment but not treatment or outcome. In addition, these data showed no relationship between assessment, treatment prescribed, and pain relief in these ambulatory settings.
Supportive Care in Cancer 10/2010; 19(11):1865-71. · 2.09 Impact Factor
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Christine H Chung,
Erin H Seeley,
Heinrich Roder,
Julia Grigorieva,
Maxim Tsypin,
Joanna Roder,
Barbara A Burtness,
Athanassios Argiris,
Arlene A Forastiere,
Jill Gilbert, Barbara Murphy,
Richard M Caprioli,
David P Carbone,
Ezra E W Cohen
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ABSTRACT: We hypothesized that a serum proteomic profile predictive of survival benefit in non-small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) reflects tumor EGFR dependency regardless of site of origin or class of therapeutic agent.
Pretreatment serum or plasma from 230 patients treated with cetuximab, EGFR-TKIs, or chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC) were analyzed by mass spectrometry. Each sample was classified into "good" or "poor" groups using VeriStrat, and survival analyses of each cohort were done based on this classification. For the CRC cohort, this classification was correlated with the tumor EGFR ligand levels and KRAS mutation status.
In the EGFR inhibitor-treated cohorts, the classification predicted survival (HNSCC: gefitinib, P = 0.007 and erlotinib/bevacizumab, P = 0.02; CRC: cetuximab, P = 0.0065) whereas the chemotherapy cohort showed no survival difference. For CRC patients, tumor EGFR ligand RNA levels were significantly associated with the proteomic classification, and combined KRAS and proteomic classification provided improved survival classification.
Serum proteomic profiling can detect clinically significant tumor dependence on the EGFR pathway in non-small cell lung cancer, HNSCC, and CRC patients treated with either EGFR-TKIs or cetuximab. This classification is correlated with tumor EGFR ligand levels and provides a clinically practical way to identify patients with diverse cancer types most likely to benefit from EGFR inhibitors. Prospective studies are necessary to confirm these findings.
Cancer Epidemiology Biomarkers & Prevention 02/2010; 19(2):358-65. · 4.12 Impact Factor
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Hiromitsu Hatakeyama,
Haixia Cheng,
Pamela Wirth,
Ashley Counsell,
Samuel R Marcrom,
Carey Burton Wood,
Paula R Pohlmann,
Jill Gilbert, Barbara Murphy,
Wendell G Yarbrough,
Deric L Wheeler,
Paul M Harari,
Yan Guo,
Yu Shyr,
Robbert J Slebos,
Christine H Chung
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ABSTRACT: We hypothesized that chronic inhibition of epidermal growth factor receptor (EGFR) by cetuximab, a monoclonal anti-EGFR antibody, induces up-regulation of its ligands resulting in resistance and that microRNAs (miRs) play an important role in the ligand regulation in head and neck squamous cell carcinoma (HNSCC).
Genome-wide changes in gene and miR expression were determined in cetuximab-sensitive cell line, SCC1, and its resistant derivative 1Cc8 using DNA microarrays and RT-PCR. The effects of differentially expressed EGFR ligands and miRs were examined by MTS, colony formation, ELISA, and western blot assays. Heparin-binding EGF-like growth factor (HB-EGF) and its regulator, miR-212, were differentially expressed with statistical significance when SCC1 and 1Cc8 were compared for gene and miR expression. Stimulation with HB-EGF induced cetuximab resistance in sensitive cell lines. Inhibition of HB-EGF and the addition of miR-212 mimic induced cetuximab sensitivity in resistant cell lines. MicroRNA-212 and HB-EGF expression were inversely correlated in an additional 33 HNSCC and keratinocyte cell lines. Six tumors and 46 plasma samples from HNSCC patients were examined for HB-EGF levels. HB-EGF plasma levels were lower in newly diagnosed HNSCC patients when compared to patients with recurrent disease.
Increased expression of HB-EGF due to down-regulation of miR-212 is a possible mechanism of cetuximab resistance. The combination of EGFR ligand inhibitors or miR modulators with cetuximab may improve the clinical outcome of cetuximab therapy in HNSCC.
PLoS ONE 01/2010; 5(9):e12702. · 4.09 Impact Factor
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Anthony W Tolcher,
John Sarantopoulos,
Amita Patnaik,
Kyriakos Papadopoulos,
Chia-Chi Lin,
Jordi Rodon, Barbara Murphy,
Bruce Roth,
Ian McCaffery,
Kevin S Gorski,
Brianne Kaiser,
Min Zhu,
Hongjie Deng,
Greg Friberg,
Igor Puzanov
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ABSTRACT: To determine the maximum-tolerated dose (MTD) and to assess the safety, pharmacokinetics, and evidence of antitumor activity of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1 (IGF-1R).
Patients with advanced solid malignancies or non-Hodgkin's lymphoma received escalating doses of AMG 479 intravenously (IV) every 2 weeks (Q2W). Blood samples were assayed to determine pharmacokinetic parameters and IGF-1R occupancy on neutrophils; fluorodeoxyglucose-positron emission tomography scans were used to assess tumor metabolic effects.
Fifty-three patients received 312 infusions of AMG 479 Q2W. Overall, the most common grades 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. One dose-limiting toxicity (ie, grade 3 thrombocytopenia) occurred in a patient at 20 mg/kg during course 1; grade 3 thrombocytopenia (n = 8) and grade 3 transaminitis elevations (n = 1) also were reported but not in the escalation phase. The maximum-planned dose of 20 mg/kg was safely administered; thus, an MTD was not reached. High levels of neutrophil IGF-1R binding and increases from baseline in serum IGF-1 levels were observed in the 12- and 20-mg/kg cohorts. Tumor responses included one durable complete response (CR) and one unconfirmed partial response (PR) in two patients with Ewing/primitive neuroectodermal tumors and included one PR and one minor response in two patients with neuroendocrine tumors. The patients with Ewing/PNET who had a CR have remained disease free on therapy after 28 months.
AMG 479 can be administered safely at 20 mg/kg IV Q2W. The absence of severe toxicities, attainment of serum concentrations associated with high levels of IGF-1R binding on neutrophils, and provocative antitumor activity warrant additional studies of this agent.
Journal of Clinical Oncology 09/2009; 27(34):5800-7. · 18.37 Impact Factor
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Barbara A Murphy
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ABSTRACT: Head and neck cancer and its therapy are associated with marked symptom burden, functional impairment and decreased quality of life. This review will encompass the recent studies addressing supportive care issues facing head and neck cancer patients.
Although it has long been recognized that head and neck cancer therapy results in significant acute toxicity, it is now becoming recognized that the late effects of therapy are equally problematic. In addition, it is clear that many acute and late effects of therapy, including oral health issues, nutritional deficiencies and the role of physical therapy and rehabilitation, are under recognized and under studied. Although supporting data are scant, allied health professions play a critical role in managing acute and late effects of therapy.
Healthcare providers must take an active role in the evaluation and management of the acute and late effects of therapy. Referral for appropriate supportive care and rehabilitative services is critical in order to minimize the acute and late effects of therapy and to maximize long-term function.
Current opinion in oncology 04/2009; 21(3):242-7. · 4.09 Impact Factor
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ABSTRACT: Taxane-based concurrent chemoradiotherapy (CCR) for head and neck cancers has proven to have a favorable toxicity profile compared with cisplatin and radiation. This phase II multi-institutional trial evaluates taxane-based induction chemotherapy followed by CCR for organ preservation in resectable stage III/IVA and IVB larynx and oropharynx (OP) cancer patients.
Eligibility required resectable stage T2N+, or T3-T4N0-3M0 biopsy-proven squamous carcinoma, age at least 18 years, PS 0 to 2, good organ function, and no prior chemotherapy or radiation. Treatment was induction paclitaxel 175 mg/m(2) and carboplatin area under the concentration-time curve (AUC) 6 for two cycles every 21 days followed by concurrent paclitaxel 30 mg/m(2) every 7 days with 70 Gy if no evidence of tumor progression. Weekly erythropoietin alpha 40 kU was used for suboptimal hemoglobin (< 14 gm/dL men, < 13 gm/dL women). The primary end point was organ preservation (freedom from primary site salvage surgery or primary tumor recurrence).
One hundred five of 111 patients (36 larynx, 69 OP) were eligible. Median follow-up was 36.7 months. Ninety-four percent received full-dose radiotherapy and 91% received at least five cycles of concurrent paclitaxel. No patient progressed while receiving chemotherapy. Organ preservation was 81% at 2 years after completion of therapy (larynx 74%, OP 84%). Thirteen patients required primary-site salvage surgery (seven larynx, six OP), and six of these have progressed and died (three larynx, three OP). Thirteen patients developed distant metastases (seven larynx, six OP; P = .02) and 10 of 36 larynx and 11 of 69 OP patients have died as a result of their disease. Two-year survival is 76% (63% larynx v 83% OP).
A high organ preservation rate was obtained with this regimen for OP but not for larynx patients. Toxicity was low, and induction chemotherapy did not preclude delivery of concurrent chemoradiotherapy.
Journal of Clinical Oncology 10/2007; 25(25):3971-7. · 18.37 Impact Factor
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ABSTRACT: To determine the response rate, survival and toxicity of infusional cisplatin plus fluorouracil (CF) versus cisplatin plus paclitaxel (CP) in patients with incurable squamous cell cancer of the head and neck, with the hypothesis that CP is superior.
Two hundred eighteen patients with locally advanced, recurrent, or metastatic disease were randomly assigned to CF (cisplatin 100 mg/m2 day 1 and fluorouracil 1,000 mg/m2/24 hours by continuous intravenous infusion day 1 through 4) or CP (cisplatin 75 mg/m2 day 1 and paclitaxel 175 mg/m2 over 3 hours on day 1). Cycles were repeated every 3 weeks until progression or a minimum of 6 cycles with complete response or stable disease. The primary outcome was overall survival. Secondary outcomes included response rate and toxicity.
No significant difference in overall survival or response rate was seen. Estimated median survival was 8.7 months in the CF group and 8.1 month in the CP group. Objective response rate (complete response plus partial response) was 27% in the CF group and 26% in the CP group. Toxicity was similar between groups, with the most frequent including myelosuppression, thrombocytopenia, anemia, nausea, vomiting, and stomatitis. A total of 12 deaths occurred (CF, seven; CP, five) during treatment; eight from infection, two from hemorrhage, one from cardiac causes and one from unknown causes. Gastrointestinal and hematologic toxicities were more common in the CF group, whereas neurotoxicity was equivalent between groups.
This phase III, randomized, multicenter trial showed no difference in survival between patients treated with CF or CP.
Journal of Clinical Oncology 06/2005; 23(15):3562-7. · 18.37 Impact Factor
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ABSTRACT: To examine the unique and combined effects of pain intensity, pain-related distress, analgesic prescription, and negative mood on interference with daily life because of pain.
Descriptive, cross-sectional.
Two cancer clinics in academic medical centers in the southeastern United States.
64 ambulatory patients with cancer who had pain that required analgesics.
Participants completed a number of self-report instruments during a regularly scheduled clinic visit. Standard instruments were selected to measure the main research variables.
Worst pain intensity, pain-related distress, analgesic adequacy, negative mood, and interference with daily life.
Patients with higher levels of worst pain, pain-related distress, and negative mood and inadequately prescribed analgesics reported greater interference with daily life because of pain. Multiple regression analysis indicated that interference with daily life was explained by the combination of these four predictors. All variables except negative mood were significant predictors of interference. The unique variance explained by pain-related distress exceeded that explained by worst pain intensity or inadequately prescribed analgesics.
Data suggest that pain-related distress may be an important factor when investigating interference with daily life caused by pain. In addition, pain-related distress may provide a target for future intervention studies aimed at improving the impact of cancer-related pain on daily life.
Assessment of pain-related distress may be important in planning interventions. Common nursing interventions may be employed to reduce pain intensity and pain-related distress, which may result in enhanced physical and emotional well-being.
Oncology Nursing Forum 30(6):977-86. · 1.91 Impact Factor
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ABSTRACT: The primary goal of this single-group study was to determine the safety of a standard opioid titration order sheet to manage pain in ambulatory cancer patients. Secondary goals were to examine opioid toxicity and efficacy of this pain protocol. Twenty-seven patients who required fixed-dose opioids and who had uncontrolled pain were enrolled. All patients had their initial opioid dose titrated by the study physician using the opioid titration order sheet. Data were obtained by the study nurse during a weekly telephone interview and used to determine if pain was controlled. After initial titration, a trained study nurse titrated opioid doses based upon the standing order sheet. At each contact, patients were assessed for adverse effects, pain intensity, and analgesics used. Patients who completed the four-week trial (n = 17) did not differ from patients who did not complete the trial. No adverse effects were observed in 39 opioid titrations completed by the study nurse. Opioid toxicities, worst pain, usual pain, and pain-related distress declined from baseline to week four Patients who were adherent to their prescribed medications reported significantly lower pain intensity and distress (ps < or = . 06). The opioid titration order sheet, used by a trained nurse, is safe to use in ambulatory cancer patients who have moderate to severe pain. Common opioid toxicities were reduced. The protocol also demonstrated initial efficacy in improving worst and usual pain and pain-related distress. Further research to establish efficacy of the protocol is recommended.
American Journal of Hospice and Palliative Medicine 21(5):373-80. · 1.15 Impact Factor
