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Dr. A Colevas, MD
Internist
21 years of experience
Video profile
Accepting new patients

Education ?

Medical School Score Rankings
Johns Hopkins University (1989)
  • Currently 4 of 4 apples
Top 25%
Residency
Johns Hopkins Hospital (1992) *
Fellowship
Dana-Farber Cancer Institute (1995) *
* This information was reported to Vitals by the doctor or doctor's office.

Awards & Distinctions ?

Appointments
Stanford Medical School
Associate Professor of Medicine, 2007
Harvard Medical School
Assistant Professor in Medicine, 2000
Harvard Medical School, 1995
Instructor in Medicine
Associations
American Board of Internal Medicine
American Society of Clinical Oncology

Affiliations ?

Dr. Colevas is affiliated with 2 hospitals.

Hospital Affilations

Score

Rankings

  • Stanford Hospital and Clinics
    Medical Oncology
    300 Pasteur Dr, Stanford, CA 94305
    • Currently 4 of 4 crosses
    Top 25%
  • Stanford University Hospital
  • Publications & Research

    Dr. Colevas has contributed to 56 publications.
    Title National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Head and Neck Cancers.
    Date November 2011
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    Title A Phase Ii First-line Study of Gemcitabine, Carboplatin, and Bevacizumab in Advanced Stage Nonsquamous Non-small Cell Lung Cancer.
    Date February 2011
    Journal Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
    Excerpt

    Bevacizumab improves responses and progression-free survival when added to first-line paclitaxel/carboplatin or cisplatin/gemcitabine for patients with advanced nonsquamous non-small cell lung cancer. This study was designed to evaluate toxicities and efficacy of gemcitabine/carboplatin/bevacizumab.

    Title Higher Incidence of Head and Neck Cancers Among Vietnamese American Men in California.
    Date February 2011
    Journal Head & Neck
    Excerpt

    Our aim was to determine the incidence rates of head and neck cancer in Vietnamese Californians compared with other Asian and non-Asian Californians.

    Title Molecular and Clinical Responses in a Pilot Study of Gefitinib with Paclitaxel and Radiation in Locally Advanced Head-and-neck Cancer.
    Date May 2010
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    Epidermal growth factor receptor (EGFR) overexpression in head-and-neck squamous cell carcinoma (HNSCC) stimulates tumor cell proliferation, inhibits apoptosis, and increases chemotherapy and radiation resistance. We examined the toxicity, safety and the effects on EGFR signaling in tumor biopsy samples from patients with locally advanced HNSCC treated with the EGFR signaling inhibitor gefitinib (GEF) combined with weekly intravenous paclitaxel (PAC) and radiation therapy (RT).

    Title Long-term Outcomes and Toxicity of Concurrent Paclitaxel and Radiotherapy for Locally Advanced Head-and-neck Cancer.
    Date July 2009
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    To report the long-term outcomes and toxicity of a regimen of infusion paclitaxel delivered concurrently with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck.

    Title Phase Ii Study of Ispinesib in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck.
    Date July 2008
    Journal Investigational New Drugs
    Excerpt

    Ispinesib (SB-715992) inhibits the mitotic kinesin spindle protein (KSP), a novel target for anticancer therapy. A phase II study was conducted to examine the efficacy of ispinesib in recurrent or metastatic head and neck squamous cell carcinoma (RMHNSC). Patients with up to one prior line of chemotherapy for RMHNSC were treated with ispinesib 18 mg/m2 IV over 1 hour every 21 days. Twenty-one patients were enrolled onto this study with a target stage I sample size of 19. Of 20 evaluable patients, no objective responses were seen and stable disease > 2 cycles was observed in five patients (25%). The median time to progression was 1.4 (95% CI 1.3-2.3) months, median survival was 3.5 (95% CI 2.8-7.8) months, and 1 year overall survival was 20% (95% CI 8.3-48.1%). The most frequent attributable grades III-V adverse events were neutropenia (60% of patients) and leukopenia (55%). The pharmacokinetic profile was consistent with results from phase I studies. Archival tissues (n = 14) demonstrated low to moderate KSP expression by immunohistochemistry. In addition, no pharmacodynamic changes were observed in peripheral blood mononuclear cells. We detected no antitumor activity of ispinesib in RMHNSC on this dosing schedule.

    Title A Phase Ii Study of Ixabepilone (bms-247550) in Metastatic Renal-cell Carcinoma.
    Date December 2007
    Journal Cancer Biology & Therapy
    Excerpt

    INTRODUCTION: Ixabepilone (BMS-247550) is a semi-synthetic analog of epothilone B that has been characterized as a microtubule stabilizing agent with a mechanism of action distinct from taxanes. Suggestion of activity in renal cell carcinoma (RCC) has been seen in early clinical studies. METHODS: Eligible patients had metastatic RCC as well as ECOG performance status 0-2 and normal organ function. Patients received ixabepilone at a dose of 40 mg/m2 intravenously over three hours every 21 days. There was no restriction on RCC histology or prior treatment type, but prior treatment with tubule inhibitors was not allowed. The primary endpoint was RECIST defined response and radiographic evaluations were performed every three cycles. Toxicity evaluations utilized CTCAE v3.0 and were performed every cycle. Using a Simon two-stage optimal design with alpha = 0.1, beta = 0.1, a null hypothesized response rate of 0.05 and an alternative response rate of 0.2, an initial 12 patients were to be accrued with full accrual of 37 patients if at least one response were observed. RESULTS: A median of five cycles were administered. No objective responses were observed in the first 12 evaluable patients, and six patients showed stable disease for more than 18 weeks on therapy. Median time to progression among those with objective progression was nine weeks. One patient experienced grade 4 anemia and lymphopenia. Grade 3 adverse events included lymphopenia, neutropenia, leukopenia, diarrhea, and infection. Common grade 2 toxicities included alopecia, fatigue and anemia. CONCLUSION: Ixabepilone administered at a dose of 40 mg/m2 every 21 days should not be advanced for further study in metastatic RCC. Given previous results, however, other dosing schedules may be worthy of further investigation.

    Title Patient-reported Outcomes and the Evolution of Adverse Event Reporting in Oncology.
    Date November 2007
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    Adverse event (AE) reporting in oncology has evolved from informal descriptions to a highly systematized process. The Common Terminology Criteria for Adverse Events (CTCAE) is the predominant system for describing the severity of AEs commonly encountered in oncology clinical trials. CTCAE clinical descriptors have been developed empirically during more than 30 years of use. The method of data collection is clinician based. Limitations of the CTC system include potential for incomplete reporting and limited guidance on data analysis and presentation methods. The Medical Dictionary for Regulatory Activities (MedDRA) is a comprehensive medical terminology system used for regulatory reporting and drug labeling. MedDRA does not provide for severity ranking of AEs. CTC-based data presentations are the primary method of AE data reporting used in scientific journals and oncology meetings. Patient-reported outcome instruments (PROs) cover the subjective domain of AEs. Exploratory work suggests PROs can be used with a high degree of patient engagement and compliance. Additional studies are needed to determine how PROs can be used to complement current AE reporting systems. Potential models for integrating PROs into AE reporting are described in this review. AE reporting methods will continue to evolve in response to changing therapies and growing interest in measuring the impact of cancer treatment on health status. Although integration of PROs into AE reporting may ultimately improve the comprehensiveness and quality of collected data, it may also increase the administrative burden and cost of conducting trials. Therefore, care must be used when developing health outcomes and safety data collection plans.

    Title Cisplatin and Fluorouracil Alone or with Docetaxel in Head and Neck Cancer.
    Date October 2007
    Journal The New England Journal of Medicine
    Excerpt

    BACKGROUND: A randomized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) with cisplatin and fluorouracil (PF), followed by chemoradiotherapy. METHODS: We randomly assigned 501 patients (all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were candidates for organ preservation) to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week. The primary end point was overall survival. RESULTS: With a minimum of 2 years of follow-up (> or =3 years for 69% of patients), significantly more patients survived in the TPF group than in the PF group (hazard ratio for death, 0.70; P=0.006). Estimates of overall survival at 3 years were 62% in the TPF group and 48% in the PF group; the median overall survival was 71 months and 30 months, respectively (P=0.006). There was better locoregional control in the TPF group than in the PF group (P=0.04), but the incidence of distant metastases in the two groups did not differ significantly (P=0.14). Rates of neutropenia and febrile neutropenia were higher in the TPF group; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group. CONCLUSIONS: Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy. (ClinicalTrials.gov number, NCT00273546 [ClinicalTrials.gov].).

    Title Sequential Flavopiridol, Cytosine Arabinoside, and Mitoxantrone: a Phase Ii Trial in Adults with Poor-risk Acute Myelogenous Leukemia.
    Date October 2007
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: Flavopiridol is a cyclin-dependent kinase inhibitor that is cytotoxic to leukemic blasts. In a phase I study of flavopiridol followed by 1-beta-d-arabinofuranosylcytosine (ara-C) and mitoxantrone, overall response rate for adults with relapsed and refractory acute myelogenous leukemias (AML) was 31%. We have now completed a phase II study of sequential flavopiridol, ara-C, and mitoxantrone in 62 adults with poor-risk AML. EXPERIMENTAL DESIGN: Flavopiridol (50 mg/m(2)) was given by 1-h infusion daily x 3 beginning day 1 followed by 2 gm/m(2)/72 h ara-C beginning day 6 and 40 mg/m(2) mitoxantrone on day 9. RESULTS: Flavopiridol caused a > or =50% decrease in peripheral blood blasts in 44% by median day 2 and > or =80% decrease in 26% by day 3. Self-limited tumor lysis occurred in 53%. Three (5%) died during therapy (2 multiorgan failure and 1 fungal pneumonia). Complete remissions (CR) were achieved in 12 of 15 (75%) newly diagnosed secondary AML, 18 of 24 (75%) first relapse after short CR (median CR, 9 months, including prior allotransplant), and 2 of 13 (15%) primary refractory but 0 of 10 multiply refractory AML. Disease-free survival for all CR patients is 40% at 2 years, with newly diagnosed patients having a 2-year disease-free survival of 50%. CONCLUSIONS: Flavopiridol has anti-AML activity directly and in combination with ara-C and mitoxantrone. This timed sequential regimen induces durable CRs in a significant proportion of adults with newly diagnosed secondary AML (including complex cytogenetics) and adults with AML in first relapse after short first CR.

    Title Flavopiridol Administered Using a Pharmacologically Derived Schedule is Associated with Marked Clinical Efficacy in Refractory, Genetically High-risk Chronic Lymphocytic Leukemia.
    Date August 2007
    Journal Blood
    Excerpt

    Despite promising preclinical studies with the cyclin-dependent kinase inhibitor flavopiridol in chronic lymphocytic leukemia (CLL) and other diseases, previous clinical trials with this agent have been disappointing. The discovery of differential protein binding of flavopiridol in human and bovine serum contributed to an effective pharmacokinetic-derived schedule of administration of this agent. On the basis of pharmacokinetic modeling using our in vitro results and data from a previous trial, we initiated a phase 1 study using a 30-minute loading dose followed by 4 hours of infusion administered weekly for 4 of 6 weeks in patients with refractory CLL. A group of 42 patients were enrolled on 3 cohorts (cohort 1, 30 mg/m2 loading dose followed by 30 mg/m2 4-hour infusion; cohort 2, 40 mg/m2 loading dose followed by 40 mg/m2 4-hour infusion; and cohort 3, cohort 1 dose for treatments 1 to 4, then a 30 mg/m2 loading dose followed by a 50 mg/m2 4-hour infusion). The dose-limiting toxicity using this novel schedule was hyperacute tumor lysis syndrome. Aggressive prophylaxis and exclusion of patients with leukocyte counts greater than 200x10(9)/L have made this drug safe to administer at the cohort 3 dose. Of the 42 patients treated, 19 (45%) achieved a partial response with a median response duration that exceeds 12 months. Responses were noted in patients with genetically high-risk disease, including 5 (42%) of 12 patients with del(17p13.1) and 13 (72%) of 18 patients with del(11q22.3). Flavopiridol administered using this novel schedule has significant clinical activity in refractory CLL. Patients with bulky disease and high-risk genetic features have achieved durable responses, thereby justifying further study of flavopiridol in CLL and other diseases.

    Title A Phase I Trial of Bms-247550 (nsc# 710428) and Gemcitabine in Patients with Advanced Solid Tumors.
    Date August 2007
    Journal Investigational New Drugs
    Excerpt

    The purpose of this study is to establish the maximum tolerated dose and define the dose-limiting toxicity of the investigational epothilone BMS-247550 in combination with fixed dose-rate gemcitabine. Patients with advanced, recurrent solid tumors who had received <or=2 prior cytotoxic regimens for recurrent disease were treated with gemcitabine over 90 min on days 1 and 8 plus BMS-247550 over 3 h on day 8, every 21 days in a phase I study. Dose-limiting toxicity definitions were based on severe myelosuppression, or grade 3 or 4 treatment-related non-hematologic toxicity, or dose delay of greater than 2 weeks due to treatment toxicity observed in the first treatment cycle. Dose cohort 1 received gemcitabine 900 mg/m2 and BMS-247550 20 mg/m2. Grade 4 neutropenia lasting >or=7 days occurred in one of six patients. Two of three patients in cohort 2 (gemcitabine 900 mg/m2 plus BMS-247550 30 mg/m2) had dose-limiting toxicities of grade 4 neutropenia. An additional three patients were treated at dose level 1 with no additional dose-limiting toxicities observed. At an intermediate dose level (gemcitabine 750 mg/m2 plus BMS-247550 30 mg/m2), two of six patients experienced a dose-limiting toxicity (febrile neutropenia and grade 3 hypophosphatemia in 1, grade 3 hypophosphatemia and grade 3 hyponatremia in (1), and five of six patients experienced dose delays. In the final cohort (gemcitabine 750 mg/m2 plus BMS-247550 25 mg/m2), two of two patients experienced a dose-limiting toxicity. Treatment-related toxicities included neutropenia, thrombocytopenia, neutropenic fever, hypophosphatemia, and hyponatremia. Nine of 14 patients evaluable for response had stable disease. The maximum tolerated dose for this schedule is gemcitabine 900 mg/m2 over 90 min days 1 and 8 plus BMS-247550 20 mg/m2 on day 8. Attempts to increase the dose of BMS-247550 by decreasing the gemcitabine dose did not sufficiently ameliorate myelosuppression. Stable disease was observed in some patients with prior taxane exposure.

    Title Inhibition of Poly(adp-ribose) Polymerase Enhances Cell Death and Improves Tumor Growth Delay in Irradiated Lung Cancer Models.
    Date August 2007
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: Poly(ADP-ribose) polymerase-1 (PARP-1) is the founding member of a family of enzymes that catalyze the addition of ADP-ribose units to proteins that mediate DNA repair pathways. Ionizing radiation induces DNA strand breaks, suggesting that PARP-1 inhibition may sensitize tumor cells to radiation. EXPERIMENTAL DESIGN: We investigated the combination of PARP-1 inhibition with radiation in lung cancer models. ABT-888, a novel potent PARP-1 inhibitor, was used to explore the effects of PARP-1 inhibition on irradiated tumors and tumor vasculature. RESULTS: ABT-888 reduced clonogenic survival in H460 lung cancer cells, and inhibited DNA repair as shown by enhanced expression of DNA strand break marker histone gamma-H2AX. Both apoptosis and autophagy contributed to the mechanism of increased cell death. Additionally, ABT-888 increased tumor growth delay at well-tolerated doses in murine models. For a 5-fold increase in tumor volume, tumor growth delay was 1 day for ABT-888 alone, 7 days for radiation alone, and 13.5 days for combination treatment. Immunohistochemical staining of tumor sections revealed an increase in terminal deoxyribonucleotide transferase-mediated nick-end labeling apoptotic staining, and a decrease in Ki-67 proliferative staining after combination treatment. Matrigel assay showed a decrease in in vitro endothelial tubule formation with ABT-888/radiation combination treatment, and von Willebrand factor staining of tumor sections revealed decreased vessel formation in vivo, suggesting that this strategy may also target tumor angiogenesis. CONCLUSIONS: We conclude that PARP-1 inhibition shows promise as an effective means of enhancing tumor sensitivity to radiation, and future clinical studies are needed to determine the potential of ABT-888 as a radiation enhancer.

    Title Phase I and Correlative Biology Study of Cilengitide in Patients with Recurrent Malignant Glioma.
    Date May 2007
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: This multi-institutional phase I trial was designed to determine the maximum-tolerated dose (MTD) of cilengitide (EMD 121974) and to evaluate the use of perfusion magnetic resonance imaging (MRI) in patients with recurrent malignant glioma. PATIENTS AND METHODS: Patients received cilengitide twice weekly on a continuous basis. A treatment cycle was defined as 4 weeks. Treatment-related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity of any duration. RESULTS: A total of 51 patients were enrolled in cohorts of six patients to doses of 120, 240, 360, 480, 600, 1,200, 1,800, and 2,400 mg/m2 administered as a twice weekly intravenous infusion. Three patients progressed early and were inevaluable for toxicity assessment. The DLTs observed were one thrombosis (120 mg/m2), one grade 4 joint and bone pain (480 mg/m2), one thrombocytopenia (600 mg/m2) and one anorexia, hypoglycemia, and hyponatremia (800 mg/m2). The MTD was not reached. Two patients demonstrated complete response, three patients had partial response, and four patients had stable disease. Perfusion MRI revealed a significant relationship between the change in tumor relative cerebral blood flow (rCBF) from baseline and area under the plasma concentration versus time curve after 16 weeks of therapy. CONCLUSION: Cilengitide is well tolerated to doses of 2,400 mg/m2, durable complete and partial responses were seen in this phase I study, and clinical response appears related to rCBF changes.

    Title Phase I Study of Continuous Weekly Dosing of Dimethylamino Benzoylphenylurea (bpu) in Patients with Solid Tumours.
    Date March 2007
    Journal European Journal of Cancer (oxford, England : 1990)
    Excerpt

    A phase I study of dimethylamino benzoylphenylurea (BPU), a tubulin inhibitor, was performed using a weekly continuous schedule. Patients with refractory solid tumours received oral BPU once weekly without interruption at doses ranging from 5 to 320mg using an accelerated titration design. Nineteen subjects received 54 cycles of BPU. Early pharmacokinetic findings of decreased clearance with increasing dose and plasma accumulation led to the expansion of the 320mg dose level. Two subjects then developed late haematologic dose-limiting toxicities (DLTs) that were associated with the highest plasma exposure to BPU and metabolites. Study enrollment resumed at dose 150mg with real-time pharmacokinetic monitoring. Seven additional subjects (6 evaluable) were treated for a median of 2 cycles (range 1.5-4) without further myelotoxicity. A long half-life and accumulation of BPU and active metabolites were observed, recommending against a continuous administration. Weekly oral BPU therapy should be further tested using an interrupted schedule.

    Title Adverse Event Reporting in Publications Compared with Sponsor Database for Cancer Clinical Trials.
    Date September 2006
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: Prospectively planned collection and analysis of adverse event (AE) data are essential parts of well-conducted clinical trials. The AE data in a trial sponsor's database should be comparable with what is stipulated in the protocol and with the AE data published. We examined whether the published AE data differ from those in the sponsor's database and from the data collection requirements stated in study protocols. METHODS: We searched the National Cancer Institute (NCI) Clinical Data Update System (CDUS) for studies that used the Common Toxicity Criteria version 2.0 and for which a final study publication was available. We extracted from the protocols information pertaining to AE collection and reporting methods and compared it with the methods cited in the article. We also compared the AE data in the trial publication with the AE data submitted by the investigators to CDUS. RESULTS: We identified 22 studies meeting the criteria for this review. There was considerable inconsistency between AE collection and reporting methods cited in the protocols versus final publications. AE data in the article and CDUS were not identical. Twenty-seven percent of article high-grade AEs could not be matched to agent-attributable AEs in the CDUS. Twenty-eight percent of CDUS high-grade AEs could not be matched to AEs in the corresponding article. In 14 of 22 articles, the number of high-grade AEs in CDUS differed from the number in the articles by 20% or more. CONCLUSION: Lack of consistency in and reporting of AEs are associated with NCI database and trial publication AE data discrepancy.

    Title Phase Ii Evaluations of Cilengitide in Asymptomatic Patients with Androgen-independent Prostate Cancer: Scientific Rationale and Study Design.
    Date September 2006
    Journal Clinical Genitourinary Cancer
    Excerpt

    Two randomized trials demonstrated an improvement in survival with docetaxel-based chemotherapy for patients with metastatic, androgen-independent prostate disease. However, the effect of current therapy is suboptimal in that it is complicated by toxicities and has no curative potential. Cilengitide (EMD121974; NSC 707544), is a potent selective alphavbeta3 and alphavbeta5 integrin antagonist. Integrins are cell surface receptors that mediate a variety of cell activities including endothelial cell proliferation and migration. Blocking the ligation of integrins by antagonists promotes apoptosis of proliferative angiogenic cells, thereby suspending new blood vessel formation, which is essential for the growth of malignant disease. In prostate cancer specifically, integrins are known to be involved in metastases with differential expression on tumor cells. Tumors and vascular endothelial cells produce factors, such as vascular endothelial growth factor and basic fibroblast growth factor, that promote neovascularization, which has been implicated in prostate cancer progression. Cilengitide has been shown to inhibit alphavbeta3- and alphavbeta5-mediated cell adhesion and block in vitro endothelial cell migration. In vivo experiments demonstrated that cilengitide inhibited cytokine-induced basic fibroblast growth factor- and vascular endothelial growth factor-mediated angiogenesis in a dose-dependent manner. Cilengitide also inhibited tumor growth in various in vivo systems. Two Cancer Therapy Evaluation Program-sponsored, multicenter, phase II trials are designed to evaluate the safety and efficacy of this agent in patients with androgen-independent prostate cancer. National Cancer Institute trial 6735 is evaluating cilengitide at 2000 mg in patients with nonmetastatic androgen-independent prostate cancer, and National Cancer Institute trial 6372 is evaluating 2 dose levels of cilengitide, 500 mg or 2000 mg, intravenously twice weekly in patients with metastatic prostate cancer.

    Title Chemotherapy Options for Patients with Metastatic or Recurrent Squamous Cell Carcinoma of the Head and Neck.
    Date September 2006
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    The purpose of this review is to provide readers with guidance concerning treatment of patients with advanced, recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) in the context of clinical trial data. We discuss issues surrounding the treatment of patients with SCCHN, with an emphasis on recommendations based on results from phase II and III clinical trials published since 1980. Many options exist for the treatment of patients with SCCHN. The most important decisions involve determining which patients are in need of treatment and which are most likely to benefit from treatment. Although many chemotherapy treatments have been shown to induce responses, survival improvement remains an unfulfilled goal. Definitive data do not exist on the effects of chemotherapy on quality of life or progression-free survival as measures of clinical benefit in this setting. Performance status, history of prior treatment, extent of tumor, and need for palliation are the most important factors in the decision to treat a patient with chemotherapy for incurable SCCHN. Single-agent treatment with conventional doses of methotrexate remains a standard for most patients with advanced, recurrent or metastatic SCCHN. Cisplatin plus fluorouracil, cisplatin plus a taxane, and single-agent taxane are the most widely studied alternatives. There is a need for further trials with end points other than overall survival or tumor response in this patient population. Guidelines for patient selection and treatment options are provided.

    Title Ixabepilone (epothilone B Analogue Bms-247550) is Active in Chemotherapy-naive Patients with Hormone-refractory Prostate Cancer: a Southwest Oncology Group Trial S0111.
    Date February 2006
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: The epothilones are a new class of tubulin-polymerizing agents with activity in taxane-sensitive and resistant tumor models. We evaluated ixabepilone (BMS-247550) in patients with metastatic hormone-refractory prostate cancer (HRPC). METHODS: Eligible patients had chemotherapy-naive metastatic HRPC, a Zubrod performance status of 0 to 2, and adequate organ function. All patients received BMS-247550 at 40 mg/m2 over 3 hours every 3 weeks. The primary end point was proportion of patients achieving a prostate-specific antigen (PSA) response. RESULTS: Forty-eight patients with metastatic HRPC were registered. Forty-two patients were eligible, with a median age of 73 years and a median PSA level of 111 ng/mL; 78% had bone-only or bone and soft tissue metastases, and 88% had objective radiologic disease progression at registration. Grade 3 and 4 adverse events (AEs) occurred in 16 and three patients, respectively. All grade 4 toxicities were neutropenia or leukopenia. The most frequent grade 3 AEs were neuropathy (eight patients), hematologic toxicity (seven patients), flu-like symptoms, and infection (five patients each). There were no grade 3/4 thrombocytopenia or grade 5 AEs. There were 14 confirmed PSA responses (33%; 95% CI, 20% to 50%); 72% of PSA responders had declines greater than 80%, and two patients achieved an undetectable PSA. The estimated median progression-free survival is 6 months (95% CI, 4 to 8 months), and the median survival is 18 months (95% CI, 13 to 24 months). CONCLUSION: Ixabepilone has demonstrated activity in patients with chemotherapy-naive metastatic HRPC. Major toxicities were neutropenia and neuropathy. Further testing to define its activity relative to standard therapy is warranted.

    Title Phase I and Pharmacokinetic Study of Flavopiridol Followed by 1-beta-d-arabinofuranosylcytosine and Mitoxantrone in Relapsed and Refractory Adult Acute Leukemias.
    Date January 2006
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: The serine/threonine kinase inhibitor flavopiridol targets multiple cyclin-dependent kinases, induces checkpoint arrest, and interrupts transcriptional elongation. We designed a phase I clinical trial using a timed sequential therapy approach where flavopiridol was given for the dual purpose of initial cytoreduction and enhancing cell cycle progression of the remaining leukemia cell cohort followed by cycle-dependent drugs 1-beta-D-arabinofuranosylcytosine (ara-C) and mitoxantrone. EXPERIMENTAL DESIGN: Flavopiridol was given by 1-hour infusion daily for 3 days beginning day 1 followed by 2 g/m2/72 h ara-C beginning day 6 and 40 mg/m2 mitoxantrone beginning day 9. In vivo correlates included pharmacokinetics, modulation of blast cycle regulators, and serum and marrow supernatant vascular endothelial growth factor levels. RESULTS: Of 34 adults receiving induction therapy, 16 (47%) evinced direct leukemia cytotoxicity with > or =50% drop in peripheral blast counts and tumor lysis in 9 (26%). Four (12%) died during therapy (two fungal infections and two sudden death). Dose-limiting toxicity occurred at 60 mg/m2/d with profound neutropenia >40 days duration, and maximal tolerated dose was 50 mg/m2/d. Overall response rate was 31% in 26 acute myelogenous leukemia and 12.5% in acute lymphoblastic leukemia. Pharmacokinetics showed that a linear two-compartment model with first-order elimination provided the best fit of the observed concentration versus time data. Flavopiridol down-regulated one or more target proteins in marrow blasts in vivo. Vascular endothelial growth factor was detected in sera and marrow supernatant pretreatment, and sera obtained on day 3 inhibited bovine aortic endothelial cell proliferation by a mean of 32% (range, 10-80%). CONCLUSIONS: Our data suggest that flavopiridol is cytotoxic to leukemic cells and, when followed by ara-C and mitoxantrone, exerts biological and clinical effects in patients with relapsed and refractory acute leukemias. These findings warrant continuing development of flavopiridol at 50 mg/m2/d x 3 days in combination with cytotoxic and biological agents for acute leukemias.

    Title In Vitro and in Vivo Clinical Pharmacology of Dimethyl Benzoylphenylurea, a Novel Oral Tubulin-interactive Agent.
    Date January 2006
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    Dimethyl benzoylphenylurea (BPU) is a novel tubulin-interactive agent with poor and highly variable oral bioavailability. In a phase I clinical trial of BPU, higher plasma exposure to BPU and metabolites was observed in patients who experienced dose-limiting toxicity. The elucidation of the clinical pharmacology of BPU was sought. BPU, monomethylBPU, and aminoBPU were metabolized by human liver microsomes. Studies with cDNA-expressed human cytochrome P450 enzymes revealed that BPU was metabolized predominantly by CYP3A4 and CYP1A1 but was also a substrate for CYP2C8, CYP2D6, CYP3A5, and CYP3A7. BPU was not a substrate for the efflux transporter ABCG2. Using simultaneous high-performance liquid chromatography/diode array and tandem mass spectrometry detection, we identified six metabolites in human liver microsomes, plasma, or urine: monomethylBPU, aminoBPU, G280, G308, G322, and G373. In patient urine, aminoBPU, G280, G308, and G322 collectively represented <2% of the given BPU dose. G280, G308, G322, and G373 showed minimal cytotoxicity. When BPU was given p.o. to mice in the presence and absence of the CYP3A and ABCG2 inhibitor, ritonavir, there was an increase in BPU plasma exposure and decrease in metabolite exposure but no overall change in cumulative exposure to BPU and the cytotoxic metabolites. Thus, we conclude that (a) CYP3A4 and CYP1A1 are the predominant cytochrome P450 enzymes that catalyze BPU metabolism, (b) BPU is metabolized to two cytotoxic and four noncytotoxic metabolites, and (c) ritonavir inhibits BPU metabolism to improve the systemic exposure to BPU without altering cumulative exposure to BPU and the cytotoxic metabolites.

    Title Phase I Trial and Pharmacokinetics of Escalating Doses of Paclitaxel and Concurrent Hyperfractionated Radiotherapy with or Without Amifostine in Patients with Advanced Head and Neck Carcinoma.
    Date November 2005
    Journal Cancer
    Excerpt

    BACKGROUND: Amifostine was developed to protect normal tissues from radiation exposure. The current study was undertaken to determine whether amifostine would allow the delivery of greater numbers of weekly paclitaxel treatments with concomitant, hyperfractionated radiotherapy in patients with advanced head and neck carcinoma. METHODS: Patients received radiation therapy twice daily using 1.6-gray (Gy) fractions up to a total of 70.4 Gy over an elapsed time of 6.5 weeks. All patients received paclitaxel 60 mg/m(2) once weekly starting on Day 1. The number of doses of paclitaxel was escalated from three to a maximum of six in groups of three patients. For the patients who received amifostine, a dose of 400 mg/m(2) was given intravenously over 15 minutes on Days 1-5, 8, 29-33, and 36. Patients underwent surgery for persistent tumor after radiotherapy. The plasma pharmacokinetics of paclitaxel were characterized during treatment with the first weekly dose to determine the effect of concurrently administered amifostine. RESULTS: Thirty-six patients were evaluable for this study. In the absence of amifostine, a maximum of four doses of paclitaxel were tolerated in combination with the radiotherapy. With amifostine, up to five doses of paclitaxel could be given. Generally, the treatment resulted in Grade 2 and 3 stomatitis. Overall, 69% of patients had a complete remission, and 29% had a partial remission. Both progression-free survival and overall survival were 66% at 30 months. Amifostine had no effect on the pharmacokinetics of paclitaxel. CONCLUSIONS: The administration of amifostine allowed the authors to give an additional dose of paclitaxel to patients who were undergoing hyperfractionated radiotherapy for head and neck carcinoma. This treatment regimen resulted in a high frequency of complete remissions and an excellent progression-free survival pattern without compromising the plasma kinetics of paclitaxel.

    Title Clinical Trials Referral Resource. Current Clinical Trials of Cilengitide, an Alpha(v) Antagonist in Clinical Development As an Anticancer Agent.
    Date April 2005
    Journal Oncology (williston Park, N.y.)
    Title Multi-institutional Randomized Phase Ii Trial of the Epothilone B Analog Ixabepilone (bms-247550) with or Without Estramustine Phosphate in Patients with Progressive Castrate Metastatic Prostate Cancer.
    Date March 2005
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5. RESULTS: Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm. CONCLUSION: Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

    Title Phase Ii Trial of Flavopiridol, a Cyclin Dependent Kinase Inhibitor, in Untreated Metastatic Malignant Melanoma.
    Date November 2004
    Journal Investigational New Drugs
    Excerpt

    PURPOSE: To test the activity of the cyclin dependent kinase (cdk) inhibitor flavopiridol in malignant melanoma, a disease with frequent abnormalities of the cyclin dependent kinase system. PATIENTS AND METHODS: Patients had histologically proven, unidimensionally measurable malignant melanoma, incurable by standard therapy. Prior adjuvant immunotherapy was allowed, but patients were otherwise untreated for advanced disease. Flavopiridol was administered at a dose of 50 mg/m(2) IV over 1 hour daily x 3 days every 3 weeks. Patients were assessed for response every 2 cycles. RESULTS: 17 patients were accrued over 5 months. No objective responses were documented in the 16 patients evaluable for response. Seven patients (44%) had stable disease after 2 cycles, with a median of 2.8 months (range 1.8-9.2). The most common treatment-related non-hematologic toxicities were diarrhea (82%), nausea (47%), fatigue (41%), anorexia (35%) and vomiting (29%). Most treatment-related toxicities were mild, except for diarrhea (grade 3 in 3 patients, grade 4 in 1 patient), nausea (grade 3 in 1 patient) and tumor pain (grade 3 in 1 patient). Hematologic toxicities were minimal, none worse than grade 2. Eighty-eight percent of patients received >/=90% planned dose intensity; 2 patients had dose reductions for gastrointestinal (GI) toxicity. CONCLUSIONS: Flavopiridol is well tolerated at the dose regimen used in this study, with an acceptable (primarily GI) toxicity profile. Although 7 of the 16 patients had stable disease ranging from 1.8 to 9.2 months in duration, there was no evidence of significant clinical activity in malignant melanoma by objective response criteria.

    Title Her2 Expression in Salivary Gland Carcinomas: Dependence on Histological Subtype.
    Date September 2004
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: Previous evaluation of HER2 overexpression in salivary gland cancers indicated an incidence varying between 7 and 56%, with no clear difference among three histologically different subtypes. As part of a Phase II trial of trastuzumab for treatment of incurable salivary gland cancer, we screened 137 tumors for HER2 expression. EXPERIMENTAL DESIGN: Unstained sections of paraffin-embedded tumor samples were stained with p185/HER2 receptor antibody. Tumors with moderate (2+) to strong (3+) complete membrane staining in at least 10% of the tumor cells were scored as positive for overexpression. RESULTS: The overall frequency of overexpression for HER2 was 17% (23 of 137), whereas it was only 8% in the three most common histological subtypes screened. Overexpression was distinctly rare in the most common subtype screened, adenoid cystic carcinoma (4%, 3 of 70). Overexpression was very common in salivary duct cancers; 10 (83%) of 12 were positive for HER2. This observation is consistent with the typical high-grade histological features and aggressive behavior of this subtype as well as with its histogenetic similarity to breast cancer. Analysis based on histogenesis (intercalated duct versus excretory duct) indicated a higher frequency of overexpression in the latter (55%) than in the former (7%). CONCLUSIONS: Our overall results suggest that trastuzumab will not have a major role in treatment of salivary gland cancers of intercalated duct origin. Further systematic evaluation of trastuzumab in subtypes of excretory duct origin could be supported.

    Title Ctcae V3.0: Development of a Comprehensive Grading System for the Adverse Effects of Cancer Treatment.
    Date February 2004
    Journal Seminars in Radiation Oncology
    Excerpt

    Multiple systems have been developed for grading the adverse effects (AEs) of cancer treatment. The National Cancer Institute Common Toxicity Criteria (CTC) system has substantially evolved since its inception in 1983. The most recent version, CTCAE v3.0 (Common Terminology Criteria for Adverse Events version 3.0) represents the first comprehensive, multimodality grading system for reporting the acute and late effects of cancer treatment. The new CTC requires changes in the application of AE criteria including new guidelines regarding late effects, surgical and pediatric effects, multimodality issues, and for reporting the duration of an effect. It builds on the strengths of previous systems, represents a considerable effort among hundreds of participants, and signifies an international collaboration and consensus of the oncology research community. This article updates recent progress in the evolution of adverse effects grading systems and reviews the development of CTCAE v3.0.

    Title Herceptin in Patients with Advanced or Metastatic Salivary Gland Carcinomas. A Phase Ii Study.
    Date November 2003
    Journal Oral Oncology
    Excerpt

    Phase II study of Herceptin (Trastuzumab) in patients with advanced salivary gland tumors overexpressing Her2/neu. Patients with advanced, incurable salivary gland tumors and 2(+) or 3(+) Her2/neu expression in their tumors were enrolled in the study. After an initial dose of 4 mg/kg, patients received 2 mg/kg weekly. Patients were treated until they experienced progression of disease or unacceptable toxicity. The study was closed early when it has become clear that the majority of tumors screened did not overexpress Her2/neu. Fourteen patients were enrolled in the study. A total of 86 cycles of Herceptin were delivered with a median of three cycles per patient (range 1-40). Median time to progression was 4.2 months. One patient with metastatic mucoepidermoid carcinoma has received 40 cycles of Herceptin to date with a documented partial response. Herceptin given as a single agent has a low activity in salivary gland tumors overexpressing Her2/neu. New agents are still needed.

    Title Timed Sequential Therapy of Acute Leukemia with Flavopiridol: in Vitro Model for a Phase I Clinical Trial.
    Date July 2003
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: The survival of adults with acute leukemias remains unsatisfactory and requires new treatment approaches. Flavopiridol modulates cell cycle progression, inhibits transcription, and induces apoptosis. We designed an in vitro model of timed sequential therapy for acute leukemia to determine whether flavopiridol can: (a). trigger apoptosis in fresh acute leukemia; and (b). recruit surviving leukemic cells to a proliferative state, thereby priming such cells for the S-phase-related cytotoxicity of 1-beta-D-arabinofuranosylcytosine (ara-C). EXPERIMENTAL DESIGN: Bone marrow cells from 20 adults with relapsed and refractory acute leukemias were enriched for blasts by Ficoll Hypaque sedimentation. Blasts were cultured on day 0 in flavopiridol 250 nM for 24 h, removed from flavopiridol for 24 h, and then cultured in ara-C 1 microM for an additional 72 h (F(250)A(1)). Apoptosis and cell cycle phase distribution were estimated from cells stained with propidium iodide. Cell survival was determined after the 72 h ara-C exposure by double cytofluorescence assay with fluorescein diacetate and propidium iodide. RESULTS: Flavopiridol induced a 4.3-fold increase in apoptosis in human leukemia samples within the first 24 h of culture. Subsequent removal of flavopiridol led to a 1.7-fold increase in the proportion of cells in S phase by day 2. Mean survival in F(250)A(1) cultures after 72 h exposure to ara-C was 35.6% compared with flavopiridol alone (F(250)A(0), 56.1%; P = 0.0003) and ara-C alone (F(0)A(1), 65.2%; P < 0.00001). CONCLUSIONS: Flavopiridol induces apoptosis in marrow blasts from patients with refractory acute leukemias. Furthermore, flavopiridol pretreatment increases the proapoptotic and cytotoxic effects of ara-C. The advantage of sequential FP(250)A(1) over either agent alone is seen for both acute myelogenous leukemia and acute lymphoblastic leukemia. These findings support a clinical trial of timed sequential therapy where flavopiridol is given for cytoreduction and subsequent priming of remaining leukemic cells for enhanced cycle-dependent drug cytotoxicity.

    Title Organ Preservation-induction Chemotherapy.
    Date May 2003
    Journal Cancer Treatment and Research
    Title Development of Investigational Radiation Modifiers.
    Date May 2003
    Journal Journal of the National Cancer Institute
    Title Docetaxel, Cisplatin, and 5-fluorouracil-based Induction Chemotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck: the Dana Farber Cancer Institute Experience.
    Date March 2003
    Journal Cancer
    Excerpt

    BACKGROUND: The authors conducted a series of four Phase I-II trials of high-dose and intermediate-dose docetaxel, cisplatin, and 5-fluorouracil (TPF)-based induction chemotherapy for patients with advanced squamous cell carcinoma of the head and neck (SCCHN). The chemotherapy regimens and response rates for each trial were published previously. In the current analysis, the authors report the data on long-term survival, patterns of failure, and morbidity among the patients who were treated at their institution. METHODS: A total of 101 patients with previously untreated, locally advanced, curable SCCHN were entered onto the studies. Overall, 68 patients (67%) had N2-N3 disease, and 86 patients (85%) had Stage IV disease. Patients were treated with combinations of TPF with or without leucovorin. Cycles were repeated every 21-28 days for a total of 3 cycles followed by hyperfractionated radiotherapy. RESULTS: After a median follow-up of 49 months, 65 patients (64%) remain alive with no evidence of disease (NED), and 3 patients remain alive with disease, for an overall survival rate of 67% (68 patients). Twenty-six patients had locoregional recurrences (LRR), and 5 patients had both LRR and distant metastasis (DM). Only five patients had DM as the sole site of failure. Four patients underwent salvage surgery at the primary site and remain alive with NED. Excluding 17 patients with nasopharyngeal carcinoma, of 84 patients, 55 patients remain alive with NED (65%). Notably, 43 of 84 patients (51%) had oropharyngeal primary tumors, and 30 of those patients remain alive with NED (70%). Significant morbidity was low, with two treatment-related deaths. All but two of the surviving patients are able to swallow and had their feeding tubes removed. CONCLUSIONS: These data suggest that docetaxel adds incrementally to the efficacy of cisplatin and fluorouracil. Local-regional failures continue to be the major impediment to cure in these patients. Given the increase in local-regional dose intensity with chemoradiation, sequential treatment plans that integrate induction chemotherapy and chemoradiotherapy seem to be the logical next step.

    Title A Phase I/ii Trial of Concurrent Docetaxel and Radiation After Induction Chemotherapy in Patients with Poor Prognosis Squamous Cell Carcinoma of the Head and Neck.
    Date October 2002
    Journal Cancer
    Excerpt

    BACKGROUND: The authors conducted a Phase I/II study in patients with a poor prognosis who had locally advanced squamous cell carcinoma of the head and neck (SCCHN) and who were treated initially with induction chemotherapy. Patients were treated with weekly docetaxel and concurrent daily fractionated radiation therapy to determine the maximum tolerated dose (MTD) of docetaxel and the efficacy of the regimen. METHODS: Twenty-two patients were enrolled, and 21 patients were treated. Eight patients had Stage III SCCHN, and 13 patients had Stage IV SCCHN without distant metastases and were treated first with 2-3 cycles of induction chemotherapy, which consisted of cisplatin plus 5-fluorouracil with or without leucovorin. Patients with a poor prognosis were identified as those who achieved a partial response to induction treatment, achieved a complete response with a positive biopsy, or were at high risk for developing recurrent disease. Patients were treated subsequently with concurrent, escalating doses of docetaxel (given weekly x 6) and once daily 200-centigray radiation fractions. RESULTS: Three patients were treated with a weekly docetaxel dose of 20 mg/m(2) without dose-limiting toxicity (DLT). Both patients who were treated at the next dose level of 30 mg/m(2) experienced DLT. A dose of 25 mg/m(2) was studied without DLT in the 16 patients who were treated, establishing this as the MTD. Sixty-seven percent of the patients are alive without disease at a median follow-up of 35 months (range, 12-59 months) after the initiation of chemoradiotherapy. CONCLUSIONS: The MTD of weekly docetaxel with concurrent daily radiation therapy in the postinduction setting was 25 mg/m(2). Disease free survival data from this study were good and indicated that this regimen was effective in the treatment of patients with SCCHN who had a poor prognosis.

    Title Phase I/ii Trial of Outpatient Docetaxel, Cisplatin, 5-fluorouracil, Leucovorin (optpfl) As Induction for Squamous Cell Carcinoma of the Head and Neck (scchn).
    Date April 2002
    Journal American Journal of Clinical Oncology
    Excerpt

    The purpose of this study was to establish the maximum tolerated dose (MTD) of docetaxel in an outpatient docetaxel (T), cisplatin (P), 5-fluorouracil (5-FU) (F), and leucovorin (L) (opTPFL) regimen and to obtain preliminary assessment of opTPFL efficacy. Thirty-four patients with stage III or IV squamous cell carcinoma of the head and neck were treated with opTPFL. Docetaxel was escalated from 60 to 95 mg/m(2) in combination with 100 mg/m(2) cisplatin intravenous bolus, and 2,800 mg/m(2) 5-FU continuous infusion and 2,000 mg/m(2) leucovorin continuous infusion with prophylactic growth factors and antibiotics. Patients who achieved a complete (CR) or partial (PR) response to three cycles received definitive twice-daily radiation therapy. A total of 97 cycles were administered to 34 patients. The major acute toxicities were neutropenia and mucositis. The MTD of docetaxel was 90 mg/m(2) . Seventy-seven of 97 cycles of were administered on an outpatient basis. The overall clinical response rate to opTPFL was 94%, with 44% CRs and 50% PRs. The MTD of opTPFL is 90 mg/m(2) docetaxel. Outpatient administration of opTPFL is tolerable, feasible, and does not alter the ability to administer definitive radiation therapy on schedule.

    Title Clinical Trials Referral Resource. Current Clinical Trials of Epothilone B Analog (bms-247550).
    Date January 2002
    Journal Oncology (williston Park, N.y.)
    Title Hypothyroidism Incidence After Multimodality Treatment for Stage Iii and Iv Squamous Cell Carcinomas of the Head and Neck.
    Date December 2001
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: Treatment of head-and-neck cancer patients with surgery, radiotherapy (RT), and chemotherapy has been associated with posttherapy hypothyroidism (HT). We evaluated the rate of posttherapy HT in patients with locally advanced squamous cell carcinoma of the head and neck, treated with multimodality therapy to determine which factors might predict this condition and at what interval the condition developed. METHODS: We reviewed the prospectively collected thyroid function data of patients treated with sequential chemotherapy, RT, and neck dissection. The incidence of posttherapy HT was estimated. The patient, tumor, and treatment factors possibly associated with HT were evaluated. RESULTS: Of 203 patients, 118 had data adequate for evaluation. HT developed in 45% at a median of 24.4 months after therapy. HT occurred in 14% and 27% of patients at 6 months and 1 year after treatment, respectively. Univariate and multivariate analyses of sex, age, RT dose, RT fractionation, T and N stage, tumor site, and neck dissection failed to identify a clinically relevant risk factor. CONCLUSIONS: A high number of patients undergoing aggressive organ-sparing multimodality therapy for advanced squamous cell carcinoma of the head and neck are at risk for subsequent HT. We recommend that all patients definitively irradiated to the head and neck region undergo frequent serum thyroid-stimulating hormone screening for HT, beginning 6 months after RT.

    Title A Phase Ii Study of Combined Oral Uracil and Ftorafur with Leucovorin for Patients with Squamous Cell Carcinoma of the Head and Neck.
    Date August 2001
    Journal Cancer
    Excerpt

    BACKGROUND: The objective of this Phase II study was to define the response rate, safety profile, and toxicity of oral uracil and ftorafur (UFT) with leucovorin (UFT/LV) as a palliative treatment for patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients with metastatic or recurrent SCCHN with an Eastern Cooperative Oncology Group performance status < 2 and adequate organ function were enrolled in an institutional review board-approved trial. Prior induction or adjuvant chemotherapy was permitted provided 6 months had elapsed since the last chemotherapy. Patients were treated with UFT 300 mg/m(2) per day and leucovorin 90 mg per day administered in three doses daily for 28 days followed by a 7-day break for a 35-day cycle. Planned intrapatient dose modifications were based on individual toxicity. Patients were removed from the study for progression of disease or unacceptable toxicity. RESULTS: One hundred six cycles of UFT/LV had been administered to 42 patients as of January 1, 2000. The most common toxicities, in descending order of incidence, were anemia, pain, fatigue, diarrhea, nausea, mucositis, and anorexia. Clinically significant toxicities attributable to UFT/ LV were primarily gastrointestinal. On an intent-to-treat basis, three patients (7%) achieved a complete response, and six patients (14%) achieved a partial response. The overall response rate was 21% (95% confidence interval, 10--37%). CONCLUSIONS: UFT/LV therapy is feasible in this patient population and is generally well tolerated. Response rates are similar to the rates expected with continuous-infusion 5-fluorouracil. UFT/LV should be studied further both alone and in combination therapy for patients with SCCHN.

    Title Multicenter Phase I-ii Trial of Docetaxel, Cisplatin, and Fluorouracil Induction Chemotherapy for Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck.
    Date April 2001
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: We conducted a phase I-II, multi-institutional trial to determine the maximum-tolerated dose (MTD) of cisplatin in an induction chemotherapy regimen of docetaxel, cisplatin, and fluorouracil for squamous cell cancer of the head and neck (SCCHN) and to determine the safety, tolerability, and efficacy of the regimen at MTD. PATIENTS AND METHODS: A total of 43 patients with previously untreated, locally advanced, curable SCCHN were entered. Overall, 29 patients (67%) had N2 or N3 nodal disease and nine (21%) had T4 primary tumors. All patients received docetaxel 75 mg/m(2) on day 1; cisplatin at 75 (level I) or 100 (level II) mg/m(2) on day 1; and a continuous fluorouracil infusion at 1,000 mg/m(2)/d on days 1 through 4. Patients were treated with prophylactic antibiotics on days 5 through 15. Cycles were repeated every 21 days for a total of three cycles. Patients then received definitive therapy based on institutional preferences. RESULTS: Thirteen patients were treated at level I, and 30 patients were treated at level II. All 43 patients were assessable for toxicity. There were no major differences in toxicity between level I and level II. Cisplatin-associated grade 3 or 4 hypomagnesemia or hypocalcemia occurred in 13 (30%) and hearing loss in two patients (5%). Grade 3 or 4 neutropenia was observed in 41 patients (95%) and febrile neutropenia occurred in eight (19%). There was one serious infection (2%). There were 17 (40% [95% confidence interval [CI], 25% to 56%]) clinical complete responders (CR), 23 (54% [95% CI, 39% to 69%]) partial responders (PR), one (2%) with no change, and two (5%) unassessable patients. Major responses (CR, PR) were observed in 40 (93% [95% CI, 81% to 99%]) patients. Primary site CR was documented in 24 (54%) of patients. Postchemotherapy primary site biopsies were performed in 25 patients (58%) and pathologically negative biopsy was obtained in 11 (92%) of 12 primary site clinical CRs and seven (54%) of 13 with PR or no change. Overall, negative biopsies were obtained in 18 patients (72%). CONCLUSION: TPF induction chemotherapy can be delivered safely with a cisplatin dose of 100 mg/m(2) in previously untreated patients with SCCHN. The regimen is associated with a high rate of primary site clinical and pathologic CRs. Phase III comparison with cisplatinum and fluorouracil chemotherapy is warranted.

    Title Nccn Practice Guidelines for Head and Neck Cancers.
    Date March 2001
    Journal Oncology (williston Park, N.y.)
    Title A Phase Ii Trial of Palliative Docetaxel Plus 5-fluorouracil for Squamous-cell Cancer of the Head and Neck.
    Date December 2000
    Journal Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo
    Excerpt

    PURPOSE: A phase II study to determine the response rate and toxicity of docetaxel and 5-fluorouracil (5-FU) every four weeks ('TF'), in patients with incurable SCCHN. PATIENTS AND METHODS: Patients with metastatic or recurrent SCCHN with an ECOG PS < 3 were enrolled in an institutional review board approved trial. Prior induction or adjuvant chemotherapy was permitted provided six months had elapsed. The regimen was docetaxel 70 mg/m2 i.v., day 1 and 5-FU 800 mg/m2/d x 5 days, days 1-5, as a continuous intravenous infusion, repeated every 28 days. Planned intra-patient dose modifications were based on hematological, cutaneous, and gastrointestinal toxicities. Patients were removed from the study for progression of disease or unacceptable toxicity. RESULTS: Seventeen patients were enrolled. Fourty-six cycles of TF were administered. Reasons for discontinuance of TF included: progressive disease, 12 patients; toxicity, 3 patients; concomitant illness, 1 patient; death, 1 patient. The most common toxicities were neutropenia, mucositis, anemia, fatigue, alopecia, pain, diarrhea and nausea. Evaluation of responses to TF showed that there were four patients of seventeen (24%, 95% exact CI: 6.8-49.9) who achieved a PR or CR. Accrual was terminated after interim analysis of the response rate of the first 17 patients failed to exceed 4 of 17. CONCLUSIONS: The response rate to TF in patients with SCCHN was lower than expected. Trials of other regimens should take precedence over further exploration of the TF regimen.

    Title The Role of Induction Chemotherapy in the Curative Treatment of Squamous Cell Cancer of the Head and Neck.
    Date September 2000
    Journal Seminars in Oncology
    Excerpt

    Induction chemotherapy is appropriate for the treatment of locally advanced squamous cell carcinoma of the head and neck because it allows organ preservation without compromising survival and improves survival in unresectable disease. Radiation therapy, not surgery, should immediately follow induction chemotherapy in potentially resectable patients to prevent tumor repopulation. The results of three phase II studies of docetaxel-based regimens as induction therapy of patients with locally advanced squamous cell carcinoma of the head and neck are reviewed and reported. Overall response rates ranged from 93% to 100%, with complete response rates of 40% to 63%. The primary toxicities were neutropenia and febrile neutropenia. A North American phase III trial, randomizing patients to docetaxel/cisplatin/fluorouracil or cisplatin/fluorouracil sequentially followed by chemoradiotherapy is being performed to determine whether docetaxel improves the complete response rate, organ preservation rate, and survival of patients treated with induction chemotherapy.

    Title Phase Ii Trial of Docetaxel, Cisplatin, Fluorouracil, and Leucovorin As Induction for Squamous Cell Carcinoma of the Head and Neck.
    Date January 2000
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: To evaluate the toxicity and efficacy of a 4-day regimen of docetaxel, cisplatin, fluorouracil, and leucovorin (TPFL4) in patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Thirty previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status of 2 or less were treated with TPFL4. Postchemotherapy support included prophylactic growth factors and antibiotics. Patients who achieved a complete response (CR) or partial response (PR) to three cycles of TPFL4 received definitive twice-daily radiation therapy. The primary end points were toxicity and response to TPFL4. RESULTS: Eighty-five cycles were administered to 30 patients. The major acute toxicities to TPFL4 were mucositis and nausea. One patient died of neutropenic sepsis during therapy. Additional major toxicities were neutropenia, anorexia, nephropathy, neuropathy, and diarrhea. Fourteen percent of all cycles were associated with hospitalization for toxicity. The overall clinical response rate to TPFL4 was 93%, with 63% CRs and 30% PRs. Primary tumor site clinical and pathologic response rates were 93% and 68%, respectively. CONCLUSION: TPFL4 has an acceptable toxicity profile in good-performance-status patients. Modification of the 5-day TPFL regimen (TPFL5: shorter chemotherapy infusion time, earlier intervention with growth factors and antibiotics) led to fewer episodes of febrile neutropenia and hospitalization. Response rates to TPFL justify further evaluation of combinations of these agents in the context of formal clinical trials.

    Title Re: "sialadenosis: a Presenting Sign in Bulemia" (head and Neck 20: 758-762, 1998)
    Date October 1999
    Journal Head & Neck
    Title An Initial Experience Using Concurrent Paclitaxel and Radiation in the Treatment of Head and Neck Malignancies.
    Date April 1999
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    BACKGROUND: Combined modality therapy plays a central role in the management of head and neck malignancies. This study examined the feasibility and preliminary results of treating a group of patients using concurrent bolus paclitaxel (Taxol) and radiation therapy. METHODS: Fourteen patients with a median age of 56 years (range 42-81) were treated. Paclitaxel was given every 3 weeks at a dose of 100 mg/m2 concurrently with external beam radiation. The patients treated included those who had failed to achieve a complete response (CR) to induction chemotherapy with cisplatin, 5-fluorouracil, and leucovorin (PFL), or who had locally advanced disease not previously treated. RESULTS: Median follow-up from the initiation of treatment is 40 months (range 23-48). The majority of patients (13/14) achieved clinical CRs at the primary site. The development of responses was characterized by a long time course. Three patients who were nonresponders (NRs) to induction PFL chemotherapy were treated. One was a clinical CR at the primary site, one did not achieve a CR, and the other had residual disease in the neck. Four patients have failed, one with local-regional disease, one with a marginal failure, one with distant metastases, and one was not rendered disease-free by the treatment. As expected, significant local toxicity was observed. Most patients were managed with the aid of a percutaneous endoscopic gastrostomy (PEG). Two patients experienced significant moist desquamation and required treatment breaks of greater than 1 week. CONCLUSION: Paclitaxel can be given on a 3-week schedule at 100 mg/m2 concurrently with radiation. The preliminary results indicate good local responses and acceptable toxicity. This treatment approach merits further study in the treatment of head and neck malignancies, and should be considered as an option in other sites.

    Title Intramucosal Spread of Malignant Melanoma of the Oral Cavity.
    Date February 1999
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Title Docetaxel in Head and Neck Cancer: a Review.
    Date November 1998
    Journal American Journal of Clinical Oncology
    Excerpt

    Docetaxel has been shown to have significant antitumor activity. The mechanism of action is through stabilization of tubulin, arresting cells in the G2M phase of the cell cycle. The maximum tolerated dose of docetaxel is 100 mg/m2 every 21 days. Short-lasting neutropenia is the dose-limiting toxicity. Other significant toxicities include alopecia, mucositis, fatigue, sensory neuropathy, fluid retention, rash, and hypersensitivity reactions. Phase II studies of docetaxel as a single agent in patients with squamous cell carcinoma of the head and neck (SCCHN) have documented response rates of 27% to 43%. Studies of docetaxel combined with cisplatin, and docetaxel, cisplatin, and 5-fluorouracil (TPF) as induction therapy for patients with SCCHN demonstrate that these regimens are highly active. An early trial of induction TPF with leucovorin (TPFL) has yielded an overall response rate of 100% and complete response rate of 61%. In vitro studies have shown docetaxel to be a potent radiation sensitizer for squamous cell carcinoma cell lines, and phase I trials using concurrent docetaxel and radiotherapy are ongoing.

    Title Induction Chemotherapy with Docetaxel, Cisplatin, Fluorouracil, and Leucovorin for Squamous Cell Carcinoma of the Head and Neck: a Phase I/ii Trial.
    Date May 1998
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: A phase I/II trial of docetaxel, cisplatin, fluorouracil (5-FU), and leucovorin (TPFL5) induction chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Twenty-three previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status less than or equal to 2 were treated with TPFL5. Postchemotherapy home support included intravenous fluids, prophylactic antibiotics, and granulocyte colony-stimulating factor (G-CSF). Docetaxel dose was escalated to determine the maximum-tolerated dose (MTD). Fifteen patients were treated with three cycles of TPFL5 at MTD. Patients who achieved either a partial response (PR) or complete response (CR) to three cycles of TPFL5 then received definitive twice-daily radiation therapy. Toxicity and clinical and pathologic response to TPFL5 were assessed. RESULTS: Twenty-three patients received a total of 69 cycles of TPFL5. The MTD was determined to be docetaxel 60 mg/m2. Dose-limiting toxicity (DLT) was neutropenia. Additional significant toxicities at MTD were nausea, mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The overall response rate to TPFL5 was 100%, which included 14 of 23 (61%) clinical CRs and nine of 23 (39%) clinical PRs. Primary-site clinical and pathologic CR rates were 19 of 22 (86%) CRs and 20 of 22 (91%) CRs, respectively. Eight patients had less than a CR in the neck to chemotherapy and, therefore, had postradiation neck dissections, four of which were positive for residual tumor. CONCLUSION: TPFL5 is a tolerable induction regimen in patients with good performance status. The DLT is neutropenia with significant mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The high response rates to TPFL5 justify further evaluation of this combination of agents in the context of formal clinical trials.

    Title Future Directions in the Treatment of Squamous Cell Carcinoma of the Head and Neck: the Role of Uft.
    Date November 1997
    Journal Oncology (williston Park, N.y.)
    Excerpt

    Squamous cell carcinoma of the head and neck is a potentially curable neoplasm. Historically, the standard approach to treatment has been either surgery or radiation therapy, or a combination of the two. Over the past two decades, the role of chemotherapy in the curative approach to head and neck cancer has been evolving. Drugs like fluorouracil (5-FU), cisplatin (Platinol), methotrexate, paclitaxel (Taxol), docetaxel (Taxotere), and bleomycin (Blenoxane) have been investigated in both the palliative and curative settings. Multiple combination regimens have been used as neoadjuvant or induction regimens, but to date the original combination of cisplatin and fluorouracil is still the standard of therapy. UFT, a combination of uracil and tegafur (a fluorinated pyridine analogue), has been available in Japan as an oral form of treatment for squamous cell head and neck cancers. This article describes the rationale behind the use of UFT as an agent for the treatment of squamous cell carcinoma of the head and neck as well as data from ongoing investigations exploring its use in this disease.

    Title Induction Chemotherapy with Cisplatin, Fluorouracil, and High-dose Leucovorin for Squamous Cell Carcinoma of the Head and Neck: Long-term Results.
    Date October 1997
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: A phase II trial of cisplatin, fluorouracil, and leucovorin (PFL) induction chemotherapy in patients with locally advanced squamous cell carcinomas of the head and neck region (HNCA). PATIENTS AND METHODS: One hundred two patients (stage III/IV, previously untreated) were treated with induction PFL. Patients with resectable primary tumor site lesions and clinical complete response (CR) were offered radiotherapy (RT) without surgery to the primary tumor site. Response, toxicity, local-regional therapy, survival, and preservation of the primary tumor site were assessed. RESULTS: Among 279 courses, the overall response rate was 81%. Nineteen (19%) failed to respond, including three who died during therapy. Sixty-seven (69%) of 97 with assessable primary lesions had a clinical CR at the primary tumor site. Pathologic CR was recorded in 46 of 55 (84%) clinical CR patients who had biopsies performed on the primary tumor site. Toxicities resulted in unexpected hospitalizations in 19% of cases. After definitive local-regional therapy, 84 (82%) were disease-free including 71 (69%) with preserved primary tumor site anatomy. With a median follow-up time of 63 months, the cause-specific, overall (OS), and failure-free survival (FFS) rates at 5 years are 58%, 52%, and 51%. Local failure occurred in 29 of 102 (29%) and the local control rate at 5 years was 68%. CONCLUSION: PFL has significant activity with acceptable toxicity in patients with advanced disease who have a good performance status. Preservation of the primary tumor site could be achieved without apparent loss of local control or survival. Management of neck disease by surgery or RT must be individualized and separate from management of primary tumor. Survival compares favorably with similar trials of induction chemotherapy or chemoradiotherapy.

    Title Induction Chemotherapy in the Management of Squamous Cell Cancer of the Head and Neck.
    Date June 1997
    Journal The Cancer Journal from Scientific American
    Title Glutaric Acidemia Type Ii. Comparison of Pathologic Features in Two Infants.
    Date November 1988
    Journal Archives of Pathology & Laboratory Medicine
    Excerpt

    Glutaric acidemia type II (GA II) is a metabolic disorder caused by deficiency of electron transport flavoprotein or its oxyreductase. It is characterized by acidosis, hypoglycemia, hyperammonemia, organic aciduria, and "sweat-sock" odor. Neonatal GA II differs from most inborn metabolic errors in that there are prominent congenital malformations. We recently observed two infants at autopsy with GA II whose malformations included: subcortical renal glomerular cysts, renal medullary dysplasia, cerebral pachygyria, pulmonary hypoplasia, and facial dysmorphism. In addition, there was lipid accumulation in liver, heart, and renal tubular epithelium, tissues that use fatty acids as a primary source of energy. Review of previous reports of 12 patients showed that these lesions are typical of neonatal GA II. The pattern of lesions, in particular the striking localization of renal dysplasia to the medulla, suggests that the malformations may be the consequence of an accumulation of toxic metabolites that is not corrected by placental transfer.

    Title The Prognostic Value of Thymidylate Synthase and P53 Expression in Patients Treated with Induction Chemotherapy for Squamous Cell Carcinoma of the Head and Neck.
    Date
    Journal The Oncologist
    Excerpt

    Thymidylate synthase (TS) and p53 are central molecules in the regulation of cell growth. Differences in the intracellular expression of these proteins by tumor cells may have predictive value for response to chemotherapy and early failure in patients with squamous cell cancer of the head and neck (SCCHN). Immunohistochemistry was used to assess the tumor cell expression of TS and p53 in pre-therapy biopsies from patients with advanced SCCHN treated with an induction chemotherapy protocol, PFL. Samples were available from 11 of 16 nonresponders, 13 of 19 early failures with progression within 24 months of treatment, and a random selection of 13 from 45 long-term, disease-free survivors (LTS). High TS expression was seen in the majority of samples from all three groups, 67% versus 78% versus 93%, respectively; however, only one of seven (14%) samples with low TS was from a LTS patient. TS expression did not differ in patients by sex, age, site of primary tumor, differentiation or stage. p53 was expressed in 33% of patient samples and did not predict response or correlate with sex, age, site of primary tumor, differentiation, or stage. Small primary tumors with extensive nodal disease were less likely to express p53 than larger primary tumors with or without nodal involvement. The data suggest that TS and p53 content have a limited prognostic value in patients treated with PFL, although tumors with lower TS expression appeared to be less likely to respond. Differences between this study and other investigations of TS and p53 may be disease site- and regimen-specific. Statistically significant differences between response groups may emerge from larger, site-specific, protocol-driven studies of TS and p53.

    Title A Multicentre Phase Ii Clinical Experience with the Novel Aza-epothilone Ixabepilone (bms247550) in Patients with Relapsed or Refractory Indolent Non-hodgkin Lymphoma and Mantle Cell Lymphoma.
    Date
    Journal British Journal of Haematology
    Excerpt

    The epothilones represent a novel group of microtubule stabilization agents that appear to retain activity even in chemotherapy-resistant cell lines and animal models. Because of their ability to overcome chemotherapy resistance, we conducted a phase II study of Ixabepilone in patients with indolent non-Hodgkin lymphoma and mantle cell lymphoma (MCL). Ixabepilone was given at a dose of 25 mg/m(2) weekly for three of four consecutive weeks. Patients were required to have received </=4 prior chemotherapy regimens, with an interval of at least one month since the last treatment, 3 months from prior rituximab, and 7 d from prior steroids, an absolute neutrophil count >1 x 10(9)/l and a platelet count >50 x 10(9)/l. Dose reductions were allowed. The overall response rate in assessable patients was 27% in this otherwise heavily treated population. One patient with chemotherapy-refractory follicular lymphoma attained a complete remission that lasted approximately 8 months. Three responses were also seen in refractory MCL and one in small lymphocytic lymphoma. The duration of response ranged from 2 to 8 months. Major toxicities included fatigue, myelosuppression and neuropathy. These data suggest that Ixabepilone has activity in chemotherapy-refractory lymphoma.

    Title Head and Neck Cancers.
    Date
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    Title Intensity-modulated Radiotherapy for Locally Advanced Cancers of the Larynx and Hypopharynx.
    Date
    Journal Head & Neck
    Excerpt

    Limited data evaluate intensity-modulated radiotherapy (IMRT) for cancers of the hypopharynx and larynx. We report clinical outcomes and failure patterns for these patients.

    Title Intensity-modulated Radiotherapy for Tumors of the Nasal Cavity and Paranasal Sinuses: Clinical Outcomes and Patterns of Failure.
    Date
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    To report outcomes in patients treated with intensity-modulated radiotherapy (IMRT) for tumors of the paranasal sinuses and nasal cavity (PNS/NC).

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