Bio

Clinical Focus


  • combined chemotherapy and radiation treatment
  • investigational new drugs
  • Thyroid Cancer
  • Oncology (Cancer)
  • Medical Oncology
  • developmental therapeutics
  • Adverse event( toxicity) evaluation and reporting
  • Cancer > Head and Neck Cancer

Academic Appointments


Professional Education


  • Residency:Johns Hopkins School of Medicine (1992) MD
  • Internship:Johns Hopkins School of Medicine (1990) MD
  • Board Certification: Medical Oncology, American Board of Internal Medicine (1995)
  • Fellowship:Dana-Farber Cancer Institute (1995) MA
  • Medical Education:Johns Hopkins School of Medicine (1989) MD
  • B. A., Columbia, Chemistry (1985)
  • M.D., Johns Hopkins, Medicine (1989)

Research & Scholarship

Current Research and Scholarly Interests


Multi- modality treatment of Head and Neck Cancer

Phase 1 clinical trials

Clinical Trials


  • A Phase II Study of Amrubicin in Relapsed or Refractory Thymic Malignancies Recruiting

    Primary Objectives: Assessment of efficacy Secondary Objectives: Assessment of toxicity

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  • Erlotinib in Patients With Resected, Early Stage NSCLC With Confirmed Mutations in the EGFR Not Recruiting

    In this research study erlotinib will be given to eligible participants whose lung cancer has been removed by surgery. Eligible patients have adenocarcinoma, a type of non-small lung cancer, and must have 1 or more of the following characteristics: be female, be of Asian or Pacific Rim descent and/or be a never smoker. The potential participant's tumor will be examined for Epidermal growth factor (EGFR) mutations. EGFR is a protein that is overexpressed in most non-small cell lung cancers. Some EGFR has been found to have specific mutations and the participant must have one of these mutations in his tumor. Erlotinib blocks this protein and may control tumor growth and increase survival. Previous research has shown that erlotinib is most effective for people who have these specific mutations in the EGFR.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lei Shura, 650-723-2312.

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  • Three Different Radiation Therapy Regimens in Treating Patients With Limited-Stage Small Cell Lung Cancer Receiving Cisplatin and Etoposide Recruiting

    Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as etoposide and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known which radiation therapy regimen is more effective when given together with chemotherapy in treating patients with limited-stage small cell lung cancer. This randomized phase III trial is comparing different chest radiation therapy regimens to see how well they work in treating patients with limited-stage small cell lung cancer.

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  • Radiation Therapy in Treating Patients With Stage I Non-Small Cell Lung Cancer Not Recruiting

    RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. It is not yet known which regimen of stereotactic body radiation therapy is more effective in treating patients with non-small cell lung cancer. PURPOSE: This randomized phase II trial is studying the side effects of two radiation therapy regimens and to see how well they work in treating patients with stage I non-small cell lung cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact laura gable, (650) 736 - 0798.

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  • 4D-CT-based Ventilation Imaging for Adaptive Functional Guidance in Radiotherapy Recruiting

    To determine the appropriate class of deformable image registration algorithm and metric best suited for four-dimensional (4D) CT-based ventilation assessment.

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  • PR104 in Treating Patients With Previously Untreated or Relapsed Small Cell Lung Cancer Not Recruiting

    RATIONALE: Drugs used in chemotherapy, such as PR-104, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. PURPOSE: This phase II trial is studying how well PR-104 works in treating patients with previously untreated or relapsed small cell lung cancer (SCLC).

    Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, (650) 723 - 1367.

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  • A Study of ASA404 or Placebo in Combination With Docetaxel in Second-line Treatment for (Stage IIIb/IV) Non-small Cell Lung Cancer Not Recruiting

    The purpose of this study is to determine if adding ASA404 to docetaxel chemotherapy makes the cancer treatment more effective in patients with locally advanced or metastatic non-small cell lung cancer

    Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.

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  • Phase 2 Study of GSK1363089 (Formerly XL880) in Adults With Squamous Cell Cancer of the Head and Neck Not Recruiting

    This study is being conducted to determine the best confirmed response rate, safety, and tolerability of GSK1363089 treatment in adult subjects with squamous cell carcinoma of the head and neck (SCCHN). GSK1363089 is a new chemical entity that inhibits multiple receptor tyrosine kinases (RTKs) with growth-promoting and angiogenic properties. The primary targets of GSK1363089 are the HGF and vascular endothelial growth factor (VEGF) RTK families (eg, MET, VEGFR2/kinase insert domain receptor [KDR]). Since MET overexpression has been associated with poorer prognosis and MET tyrosine kinase mutations have been reported in SCCHN, inhibition of MET receptor and VEGFR2/KDR activation by agents such as GSK1363089 may be of therapeutic benefit in this patient population.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, (650) 723 - 1367.

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  • An Investigational Drug, PF-02341066, Is Being Studied In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene Not Recruiting

    This is a Phase 2 trial that will evaluate the safety and efficacy of PF-02341066 in patients with advanced non-small cell lung cancer with a specific gene profile involving the ALK gene. This trial will also allow patients from a Phase 3 trial who received standard of care chemotherapy (Study A8081007) to receive PF-02341066.

    Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.

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  • Radiation Therapy With or Without Cetuximab in Treating Patients Who Have Undergone Surgery for Locally Advanced Head and Neck Cancer Not Recruiting

    RATIONALE: Giving radiation therapy that uses a 3-dimensional (3-D) image of the tumor to help focus thin beams of radiation directly on the tumor, and giving radiation therapy in higher doses over a shorter period of time, may kill more tumor cells and have fewer side effects. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether radiation therapy is more effective when given alone or together with cetuximab in treating patients with head and neck cancer that has been removed by surgery. PURPOSE: This randomized phase III trial is studying radiation therapy to see how well it works compared with radiation therapy given together with cetuximab in treating patients who have undergone surgery for locally advanced head and neck cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Alice Banh, 650-723-1423.

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  • Nexavar® Versus Placebo in Locally Advanced/Metastatic RAI-Refractory Differentiated Thyroid Cancer Not Recruiting

    Trial of sorafenib versus placebo in the treatment of locally advanced or metastatic differentiated thyroid cancer refractory to radioiodine

    Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, (650) 723 - 1367.

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  • Paclitaxel, Cisplatin, and Cetuximab Followed By Cetuximab and Intensity-Modulated Radiation Therapy in Treating Patients With HPV-Associated Stage III or Stage IV Cancer of the Oropharynx That Can Be Removed By Surgery Not Recruiting

    RATIONALE: Drugs used in chemotherapy, such as paclitaxel and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high energy x-rays to kill tumor cells. Giving paclitaxel, cisplatin, and cetuximab together with radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying paclitaxel, cisplatin, and cetuximab to see how well they work when followed by cetuximab and two different doses of intensity-modulated radiation therapy in treating patients with HPV-associated stage III or stage IV cancer of the oropharynx that can be removed by surgery.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lauren Pernicka, (650) 721 - 6977.

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  • A Phase 1 Dose Escalation Study of OMP-21M18 in Subjects With Solid Tumors Not Recruiting

    This is an open-label Phase 1 dose escalation study of OMP-21M18 in subjects with previously treated solid tumors for which there is no remaining standard curative therapy and no therapy with a demonstrated survival benefit. Up to 30 subjects will be enrolled at up to 4 centers. Subjects will be assessed for safety, immunogenicity, pharmacokinetics, biomarkers, and efficacy. No formal interim analyses will be performed. Prior to enrollment, subjects will undergo screening to determine study eligibility. Upon enrollment, subjects will receive weekly intravenous (IV) infusions of OMP-21M18 for 9 weeks. After 9 weeks of treatment, subjects will be assessed for disease status. If there is no evidence of disease progression or if the tumor is smaller, then subjects may continue to receive IV infusions of OMP-21M18 every other week until disease progression. Dose escalation will be conducted to determine the maximum tolerated dose (MTD). The dose levels of OMP 21M18 will be 0.5, 1.0, 2.5, 5, and 10 mg/kg administered IV weekly for 9 doses. No dose escalation or reduction will be allowed within a dose cohort. The dose may be administered at any time during the day. Three subjects will be treated at each dose level if no dose-limiting toxicities (DLTs) are observed. If 1 of 3 subjects experience a DLT, that dose level will be expanded to 6 subjects. If 2 or more subjects experience a DLT, no further subjects will be dosed at that level and 3 additional subjects will be added to the preceding dose cohort unless 6 subjects have already been treated at that dose level. Subjects will be assessed for DLTs from the time of the first dose through 7 days after administration of the 4th dose, but prior to administration of the 5th dose (i.e., Days 0-28). Dose escalation, if appropriate, will occur after all subjects in a cohort have completed their Day 28 DLT assessment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.

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  • Safety, Tolerability, Pharmacokinetics, and Immunoregulatory Study of Urelumab (BMS-663513) in Subjects With Advanced and/or Metastatic Solid Tumors and Relapsed/Refractory B-cell Non-Hodgkin's Lymphoma Recruiting

    The purpose of the study is to assess the safety, tolerability, pharmacokinetics and immunoregulatory activity of urelumab (BMS-663513) in cancer subjects with advanced and/or metastatic tumors and relapsed/refractory B-Cell Non-Hodgkin's Lymphoma

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  • BIBW 2992 (Afatinib) in Head & Neck Cancer Not Recruiting

    The primary objective of this study is to explore the efficacy of BIBW 2992 compared with cetuximab (Erbitux) in patients with metastatic or recurrent head and neck cancer after failure of platinum-containing therapy. In addition, the trial aims to clarify the influence of EGFR genotype on tumor response to the treatment regimens.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, (650) 723 - 1367.

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  • Chemotherapy With or Without Bevacizumab in Treating Patients With Recurrent or Metastatic Head and Neck Cancer Recruiting

    This randomized phase III trial studies chemotherapy to see how well it works with or without bevacizumab in treating patients with recurrent or metastatic head and neck cancer. Drugs used in chemotherapy, such as docetaxel, cisplatin, carboplatin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also make tumor cells more sensitive to chemotherapy and stop the growth of head and neck cancer by blocking blood flow to the tumor. It is not yet known whether combination chemotherapy is more effective when given with or without bevacizumab in treating patients with head and neck cancer.

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  • Phase II Sequential and Concurrent Chemoradiation for Advanced Nasopharyngeal Carcinoma (NPC) Recruiting

    This phase II trial is studying whether giving a combination of docetaxel, cisplatin, and fluorouracil chemotherapy followed by the combination of cisplatin with radiation therapy works in treating patients with advanced nasopharyngeal cancer. Drugs used in chemotherapy, such as docetaxel, cisplatin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Giving combination chemotherapy together with radiation therapy may kill more tumor cells.

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  • Study of XL184 (Cabozantinib) in Adults With Advanced Malignancies Not Recruiting

    The purpose of this study is to determine the best and safest dose of XL184 administered orally. XL184 is a new chemical entity that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration. To determine the highest safe dose, subjects will receive different amounts of the drug. The first group of subjects will receive the lowest dose of XL184. As long as no medically unacceptable side effects are noted, the dose will be increased for the next group. When the maximum tolerated dose (MTD) is reached, at least 20 subjects with Medullary Thyroid Cancer (MTC) will be enrolled to evaluate the effect of XL184 in this population.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, (650) 723 - 1367.

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  • Phase III Randomized, Placebo Controlled, Trial Of Docetaxel Versus Docetaxel Plus ZD1839 (Iressa, Gefitinib, NSC 715055) In Performance Status 2 Or Previously Treated Patients With Recurrent Or Metastatic Head And Neck Cancer Not Recruiting

    Drugs used in chemotherapy, such as docetaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Gefitinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Combining docetaxel with gefitinib may kill more tumor cells. It is not yet known whether docetaxel is more effective with or without gefitinib in treating head and neck cancer. This randomized phase III trial is studying docetaxel and gefitinib to see how well they work compared to docetaxel alone in treating patients with metastatic or locally recurrent head and neck cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Dimitrios Colevas, (650) 724 - 9707.

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  • Biopsy of Human Tumors for Cancer Stem Cell Characterization: a Feasibility Study Not Recruiting

    To see if a limited sampling of tumor tissue from human subjects is a feasible way to gather adequate tissue for cancer stem cell quantification.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, 650-723-1367.

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  • A Study of HGS1029 (AEG40826-2HCl) in Subjects With Advanced Solid Tumors Not Recruiting

    The purpose of this study is to evaluate the safety and tolerability of HGS1029 in subjects with advanced solid tumors and to determine a phase 2 dose.

    Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.

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  • Phase II Lapatinib and Radiation for Stage III-IV Head and Neck Cancer Patients Who Cannot Tolerate Concurrent Chemotherapy Not Recruiting

    We propose to combine lapatinib with RT alone in patients with locally advanced head and neck cancer who cannot tolerate chemotherapy. The main objective of the study is to determine the efficacy of combining concurrent radiation and lapatinib in terms of time-to-progression (TTP) in this group of patients. In addition, we will determine the 2-year locoregional control rate (LRC), progression-free survival (PFS) and overall survival (OS) in these patients. We will also evaluate the profile and frequency of late toxicity, specifically mucosal and dermatologic toxicity, of the combination of lapatinib and RT in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

    Stanford is currently not accepting patients for this trial. For more information, please contact Brian Khong, (650) 725 - 4777.

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  • Phase I Trial of Metabolic Reprogramming Therapy for Treatment of Recurrent Head and Neck Cancers Recruiting

    To determine the maximum tolerated dose of DCA in patients with recurrent head and neck cancer who have failed first-line therapy. The purpose of this study is to study the effect of the drug DCA (dichloroacetate) on recurrent head and neck cancers. Part of this study will also use EF5 PET scan to study tumor hypoxia.

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  • A 3rd/4th Line Placebo-controlled Trial of Sorafenib in Patients With Predominantly Non Squamous Non-Small Cell Lung Cancer (NSCLC). Not Recruiting

    The purpose of the study is to see if sorafenib plus best supportive care (i.e. in addition to the non-cancer treatments patients would normally receive) is an effective treatment for lung cancer compared to best supportive care alone. The safety and tolerability of the two treatment groups will also be compared. The goal of the study is to test the ability of sorafenib to improve survival compared to best supportive care alone.

    Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.

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  • AMG 655 in Combination With AMG 479 in Advanced, Refractory Solid Tumors Not Recruiting

    This is a multi-center, 2-part phase 1b/2 study of AMG 655 in combination with AMG 479 to be conducted in the United States and Spain. Part 1 is a dose escalation segment to identify a dose of AMG 655 in combination with AMG 479 that is safe and tolerable. Part 2 will evaluate the safety and estimate the efficacy of AMG 655 at the dose selected in Part 1 in combination with AMG 479 for the treatment of patients with advanced NSCLC (non-squamous histology; squamous histology), CRC, pancreatic cancer, ovarian cancer, and sarcoma.

    Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.

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  • Study to Assess Safety and Tolerability of AG013 in Oral Mucositis in Subjects Receiving Induction Chemotherapy for the Treatment of Cancers of the Head and Neck Not Recruiting

    The purpose of this study is to assess the safety and tolerability of AG013 (genetically modified L. lactis bacteria engineered to secrete human Trefoil Factor 1), and to explore the ability of AG013 to attenuate the course and severity of oral mucositis (OM) in subjects receiving induction chemotherapy for the treatment of head and neck cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, (650) 723 - 1367.

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  • A Study of MEHD7945A Versus Cetuximab in Patients With Recurrent/Metastatic Squamous Cell Carcinoma of The Head And Neck Not Recruiting

    This phase II, open-label, randomized study will evaluate the efficacy and safety of MEHD7945A versus cetuximab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck who have progressed during or following platinum-based chemotherapy. Patients will be randomized to receive either MEHD7945A 1100 mg intravenously (iv) every 2 weeks or cetuximab 400 mg/m2 iv loading dose followed by 250 mg/m2 iv weekly. Patients treated with cetuximab (Arm B) may cross-over to MEHD7945A (Arm A) upon central confirmation of progressive disease and upon meeting eligibility criteria. Anticipated time on study treatment is until disease progression or intolerable toxicity occurs.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, (650) 723 - 1367.

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  • Talactoferrin in Treating Patients With Relapsed or Refractory Non-Small Cell Lung Cancer or Squamous Cell Head and Neck Cancer Not Recruiting

    This phase I trial studies how well talactoferrin works in treating patients with relapsed or refractory non-small cell lung cancer (NSCLC) or squamous cell head and neck cancer. Biological therapies, such as talactoferrin, may stimulate the immune system in different ways and stop tumor cells from growing

    Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.

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  • Phase 1 Trial of Oral Ixabepilone Not Recruiting

    This Phase 1 study of oral ixabepilone given every 6 hours for 3 doses on Day 1, every 21 days, was a dose-finding study designed to determine the maximum tolerated dose (MTD) and safety of this dosing schedule in participants with advanced cancer

    Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.

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  • Clinical Study of BYM338 for the Treatment of Unintentional Weight Loss in Patients With Cancer of the Lung or the Pancreas Not Recruiting

    A safety & efficacy clinical study of the investigational medicinal product BYM338 for the treatment of unintentional weight loss in patients with cancer of the lung or the pancreas

    Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.

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  • A Study of CDX-1127 in Patients With Select Solid Tumor Types or Hematologic Cancers Recruiting

    This is a study of CDX-1127, a therapy that targets the immune system and may act to promote anti-cancer effects. The study enrolls patients with hematologic cancers (certain leukemias and lymphomas), as well as patients with select types of solid tumors.

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  • Study of XL647 in Subjects With NSCLC Who Have Progressed After Responding to Treatment With Gefitinib or Erlotinib Not Recruiting

    The purpose of this study is to determine the best confirmed response rate of daily administration of the multiple receptor tyrosine kinase (RTK) inhibitor (including EGFR and VEGFR2) XL647 in subjects with NSCLC who have progressed after responding to treatment with either erlotinib or gefitinib.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.

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  • Erlotinib Plus Tivantinib (ARQ 197) Versus Single Agent Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer Not Recruiting

    The purpose of this study is to evaluate progression-free survival among subjects with KRAS mutation positive Non-Small Cell Lung Cancer (NSCLC) treated with erlotinib plus tivantinib (ARQ 197) compared to single agent chemotherapy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lei Shura, 650-723-2312.

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  • A Study of Pharmacokinetic Drug Interaction Study of the Hedgehog Pathway Inhibitor GDC-0449 in Combination With Rosiglitazone or Combined Oral Contraceptive in Patients With Locally Advanced or Metastatic Solid Tumors That Are Refractory to Standard Therapy or for Whom No Standard Therapy Exists Not Recruiting

    This is a single-arm, multicenter, Phase Ib study designed to describe the effect of GDC-0449 on the pharmacokinetics of rosiglitazone and oral contraceptives in patients with advanced solid tumors who are refractory to treatment or for whom no standard therapy exists.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, (650) 723 - 1367.

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  • A Study of XL184 (Cabozantinib) With or Without Erlotinib in Adults With Non-Small Cell Lung Cancer Not Recruiting

    In Phase 1 of this study, the purpose is to evaluate the safety, tolerability, and highest safe dose of the multiple receptor tyrosine kinase inhibitor (including VEGFR2, MET, and RET) XL184 in combination with the EGFR inhibitor erlotinib administered to adults with Non-Small-Cell Lung Cancer (NSCLC). In Phase 2 of this study, the purpose is to evaluate the objective response rate of daily oral administration of XL184 with or without erlotinib in subjects with NSCLC who have progressed after responding to treatment with erlotinib.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.

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  • An Observational Study of the Ethnic Impact of Patients Undergoing Second (2nd) Line Treatment for Non-Small Cell Lung Cancer Using Pemetrexed Not Recruiting

    This large, non-randomized observational study is being conducted to provide data about the impact of ethnic origin on outcomes and resource utilization during the 2nd line treatment of non-small cell lung cancer (NSCLC) in a routine medical care setting.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.

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  • Study of Cabozantinib (XL184) in Adults With Advanced Malignancies Not Recruiting

    The purpose of this study is to determine whether or not XL184 demonstrates anti-tumor activity in selected tumor types under a randomized discontinuation trial (RDT) design. Subjects who have responded to study drug after 12 weeks of open-label XL184 administration will continue to take XL184. Subjects who are clearly progressing will discontinue study treatment and subjects who demonstrate stable disease will be randomized to either XL184 or placebo. For individual patients, once disease progression is observed, the blind will be broken and subjects who were randomized to placebo will be offered the option to receive open-label XL184. Subjects who progressed while taking XL184 will discontinue study treatment. Emerging data may support enrollment in an open-label, non-randomized expansion cohort (NRE). There will be NRE cohorts for prostate and ovarian cancers.

    Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.

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  • An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene Not Recruiting

    This is a Phase 3 trial comparing the safety and anti-tumor activity of PF-02341066 versus pemetrexed or docetaxel in patients with advanced non-small cell lung cancer with specific gene profile involving the ALK gene after failure of one previous chemotherapy regimen that included one platinum drug.

    Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.

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  • A Study of Aflibercept Administered in Combination With Pemetrexed and Cisplatin in Patients With Advanced Carcinoma Not Recruiting

    The purpose of the study is to determine whether the combination of aflibercept, pemetrexed and cisplatin is safe and effective.

    Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.

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  • A Study Evaluating the Efficacy and Safety of Vismodegib (GDC-0449, Hedgehog Pathway Inhibitor) in Patients With Advanced Basal Cell Carcinoma Not Recruiting

    This is a Phase II, single-arm, two-cohort multicenter clinical trial evaluating the efficacy and safety of vismodegib (GDC-0449) in patients with advanced basal cell carcinoma. All patients will receive vismodegib until evidence of progression, intolerable toxicities most probably attributable to vismodegib, or withdrawal from the study.

    Stanford is currently not accepting patients for this trial. For more information, please contact Katherine Connors, (650) 721 - 7159.

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  • Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer Not Recruiting

    The purpose of this research study is to evaluate the progression-free survival (PFS) with XL184 as compared with placebo (an inactive substance) in subjects with unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC). Subjects will be randomized to receive XL184 or placebo in a 2:1 ratio. XL184 is an investigational drug that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration. The Clinical Steering Committee for this study, comprised of study doctors who specialize in medullary thyroid cancer, has provided guidance regarding the design of the study. The committee includes: Douglas Ball, MD, Barry Nelkin, PhD, Martin Schlumberger, MD and Steven Sherman, MD.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, (650) 723 - 1367.

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  • Weekly Docetaxel, Cisplatin, and Cetuximab (TPC) in Palliative Treatment of Patients With Squamous Cell Carcinoma of the Head and Neck (SCCHN) Recruiting

    Docetaxel and cetuximab are FDA approved for the treatment of squamous cell carcinoma of the head and neck. Cisplatin and carboplatin, while not FDA approved for Squamous Cell Carcinoma of the Head and Neck (SCCHN), have been used as standard of care in patients with SCCHN in combination with other drugs. This study will determine if weekly cisplatin and docetaxel, in combination with cetuximab, will be effective in palliative treatment of patients with squamous cell carcinoma of the head and neck. These drugs will be given intravenously weekly, repeated 3 of every 4 weeks until evidence of disease progression or unacceptable adverse events.

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  • Erlotinib With or Without Hydroxychloroquine in Chemo-Naive Advanced NSCLC and (EGFR) Mutations Not Recruiting

    The purpose of this research study is to learn if adding hydroxychloroquine (HCQ) to erlotinib helps treat non-small cell lung cancer (NSCLC). Another goal of this research study is to learn more about NSCLC and how it may respond to study treatment. Erlotinib (Tarceva) is a type of drug called a tyrosine kinase inhibitor (TKI). TKIs block a protein called the epidermal growth factor receptor (EGFR). EGFR may control tumor growth and tumor cell survival. However, although TKI drugs can work for some lung cancer patients for a period of time, eventually the tumor finds a way to resist or counteract the TKI treatment and it begins to grow again. Hydroxychloroquine (HCQ) is a drug approved by the FDA for treating malaria, rheumatoid arthritis, and several other diseases. Laboratory research suggests that when HCQ is given with a TKI, it may help delay or prevent TKI resistance from developing.

    Stanford is currently not accepting patients for this trial. For more information, please contact Zeina Babetty, (650) 723 - 2983.

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  • A Study of Vismodegib (GDC-0449) in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma Not Recruiting

    This is an open-label, non-comparative, multicenter, expanded access study of Vismodegib (GDC-0449) in patients with locally advanced basal cell carcinoma (BCC) or metastatic BCC (mBCC) who are otherwise without satisfactory treatment options.

    Stanford is currently not accepting patients for this trial. For more information, please contact Shruthi Rangaraj, (650) 721 - 7159.

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  • A Study of GDC-0449 (Hedgehog Pathway Inhibitor) in Patients Treated With GDC-0449 in a Previous Genentech-Sponsored Phase I or II Cancer Study Not Recruiting

    This is a multicenter, open-label extension study. Patients receiving GDC-0449 in a Genentech-sponsored study who have completed the parent study or who continue to receive GDC-0449 at the time of the parent study closure are eligible for continued treatment on this protocol.

    Stanford is currently not accepting patients for this trial. For more information, please contact Shruthi Rangaraj, (650) 721 - 7159.

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  • Phase I Study of CUDC-101 With Cisplatin and Radiation in Subjects With Head & Neck Cancer Not Recruiting

    This is a phase I dose escalation study of CUDC-101 in combination with concurrent cisplatin and radiation therapy in patients with locally advanced head and neck cancer. CUDC-101 is a multi-targeted agent designed to inhibit epidermal growth factor receptor (EGFR), human epidermal growth factor receptor Type 2 (Her2) and histone deacetylase (HDAC). The study is designed to establish the safety, tolerability and maximum tolerated dose (MTD) of CUDC-101 when administered in combination with concurrent cisplatin and radiation over an 8-week treatment course, consisting of a one week run-in period of CUDC-101 administered alone, followed by seven weeks of combination treatment with CUDC-101, cisplatin and radiation therapy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, (650) 723 - 1367.

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  • Long-Term Outcomes of Surgery Followed by Radiation Therapy for Minor Salivary Gland Carcinomas LARYNGOSCOPE Zeidan, Y. H., Shultz, D. B., Murphy, J. D., Chan, C., Kaplan, M. J., Colevas, A. D., Kong, C., Chang, D. T., Le, Q. 2013; 123 (11): 2675-2680

    Abstract

    OBJECTIVES/HYPOTHESIS: Postoperative radiation therapy is often used in patients with high-risk salivary gland carcinomas. In this study we evaluated the outcomes and prognostic factors in patients with minor salivary gland cancers treated with adjuvant radiation therapy. STUDY DESIGN: Retrospective cohort study. METHODS: We performed a retrospective analysis of 90 patients treated with curative intent. Median follow-up was 71 months. Fifty-eight patients (64%) had adenoid cystic carcinomas, 22 (24%) had adenocarcinomas, and 10 (11%) had mucoepidermoid cancers. Primary disease site included 39 (43%) sinonasal, 35 (39%) oral cavity, 10 (11%) oropharynx, and six (7%) others. Twenty-seven patients (30%) were treated with intensity-modulated radiation therapy. RESULTS: Eight local, four neck, and 24 distant relapses were detected. Local control rates at 5 and 10 years were 90% and 88%, respectively. Advanced T stage was associated with worse local control. Distant metastasis rates were 24% and 28% at 5 and 10 years, respectively. Tumor stage, histology, perineural invasion, and lymphovascular space invasion were significant predictors of distant metastasis on univariate analysis. However, on multivariate analysis only the American Joint Committee on Cancer stage was significant. Overall survival rates were 76% and 63% at 5 and 10 years, respectively. More advanced T stage and N stage correlated with worse overall survival. CONCLUSIONS: Tumor stage remains the best predictor for locoregional and distant disease control of minor salivary gland cancers. Postoperative radiation therapy for high-risk patients results in excellent long-term locoregional disease control. Further work is needed to improve systemic control. LEVEL OF EVIDENCE: 4. Laryngoscope, 2013.

    View details for DOI 10.1002/lary.24081

    View details for Web of Science ID 000326231200029

    View details for PubMedID 23553253

  • Head and Neck Cancers, Version 2.2013 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Pfister, D. G., Ang, K., Brizel, D. M., Burtness, B. A., Busse, P. M., Caudell, J. J., Cmelak, A. J., Colevas, A. D., Dunphy, F., Eisele, D. W., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Kies, M. S., Lydiatt, W. M., Maghami, E., Martins, R., McCaffrey, T., Mittal, B. B., Pinto, H. A., Ridge, J. A., Samant, S., Schuller, D. E., Shah, J. P., Spencer, S., Weber, R. S., Wolf, G. T., Worden, F., Yom, S. S., McMillian, N. R., Hughes, M. 2013; 11 (8): 917-923
  • Stereotactic radiosurgery for retreatment of gross perineural invasion in recurrent cutaneous squamous cell carcinoma of the head and neck. American journal of clinical oncology Tang, C., Fischbein, N. J., Murphy, J. D., Chu, K. P., Bavan, B., Dieterich, S., Hara, W., Kaplan, M. J., Colevas, A. D., Le, Q. 2013; 36 (3): 293-298

    Abstract

    : To report outcomes, failure patterns, and toxicity after stereotactic radiosurgery (SRS) for recurrent head and neck cutaneous squamous cell carcinoma with gross perineural invasion (GPNI).: Ten patients who received SRS as part of retreatment for recurrent head and neck cutaneous squamous cell carcinoma with GPNI were included. All patients exhibited clinical and radiologic evidence of GPNI before SRS. Previous treatments included surgery alone in 3 patients and surgery with adjuvant external beam radiotherapy (EBRT) in 7 patients. Retreatment included SRS alone in 2 and EBRT boosted with SRS in 8 patients. Magnetic resonance images were obtained every 3 to 6 months after SRS to track failure patterns.: At a median 22-month follow-up, the 2-year progression-free and overall survival rates were 20% and 50%, respectively. Seven patients exhibited local failures, all of which occurred outside both SRS and EBRT fields. Five local failures occurred in previously clinically uninvolved cranial nerves (CNs). CN disease spreads through 3 distinct patterns: among different branches of CN V; between CNs V and VII; and between V1 and CNs III, IV, and/or VI. Five patients experienced side effects potentially attributable to radiation.: Although there is excellent in-field control with this approach, the rate of out-of-field failures remains unacceptably high. We found that the majority of failures occurred in previously clinically uninvolved CNs often just outside treatment fields. Novel treatment strategies targeting this mode of perineural spread are needed.

    View details for DOI 10.1097/COC.0b013e3182468019

    View details for PubMedID 22547009

  • Impact of positron emission tomography/computed tomography surveillance at 12 and 24 months for detecting head and neck cancer recurrence CANCER Ho, A. S., Tsao, G. J., Chen, F. W., Shen, T., Kaplan, M. J., Colevas, A. D., Fischbein, N. J., Quon, A., Quynh-Thu Le, Q. T., Pinto, H. A., Fee, W. E., Sunwoo, J. B., Sirjani, D., Hara, W., Yao, M. 2013; 119 (7): 1349-1356

    Abstract

    In head and neck cancer (HNC), 3-month post-treatment positron emission tomography (PET)/computed tomography (CT) reliably identifies persistent/recurrent disease. However, further PET/CT surveillance has unclear benefit. The impact of post-treatment PET/CT surveillance on outcomes is assessed at 12 and 24 months.A 10-year retrospective analysis of HNC patients was carried out with long-term serial imaging. Imaging at 3 months included either PET/CT or magnetic resonance imaging, with all subsequent imaging comprised of PET/CT. PET/CT scans at 12 and 24 months were evaluated only if preceding interval scans were negative. Of 1114 identified patients, 284 had 3-month scans, 175 had 3- and 12-month scans, and 77 had 3-, 12-, and 24-month scans.PET/CT detection rates in clinically occult patients were 9% (15 of 175) at 12 months, and 4% (3 of 77) at 24 months. No difference in outcomes was identified between PET/CT-detected and clinically detected recurrences, with similar 3-year disease-free survival (41% vs 46%, P = .91) and 3-year overall survival (60% vs 54%, P = .70) rates. Compared with 3-month PET/CT, 12-month PET/CT demonstrated fewer equivocal reads (26% vs 10%, P < .001). Of scans deemed equivocal, 6% (5 of 89) were ultimately found to be positive.HNC patients with negative 3-month imaging appear to derive limited benefit from subsequent PET/CT surveillance. No survival differences were observed between PET/CT-detected and clinically detected recurrences, although larger prospective studies are needed for further investigation.

    View details for DOI 10.1002/cncr.27892

    View details for Web of Science ID 000316811900010

  • Biased View of the Role of Site-Specific Therapy in Carcinoma of Unknown Primary. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Percival, M. E., Colevas, A. D. 2013

    View details for PubMedID 23733770

  • Population-based evaluation of incidence trends in oropharyngeal cancer focusing on socioeconomic status, sex, and race/ethnicity. Head & neck Colevas, A. D. 2013

    Abstract

    BACKGROUND: The influences of socioeconomic status (SES) on the incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) are unclear. METHODS: Data from the California Cancer Registry and U.S. Census were used to compare incidence rates and trends of OPSCC and other human papillomavirus-related and -unrelated cancer sites by neighborhood SES, race/ethnicity, and sex. RESULTS: The incidence of OPSCC rose in both higher and lower SES neighborhoods. Absolute rates were greater in the latter. Only non-Hispanic white males with OPSCC demonstrated a significant increase in the incidence rate of squamous cell carcinoma of the head and neck (SCCHN). The incidence rate for this group increased from 4.5/100,000 person-years between 1988 and 1992 to 7.1 between 2003 and 2009. Regression analysis demonstrated an annual percentage change of 1% from 1988 to 1997 and 4% thereafter. CONCLUSIONS: Increases in incidence rates are SES independent. Incidence rates are higher in lower-SES groups. The rise in OPSCC incidence is limited to non-Hispanic white males. © 2013 Wiley Periodicals, Inc. Head Neck, 2013.

    View details for PubMedID 23633438

  • Co-administration of vismodegib with rosiglitazone or combined oral contraceptive in patients with locally advanced or metastatic solid tumors: a pharmacokinetic assessment of drug-drug interaction potential CANCER CHEMOTHERAPY AND PHARMACOLOGY LoRusso, P. M., Piha-Paul, S. A., Mita, M., Colevas, A. D., Malhi, V., Colburn, D., Yin, M., Low, J. A., Graham, R. A. 2013; 71 (1): 193-202

    Abstract

    Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug-drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib's teratogenic potential warranted a DDI study with oral contraceptives (OCs).This single-arm, open-label study included two cohorts of patients with locally advanced or metastatic solid malignancies [Cohort 1: rosiglitazone 4 mg (selective CYP2C8 probe); Cohort 2: OC (norethindrone 1 mg/ethinyl estradiol 35 ?g; CYP3A4 substrate)]. On Day 1, patients received rosiglitazone or OC. On Days 2-7, patients received vismodegib 150 mg/day. On Day 8, patients received vismodegib plus rosiglitazone or OC. The effect of vismodegib on rosiglitazone and OC pharmacokinetic parameters (primary objective) was evaluated through pharmacokinetic sampling over a 24-h period (Days 1 and 8).The mean ± SD vismodegib steady-state plasma concentration (Day 8, N = 51) was 20.6 ± 9.72 ?M (range 7.93-62.4 ?M). Rosiglitazone AUC(0-inf) and C(max) were similar with concomitant vismodegib [?8% change in geometric mean ratios (GMRs); N = 24]. Concomitant vismodegib with OC did not affect ethinyl estradiol AUC(0-inf) and C(max) (?5% change in GMRs; N = 27); norethindrone C(max) and AUC(0-inf) GMRs were higher (12 and 23%, respectively) with concomitant vismodegib.This DDI study in patients with cancer demonstrated that systemic exposure of rosiglitazone (a CYP2C8 substrate) or OC (ethinyl estradiol/norethindrone) is not altered with concomitant vismodegib. Overall, there appears to be a low potential for DDIs when vismodegib is co-administered with other medications.

    View details for DOI 10.1007/s00280-012-1996-6

    View details for Web of Science ID 000313004900021

    View details for PubMedID 23064958

  • Phase I trial of ixabepilone administered as three oral doses each separated by 6 hours every 3 weeks in patients with advanced solid tumors INVESTIGATIONAL NEW DRUGS Kunz, P. L., He, A. R., Colevas, A. D., Pishvaian, M. J., Hwang, J. J., Clemens, P. L., Messina, M., Kaleta, R., Abrahao, F., Sikic, B. I., Marshall, J. L. 2012; 30 (6): 2364-2370

    Abstract

    Ixabepilone, which stabilizes microtubules, has low susceptibility to drug resistance mediated by P-glycoprotein or ?III-tubulin.This study was designed to determine the maximum tolerated dose (MTD) of oral ixabepilone when administered every 6 h for three doses, every 3 weeks, to patients with refractory advanced cancers. Eighteen patients were treated with escalating doses of ixabepilone: three at cohort 1 (30 mg/dose; 90 mg on Day 1), nine at cohort 2 (40 mg/dose; 120 mg on Day 1), and six at cohort 3 (50 mg/dose; 150 mg on Day 1). Serial plasma samples were collected during cycle 1 for pharmacokinetic (PK) measurements.Of the 18 treated patients, eight were male and ten were female. The median age was 59 years, and most had an excellent performance status (KPS 90-100; 61%). There were two dose limiting toxicities (DLT): Grade 4 febrile neutropenia at the 120 mg dose and Grade 4 neutropenic sepsis at the 150 mg dose. Because of the severity and duration of neutropenic sepsis at level 3, level 2 (120 mg) was defined as the MTD and this cohort was expanded to nine patients. High inter-individual variability in plasma drug concentrations was observed during the study, with particularly high levels in two patients with DLT.On the basis of this safety profile, the MTD of oral ixabepilone was defined as 120 mg given as three 40 mg doses each separated by 6 h on Day 1 of a 3-week cycle. However, the PK variability observed makes further development of this oral formulation unlikely.

    View details for DOI 10.1007/s10637-012-9800-3

    View details for Web of Science ID 000310470100028

    View details for PubMedID 22331549

  • A Phase 2 Trial of Flavopiridol (Alvocidib) and Cisplatin in Platin-Resistant Ovarian and Primary Peritoneal Carcinoma: MC0261 GYNECOLOGIC ONCOLOGY Bible, K. C., Peethambaram, P. P., Oberg, A. L., Maples, W., Groteluschen, D. L., Boente, M., Burton, J. K., Dahl, L. C., Tibodeau, J. D., Isham, C. R., Maguire, J. L., Shridhar, V., Kukla, A. K., Voll, K. J., Mauer, M. J., Colevas, A. D., Wright, J., Doyle, L. A., Erlichman, C. 2012; 127 (1): 55-62

    Abstract

    Based upon promising preclinical and phase 1 trial results, combined flavopiridol and cisplatin therapy was evaluated in patients with ovarian and primary peritoneal cancers.A two cohort phase 2 trial of cisplatin (60 mg/m2 IV) immediately followed by flavopiridol (100 mg/m2 IV, 24 h infusion; 21 day cycles) was undertaken in patients with recurrent platin-sensitive or platin-resistant disease (progression>vs. ?6 months following prior platin-based therapy). Measurable disease (RECIST)--or evaluable disease plus CA125>2X post-treatment nadir--and ECOG performance?2 were required.Forty-five patients were enrolled between December 23, 2004 and February 25, 2010: 40 platin-resistant (Group 1), and 5 platin-sensitive (Group 2). In Group 1, the median number of treatment cycles was 3 (range 2-12). Only 10% of patients incurred grade 4 toxicities, but grade 3 toxicities were common (65%): neutropenia (17.5%); nausea (12.5%); vomiting, fatigue, thrombosis, anemia (10% each). Seven patients (17.5%) achieved a confirmed response (1 CR, 6 PR; median duration 118 days); ten additional patients (25%) attained maintained stable disease. Median time to progression was 4.3 months; overall survival was 16.1 months. Pilot translational studies assessed ascites flavopiridol level; surrogate marker studies were uninformative. In Group 2, although 4 of 5 patients responded (2 confirmed PRs with median time to progression, 10.8 months and median overall survival 20.6 months) the cohort was closed due to poor accrual.The assessed flavopiridol and cisplatin regimen displayed clinical activity in platin resistant and sensitive ovarian/primary peritoneal cancers, meriting further study.

    View details for DOI 10.1016/j.ygyno.2012.05.030

    View details for Web of Science ID 000308783800012

    View details for PubMedID 22664059

  • Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Trakul, N., Chang, C. N., Harris, J., Chapman, C., Rao, A., Shen, J., Quinlan-Davidson, S., Filion, E. J., Wakelee, H. A., Colevas, A. D., Whyte, R. I., Dieterich, S., Maxim, P. G., Hristov, D., Tran, P., Quynh-Thu Le, Q. T., Loo, B. W., Diehn, M. 2012; 84 (1): 231-237

    Abstract

    Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy.We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18-25 Gy) (Group 1), and larger tumors (gross tumor volume ?12 mL) received multifraction regimens with BED ?100 Gy (total dose, 50-60 Gy in three to four fractions) (Group 2).The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02).A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

    View details for DOI 10.1016/j.ijrobp.2011.10.071

    View details for Web of Science ID 000308061900060

    View details for PubMedID 22381907

  • A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours BRITISH JOURNAL OF CANCER Diaz-Padilla, I., Siu, L. L., San Pedro-Salcedo, M., Razak, A. R., Colevas, A. D., Shepherd, F. A., Leighl, N. B., Neal, J. W., Thibault, A., Liu, L., Lisano, J., Gao, B., Lawson, E. B., Wakelee, H. A. 2012; 107 (4): 604-611

    Abstract

    To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin.Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg(-1) in combination with fixed doses of pemetrexed (500 mg m(-2)) plus cisplatin (75?mg?m(-2)) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations.Eighteen patients were enrolled. One patient dosed at 4 mg kg(-1) experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg(-1) cohort or the 6 mg kg(-1) dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ? 3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted.The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg(-1), to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.

    View details for DOI 10.1038/bjc.2012.319

    View details for Web of Science ID 000307770300005

    View details for PubMedID 22805331

  • Validation that metabolic tumor volume predicts outcome in head-and-neck cancer. International journal of radiation oncology, biology, physics Tang, C., Murphy, J. D., Khong, B., La, T. H., Kong, C., Fischbein, N. J., Colevas, A. D., Iagaru, A. H., Graves, E. E., Loo, B. W., Le, Q. 2012; 83 (5): 1514-1520

    Abstract

    We have previously reported that metabolic tumor volume (MTV) obtained from pretreatment (18)F-fluorodeoxydeglucose positron emission tomography (FDG PET)/ computed tomography (CT) predicted outcome in patients with head-and-neck cancer (HNC). The purpose of this study was to validate these results on an independent dataset, determine whether the primary tumor or nodal MTV drives this correlation, and explore the interaction with p16(INK4a) status as a surrogate marker for human papillomavirus (HPV).The validation dataset in this study included 83 patients with squamous cell HNC who had a FDG PET/CT scan before receiving definitive radiotherapy. MTV and maximum standardized uptake value (SUV(max)) were calculated for the primary tumor, the involved nodes, and the combination of both. The primary endpoint was to validate that MTV predicted progression-free survival and overall survival. Secondary analyses included determining the prognostic utility of primary tumor vs. nodal MTV.Similarly to our prior findings, an increase in total MTV of 17 cm(3) (difference between the 75th and 25th percentiles) was associated with a 2.1-fold increase in the risk of disease progression (p = 0.0002) and a 2.0-fold increase in the risk of death (p = 0.0048). SUV(max) was not associated with either outcome. Primary tumor MTV predicted progression-free (hazard ratio [HR] = 1.94; p < 0.0001) and overall (HR = 1.57; p < 0.0001) survival, whereas nodal MTV did not. In addition, MTV predicted progression-free (HR = 4.23; p < 0.0001) and overall (HR = 3.21; p = 0.0029) survival in patients with p16(INK4a)-positive oropharyngeal cancer.This study validates our previous findings that MTV independently predicts outcomes in HNC. MTV should be considered as a potential risk-stratifying biomarker in future studies of HNC.

    View details for DOI 10.1016/j.ijrobp.2011.10.023

    View details for PubMedID 22270174

  • A randomized phase II study of cilengitide (EMD 121974) in patients with metastatic melanoma MELANOMA RESEARCH Kim, K. B., Prieto, V., Joseph, R. W., Diwan, A. H., Gallick, G. E., Papadopoulos, N. E., Bedikian, A. Y., Camacho, L. H., Hwu, P., Ng, C. S., Wei, W., Johnson, M. M., Wittemer, S. M., Vardeleon, A., Reckeweg, A., Colevas, A. D. 2012; 22 (4): 294-301

    Abstract

    Cilengitide (EMD 121974) is a selective inhibitor of integrins ?v?3 and ?v?5. The ?v?3 promotes the proliferation of tumor-associated endothelial cells and potentially the survival of melanoma cells. We conducted a randomized phase II trial in patients with metastatic melanoma to evaluate the clinical efficacy of cilengitide. Patients with stage IV or unresectable stage III melanoma who were either chemonaive or who had previously received one systemic therapy were enrolled. Patients were randomly assigned to either 500 or 2000 mg of cilengitide administered intravenously twice weekly. The primary aim of this study was to determine the progression-free survival rate at 8 weeks. Tumor samples and blood samples were collected for pharmacodynamic and pharmacokinetic studies. Twenty-nine patients were enrolled, of whom 26 were treated (14 at 500 mg and 12 at 2000 mg). Among those treated, only three were progression free at 8 weeks: two in the 500 mg arm and one in the 2000 mg arm. One patient in the 2000 mg arm showed a prolonged partial response after an initial 28% enlargement of her target lesions. The treatment was well tolerated without clinically significant adverse events. The sole responder and one of two patients with stable disease had no ?v?3 expression at baseline. Overall, ?v?3 expression was decreased by day 8 of the treatment (P=0.05). Cilengitide was well tolerated by patients in both the treatment arms but had minimal clinical efficacy as a single-agent therapy for metastatic melanoma, and the efficacy was not related to baseline ?v?3 expression.

    View details for DOI 10.1097/CMR.0b013e32835312e4

    View details for Web of Science ID 000306278300002

    View details for PubMedID 22668797

  • Phase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl(+) hematological malignancies CANCER CHEMOTHERAPY AND PHARMACOLOGY Bose, P., Perkins, E. B., Honeycut, C., Wellons, M. D., Stefan, T., Jacobberger, J. W., Kontopodis, E., Beumer, J. H., Egorin, M. J., Imamura, C. K., Figg, W. D., Karp, J. E., Koc, O. N., Cooper, B. W., Luger, S. M., Colevas, A. D., Roberts, J. D., Grant, S. 2012; 69 (6): 1657-1667

    Abstract

    Imatinib is an inhibitor of the Bcr-Abl tyrosine kinase; however, resistance is common. Flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, down-regulates short-lived anti-apoptotic proteins via inhibition of transcription. In preclinical studies, flavopiridol synergizes with imatinib to induce apoptosis. We investigated this novel combination regimen in patients with Bcr-Abl(+) malignancies.In a phase I dose-escalation study, imatinib was administered orally daily, and flavopiridol by 1 h intravenous infusion weekly for 3 weeks every 4 weeks. Adults with chronic myelogenous leukemia or Philadelphia chromosome-positive acute leukemia were eligible. Patients were divided into two strata based on peripheral blood and bone marrow blast counts. The primary objective was to identify the recommended phase II doses for the combination. Correlative pharmacokinetic and pharmacodynamic studies were also performed.A total of 21 patients received study treatment. Four dose levels were evaluated before the study was closed following the approval of the second-generation Bcr-Abl tyrosine kinase inhibitors (TKIs). Five patients responded, including four sustained responses. Four patients had stable disease. All but one responder, and all patients with stable disease had previously been treated with imatinib. One patient had a complete response sustained for 30 months. Changes in expression of phospho-Bcr/Abl, -Stat5, and Mcl-1 were monitored. No major pharmacokinetic interaction was observed.This is the first study to evaluate the combination of a CDK inhibitor and a TKI in humans. The combination of flavopiridol and imatinib is tolerable and produces encouraging responses, including in some patients with imatinib-resistant disease.

    View details for DOI 10.1007/s00280-012-1839-5

    View details for Web of Science ID 000304622600028

    View details for PubMedID 22349810

  • A phase I dose-escalation and pharmacokinetic study of enzastaurin and erlotinib in patients with advanced solid tumors CANCER CHEMOTHERAPY AND PHARMACOLOGY Padda, S. K., Krupitskaya, Y., Chhatwani, L., Fisher, G. A., Colevas, A. D., Pedro-Salcedo, M. S., Decker, R., Latz, J. E., Wakelee, H. A. 2012; 69 (4): 1013-1020

    Abstract

    Enzastaurin, an oral serine/threonine kinase inhibitor, targets the protein kinase C and AKT pathways with anti-tumor and anti-angiogenic effects. Erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, has activity in solid tumors. Based on the promising combination of EGFR inhibitors and anti-angiogenic agents, this phase I trial was initiated.This single-institution, open-label, non-randomized trial used a standard 3 + 3 dose-escalation model in patients with advanced solid malignancies including non-small-cell lung cancer (NSCLC). Two dose levels of enzastaurin (with loading doses) were explored: 250 mg daily and 500 mg daily. Erlotinib was given at 150 mg daily.Sixteen patients were enrolled in this study (median age, 64 years). Most patients were heavily pre-treated, female, and Caucasian and had NSCLC. The highest dose of enzastaurin, 500 mg daily, was tolerated with no unexpected adverse events and no alteration in the pharmacokinetics of either drug at this dose level. The mean clearance was 5.75 L/h for erlotinib and 53.8 L/h for enzastaurin. The most common possibly drug-related grade 3-4 adverse events included diarrhea (25.0%), neurologic symptoms (18.8%), and vomiting (18.8%). Activity was noted, with a partial response in one patient and prolonged disease stability for >12 cycles in three patients.The combination of enzastaurin 500 mg daily and erlotinib 150 mg daily is well tolerated and does not alter the pharmacokinetics of the individual drugs, with clinical activity seen. A phase II trial of this combination has been initiated in patients with advanced-stage NSCLC.

    View details for DOI 10.1007/s00280-011-1792-8

    View details for Web of Science ID 000302327300019

    View details for PubMedID 22160298

  • Maintenance Bevacizumab is Associated With Increased Hemoglobin in Patients With Advanced, Nonsquamous, Non-Small Cell Lung Cancer CANCER INVESTIGATION Riess, J. W., Logan, A. C., Krupitskaya, Y., Padda, S., Clement-Duchene, C., Ganjoo, K., Colevas, A. D., San Pedro-Salcedo, M., Kuo, C. J., Wakelee, H. A. 2012; 30 (3): 231-235

    Abstract

    We retrospectively analyzed hematologic parameters in 22 patients with advanced, nonsquamous, NSCLC undergoing VEGF inhibition on a phase II clinical trial of bevacizumab, carboplatin, and gemcitabine. We also examined TTP in relation to hemoglobin changes. Median hemoglobin increased significantly from a 12.9 g/dL pretreatment to 13.8 g/dL (p =.01) after the second cycle of maintenance bevacizumab until the first off cycle measurement. There was no difference in TTP in patients who achieved a rise in hemoglobin compared with patients who did not (median 238 days vs. 268 days, p =.38.) Maintenance bevacizumab is associated with increased hemoglobin in advanced, nonsquamous, NSCLC patients.

    View details for DOI 10.3109/07357907.2012.656862

    View details for Web of Science ID 000300657200005

    View details for PubMedID 22360362

  • Mucosal Melanoma of the Head and Neck JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Pfister, D. G., Ang, K., Brizel, D. M., Burtness, B., Cmelak, A. J., Dimitrios Colevas, A., Dunphy, F., Eisele, D. W., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Kies, M. S., Lydiatt, W. M., Maghami, E., Martins, R., McCaffrey, T., Mittal, B. B., Pinto, H. A., Ridge, J. A., Samant, S., Sanguineti, G., Schuller, D. E. 2012; 10 (3): 320-338

    View details for Web of Science ID 000301222300006

    View details for PubMedID 22393194

  • Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer JOURNAL OF CLINICAL INVESTIGATION Kohrt, H. E., Houot, R., Weiskopf, K., Goldstein, M. J., Scheeren, F., Czerwinski, D., Colevas, A. D., Weng, W., Clarke, M. F., Carlson, R. W., Stockdale, F. E., Mollick, J. A., Chen, L., Levy, R. 2012; 122 (3): 1066-1075

    Abstract

    Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2; also known as HER-2/neu), is indicated for the treatment of women with either early stage or metastatic HER2(+) breast cancer. It kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. Here, we have shown that upon encountering trastuzumab-coated, HER2-overexpressing breast cancer cells, human NK cells become activated and express the costimulatory receptor CD137. CD137 activation, which was dependent on NK cell expression of the Fc?RIII receptor, occurred both in vitro and in the peripheral blood of women with HER2-expressing breast cancer after trastuzumab treatment. Stimulation of trastuzumab-activated human NK cells with an agonistic mAb specific for CD137 killed breast cancer cells (including an intrinsically trastuzumab-resistant cell line) more efficiently both in vitro and in vivo in xenotransplant models of human breast cancer, including one using a human primary breast tumor. The enhanced cytotoxicity was restricted to antibody-coated tumor cells. This sequential antibody strategy, combining a tumor-targeting antibody with a second antibody that activates the host innate immune system, may improve the therapeutic effects of antibodies against breast cancer and other HER2-expressing tumors.

    View details for DOI 10.1172/JCI61226

    View details for Web of Science ID 000301021500029

    View details for PubMedID 22326955

  • Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial LANCET ONCOLOGY Lee, N. Y., Zhang, Q., Pfister, D. G., Kim, J., Garden, A. S., Mechalakos, J., Hu, K., Le, Q. T., Colevas, A. D., Glisson, B. S., Chan, A. T., Ang, K. K. 2012; 13 (2): 172-180

    Abstract

    We aimed to improve the outcomes for locoregionally advanced nasopharyngeal carcinoma by testing the feasibility and safety of the addition of bevacizumab to chemoradiotherapy.We enrolled patients older than 18 years with stage IIB-IVB nasopharyngeal carcinoma from 19 centres in North America and Hong Kong. Treatment consisted of three cycles of bevacizumab (15 mg/kg) and cisplatin (100 mg/m(2)) both given on days 1, 22, and 43 of radiation (70 Gy) with intensity-modulated radiation therapy delivered over 33 days on a daily basis, Monday through Friday. Patients then received three cycles of bevacizumab (15 mg/kg) and cisplatin (80 mg/m(2)), both given on days 64, 85, and 106 after radiation, and three cycles of fluorouracil (1000 mg/m(2) per day), given on days 64-67, 85-88, and 106-109 after radiation. The primary endpoint was the occurrence of treatment-related grade 4 haemorrhage or any grade 5 adverse event in the first year. Analyses were done with all eligible patients who started protocol treatment. The trial is registered at ClinicalTrials.gov, number NCT00408694.From Dec 13, 2006, to Feb 5, 2009, we enrolled 46 patients, of whom 44 were eligible for analysis. We recorded no grade 3-4 haemorrhages or grade 5 adverse events; nine patients (20%) had a treatment-related grade 1-2 haemorrhage. Nine patients had one or more grade 4 blood or bone marrow-related complication (grade 4 leucopenia was noted in six patients, grade 4 lymphopenia in five, grade 4 neutrophils in five, and grade 4 anaemia in one). One patient had two grade 4 infections with grade 3-4 neutrophils. One patient reported grade 4 tinnitus, one patient reported grade 4 thrombosis, one reported grade 4 radiation mucositis, and two reported grade 4 pharyngolaryngeal pain. With a median follow-up of 2·5 years (IQR 2·1-2·9), the estimated 2 year locoregional progression-free interval was 83·7% (95% CI 72·6-94·9), the 2 year distant metastasis-free interval was 90·8% (82·2-99·5), the 2 year progression-free survival was 74·7% (61·8-87·6), and 2 year overall survival was 90·9% (82·3-99·4).The addition of bevacizumab to standard chemoradiation treatment for patients with nasopharyngeal carcinoma is feasible, and might delay the progression of subclinical distant disease.National Cancer Institute, USA.

    View details for DOI 10.1016/S1470-2045(11)70303-5

    View details for Web of Science ID 000300197400042

    View details for PubMedID 22178121

  • The use of epidermal growth factor receptor monoclonal antibodies in squamous cell carcinoma of the head and neck. Chemotherapy research and practice Russell, J. S., Colevas, A. D. 2012; 2012: 761518-?

    Abstract

    Targeting of the EGF receptor (EGFR) has become a standard of care in several tumor types. In squamous cell carcinoma of the head and neck, monoclonal antibodies directed against EGFR have become a regular component of therapy for curative as well as palliative treatment strategies. These agents have anti-tumor efficacy as a single modality and have demonstrated synergistic tumor killing when combined with radiation and/or chemotherapy. While cetuximab has been the primary anti-EGFR monoclonal antibody used in the US, variant anti-EGFR monoclonal antibodies have been used in several clinical studies and shown benefit with improved toxicity profiles. Next generation anti-EGFR monoclonal antibodies may demonstrate multi-target epitope recognition, enhanced immune cell stimulation, or conjugation with radioisotopes in order to improve clinical outcomes. Identification of the specific patient subset that would optimally benefit from anti-EGFR monoclonal antibodies remains an elusive goal.

    View details for DOI 10.1155/2012/761518

    View details for PubMedID 23150825

  • Head and Neck Cancers JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Pfister, D. G., Ang, K., Brizel, D. M., Burtness, B. A., Cmelak, A. J., Colevas, D., Dunphy, F., Eisele, D. W., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Kies, M. S., Lydiatt, W. M., Maghami, E., Martins, R., McCaffrey, T., Mittal, B. B., Pinto, H. A., Ridge, J. A., Samant, S., Sanguineti, G., Schuller, D. E., Shah, J. P., Spencer, S., Trotti, A., Weber, R. S., Wolf, G. T., Worden, F. 2011; 9 (6): 596-649

    View details for Web of Science ID 000291282100002

    View details for PubMedID 21636536

  • Controversies in the Locoregional Management of Head and Neck Cancer JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Brizel, D. M., Lydiatt, W., Colevas, A. D. 2011; 9 (6): 653-662

    Abstract

    Head and neck cancer (HNC) is a heterogeneous combination of various sites and types of disease. This manuscript elaborates on 3 important and current issues: the emerging role of human papilloma virus (HPV) in oropharyngeal cancer (OPC), current considerations in systemic therapy for advanced disease, and evolving treatment of the neck. Exogenous carcinogens, most notably tobacco, have classically been implicated in the development of HNC. A large increase in the incidence of OPC has occurred in the past few decades, predominantly in nontobacco users, and is caused by HPV. This disease is unique in many respects and presents an opportunity for novel therapeutic approaches. Because the prognosis for HPV-related HNC is better, regardless of whether surgery or radiation is used as the primary therapy, the reduction of treatment-related morbidity has assumed increasing importance and provides unique opportunities and challenges for de-escalation of therapies. Radiotherapy (RT) and concurrent cisplatin is the most commonly used nonsurgical platform for locally advanced disease. New data suggest that viable alternatives exist to the typical 3 cycles of bolus high-dose cisplatin. The role of RT and concurrent taxanes remains less understood. Similarly, the value of integrating epidermal growth factor inhibition and concurrent chemoradiation is under continuing investigation. The use of PET scanning is changing the traditional use of adjuvant neck dissection after RT or chemoradiation. Recent data support the use of surgery in the presence of a positive posttreatment PET, and observation in the setting of a negative posttreatment scan.

    View details for Web of Science ID 000291282100003

    View details for PubMedID 21636537

  • INTENSITY-MODULATED RADIOTHERAPY FOR LOCALLY ADVANCED CANCERS OF THE LARYNX AND HYPOPHARYNX HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Daly, M. E., Le, Q., Jain, A. K., Maxim, P. G., Hsu, A., Loo, B. W., Kaplan, M. J., Fischbein, N. J., Colevas, A. D., Pinto, H., Chang, D. T. 2011; 33 (1): 103-111

    Abstract

    Limited data evaluate intensity-modulated radiotherapy (IMRT) for cancers of the hypopharynx and larynx. We report clinical outcomes and failure patterns for these patients.Between September 2001 and December 2007, 42 patients with squamous cell carcinoma (SCC) of the hypopharynx (n = 23) and larynx (n = 19) underwent IMRT, 11 postoperatively and 31 definitively. Thirty-six received systemic therapy. Median follow-up was 30 months among surviving patients.Three local failures occurred within the high-dose region and 3 occurred in regional nodes. Seven patients developed distant metastasis as the initial failure. Three-year actuarial estimates of locoregional control, freedom from distant metastasis, and overall survival rates were, respectively, 80%, 72%, and 46%.IMRT provides good locoregional control for SCC of the hypopharynx and larynx compared with historical controls. Locoregional relapses occurred in the high-dose volumes, suggesting adequate target volume delineation. Hypopharyngeal tumors, which fare worse than laryngeal tumors, warrant investigation of more aggressive treatment.

    View details for DOI 10.1002/hed.21406

    View details for Web of Science ID 000286290400017

    View details for PubMedID 20848427

  • A Phase II First-Line Study of Gemcitabine, Carboplatin, and Bevacizumab in Advanced Stage Nonsquamous Non-small Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Clement-Duchene, C., Krupitskaya, Y., Ganjoo, K., Lavori, P., McMillan, A., Kumar, A., Zhao, G., Padda, S., Zhou, L., San Pedro-Salcedo, M., Colevas, A. D., Wakelee, H. A. 2010; 5 (11): 1821-1825

    Abstract

    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.Patients with untreated advanced nonsquamous non-small cell lung cancer, with no evidence of brain metastases and not on anticoagulation were eligible. Patients received gemcitabine 1000 mg/m on days 1 and 8; carboplatin area under the curve 5 day 1; and bevacizumab 15 mg/kg day 1 every 3 weeks for up to six cycles. Bevacizumab was then continued every 3 weeks until disease progression or unacceptable toxicity.From July 2006 to December 2008, 48 patients were enrolled: 23 (48%) men, 25 (52%) women, and 19 (40%) never smokers. One patient never received therapy and is not included in the analysis. Median cycle number was 8 (1-42) with 37 patients (78.7%) completing ?4 cycles of three drugs. Dose reductions occurred in 34 (72.3%) patients. Grade 3/4 toxicities included neutropenia (47%/15%), thrombocytopenia (11%/15%), anemia (6%/0%), dyspnea (6%/2%), bacterial pneumonia (4%/0%), and hypertension (4%/2%). No neutropenic fevers occurred. One patient died of hemoptysis. Grade 3 bleeding occurred in three other patients. There were seven (14.9%) partial responses. Median time to first event (progression/death/toxicity requiring discontinuation) was 6.4 months (95% confidence interval: 4.8-7.9 months). The median overall survival (OS) was 12.8 months (95% confidence interval: 10.0-16.5). The OS is 57% at 1 year and 10% at 2 years.Although perhaps skewed by a high proportion of nonsmokers and women, treatment with gemcitabine/carboplatin/bevacizumab has an acceptable toxicity profile with promising median OS despite a low response rate.

    View details for DOI 10.1097/JTO.0b013e3181f1d23c

    View details for Web of Science ID 000283491100017

    View details for PubMedID 20881641

  • HIGHER INCIDENCE OF HEAD AND NECK CANCERS AMONG VIETNAMESE AMERICAN MEN IN CALIFORNIA HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Filion, E. J., McClure, L. A., Huang, D., Seng, K., Kaplan, M. J., Colevas, A. D., Gomez, S. L., Chang, E. T., Le, Q. 2010; 32 (10): 1336-1344

    Abstract

    Our aim was to determine the incidence rates of head and neck cancer in Vietnamese Californians compared with other Asian and non-Asian Californians.Age-adjusted incidence rates of head and neck cancer between 1988 and 2004 were computed for Vietnamese Californians compared with other racial/ethnic groups by time period, ethnicity, neighborhood-level socioeconomic status (SES), and sex using data from the population-based California Cancer Registry (CCR). Data by smoking and alcohol status were tabulated from the California Health Interview Survey.Vietnamese men had a higher incidence rate of head and neck cancer than other Asian men. Specifically, the laryngeal cancer rate was significantly higher for Vietnamese men (6.5/100,000; 95% confidence interval [CI], 5.0-8.2) than all other Asian men (range, 2.6-3.8/100,000), except Korean men (5.1/100,000; 95% CI, 3.9-6.4). Both Vietnamese and Korean men had the highest percentage of current smokers. Neighborhood SES was inversely related to head and neck cancer rates among Vietnamese men and women.The higher incidence rate of head and neck cancer in Vietnamese men may correspond to the higher smoking prevalence in this group. Individual-level data are needed to establish the link of tobacco, alcohol, and other risk factors with head and neck cancer in these patients.

    View details for DOI 10.1002/hed.21330

    View details for Web of Science ID 000282707500008

    View details for PubMedID 20091688

  • MOLECULAR AND CLINICAL RESPONSES IN A PILOT STUDY OF GEFITINIB WITH PACLITAXEL AND RADIATION IN LOCALLY ADVANCED HEAD-AND-NECK CANCER INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Van Waes, C., Allen, C. T., Citrin, D., Gius, D., Colevas, A. D., Harold, N. A., Rudy, S., Nottingham, L., Muir, C., Chen, Z., Singh, A. K., Dancey, J., Morris, J. C. 2010; 77 (2): 447-454

    Abstract

    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).This was a pilot Phase I dose-escalation study. Eligibility included Stage III to IVB HNSCC, age >or=18 years, no prior RT or chemotherapy, adequate organ function, and informed consent. Endpoints included determination of maximum tolerated dose (MTD) and analysis of treatment effect on EGFR signaling, tumor cell proliferation, and apoptosis in biopsy samples.Ten patients were treated. The MTD of this combination was GEF 250 mg/d with PAC 36 mg/m(2) intravenously weekly x 6 with concurrent RT. Grade 3/4 toxicities included prolonged (>8 weeks) stomatitis (7 patients), infection (2 patients), and interstitial pneumonitis (1 patient). There were five complete responses (CR) and two partial responses (PR). Of 7 patients undergoing serial biopsies, only 1 patient demonstrated a reduction in phosphorylated EGFR, decreased downstream signaling, and reduced cellular proliferation after initiating GEF.Inhibition of EGFR by GEF was observed in only one of seven tumors studied. The addition of GEF to PAC and RT did not appear to improve the response of locally advanced HNSCC compared with our prior experience with PAC and RT alone. This treatment appeared to delay recovery from stomatitis.

    View details for DOI 10.1016/j.ijrobp.2009.05.037

    View details for Web of Science ID 000278167500018

    View details for PubMedID 19879702

  • LONG-TERM OUTCOMES AND TOXICITY OF CONCURRENT PACLITAXEL AND RADIOTHERAPY FOR LOCALLY ADVANCED HEAD-AND-NECK CANCER INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Citrin, D., Mansueti, J., Likhacheva, A., Sciuto, L., Albert, P. S., Rudy, S. F., Cooley-Zgela, T., Cotrim, A., Solomon, B., Colevas, A. D., Russo, A., Morris, J. C., Herscher, L., Smith, S., Van Waes, C. 2009; 74 (4): 1040-1046

    Abstract

    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.Between 1995 and 1999, 35 patients with nonmetastatic, Stage III or IV squamous cell carcinoma of the head and neck were treated with three cycles of paclitaxel as a 120-h continuous infusion beginning on Days 1, 21, and 42, concurrent with radiotherapy. The initial 16 patients received 105 mg/m(2)/cycle, and the subsequent 19 patients received 120 mg/m(2)/cycle. External beam radiotherapy was delivered to a dose of 70.2-72 Gy at five fractions weekly. Patients were followed to evaluate the disease outcomes and late toxicity of this regimen.The median follow-up for all patients was 56.5 months. The median survival was 56.5 months, and the median time to local recurrence was not reached. Of the 35 patients, 15 (43%) developed hypothyroidism. Of the 33 patients who underwent percutaneous endoscopic gastrostomy tube placement, 11 were percutaneous endoscopic gastrostomy tube dependent until death or their last follow-up visit. Also, 5 patients (14%) required a tracheostomy until death, and 3 (9%) developed a severe esophageal stricture. All evaluated long-term survivors exhibited salivary hypofunction. Fibrosis in the radiation field occurred in 24 patients (69%).The results of our study have shown that concurrent chemoradiotherapy with a 120-h infusion of paclitaxel provides long-term local control and survival in patients with squamous cell carcinoma of the head and neck. Xerostomia, hypothyroidism, esophageal and pharyngeal complications, and subcutaneous fibrosis were common long-term toxicities; however, the vast majority of toxicities were grade 1 or 2.

    View details for DOI 10.1016/j.ijrobp.2008.09.053

    View details for Web of Science ID 000267505000010

    View details for PubMedID 19117692

  • 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 BRITISH JOURNAL OF HAEMATOLOGY O'Connor, O. A., Portlock, C., Moskowitz, C., Straus, D., Hamlin, P., Stubblefield, M., Dumetrescu, O., Colevas, A. D., Grant, B., Zelenetz, A. 2008; 143 (2): 201-209

    Abstract

    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 < or =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.

    View details for DOI 10.1111/j.1365-2141.2008.07271.x

    View details for Web of Science ID 000259505900005

    View details for PubMedID 18691173

  • Head and neck cancers. Journal of the National Comprehensive Cancer Network Forastiere, A. A., Ang, K., Brizel, D., Brockstein, B. E., Burtness, B. A., Cmelak, A. J., Colevas, A. D., Dunphy, F., Eisele, D. W., Goepfert, H., Hicks, W. L., Kies, M. S., Lydiatt, W. M., Maghami, E., Martins, R., McCaffrey, T., Mittal, B. B., Pfister, D. G., Pinto, H. A., Posner, M. R., Ridge, J. A., Samant, S., Schuller, D. E., Shah, J. P., Spencer, S., Trotti, A., Weber, R. S., Wolf, G. T., Worden, F. 2008; 6 (7): 646-695

    View details for PubMedID 18691457

  • Phase II study of ispinesib in recurrent or metastatic squamous cell carcinoma of the head and neck INVESTIGATIONAL NEW DRUGS Tang, P. A., Siu, L. L., Chen, E. X., Hotte, S. J., Chia, S., Schwarz, J. K., Pond, G. R., Johnson, C., Colevas, A. D., Synold, T. W., Vasist, L. S., Winquist, E. 2008; 26 (3): 257-264

    Abstract

    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.

    View details for DOI 10.1007/s10637-007-9098-8

    View details for Web of Science ID 000255194000008

    View details for PubMedID 18038218

  • Patient-reported outcomes and the evolution of adverse event reporting in oncology JOURNAL OF CLINICAL ONCOLOGY Trotti, A., Colevas, A. D., Setser, A., Basch, E. 2007; 25 (32): 5121-5127

    Abstract

    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.

    View details for DOI 10.1200/JCO.2007.12.4784

    View details for Web of Science ID 000251074200013

    View details for PubMedID 17991931

  • Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer NEW ENGLAND JOURNAL OF MEDICINE Posner, M. R., Hershock, D. M., Blajman, C. R., Mickiewicz, E., Winquist, E., Gorbounova, V., Tjulandin, S., Shin, D. M., Cullen, K., Ervin, T. J., Murphy, B. A., Raez, L. E., Cohen, R. B., Spaulding, M., Tishler, R. B., Roth, B., del Carmen Viroglio, R., Venkatesan, V., Romanov, I., Agarwala, S., Harter, K. W., Dugan, M., Cmelak, A., Markoe, A. M., Read, P. W., Steinbrenner, L., Colevas, A. D., Norris, C. M., Haddad, R. I. 2007; 357 (17): 1705-1715

    Abstract

    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.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.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.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].).

    View details for Web of Science ID 000250355100006

    View details for PubMedID 17960013

  • A phase I trial of BMS-247550 (NSC# 710428) and gemcitabine in patients with advanced solid tumors INVESTIGATIONAL NEW DRUGS Hensley, M. L., Dizon, D., Derosa, F., Venkatraman, E., Sabbatini, P., Chi, D. S., Dupont, J., Colevas, A. D., Spriggs, D., Aghajanian, C. 2007; 25 (4): 335-341

    Abstract

    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=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.

    View details for DOI 10.1007/s10637-007-9035-x

    View details for Web of Science ID 000247275600006

    View details for PubMedID 17364235

  • Sequential flavopiridol, cytosine arabinoside, and mitoxantrone: A phase II trial in adults with poor-risk acute myelogenous leukemia CLINICAL CANCER RESEARCH Karp, J. E., Smith, B. D., Levis, M. J., Gore, S. D., Greer, J., Hattenburg, C., Briel, J., Jones, R. J., Wright, J. J., Colevas, A. D. 2007; 13 (15): 4467-4473

    Abstract

    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.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.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%.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.

    View details for DOI 10.1158/1078-0432.CCR-07-0381

    View details for Web of Science ID 000248525100024

    View details for PubMedID 17671131

  • Inhibition of poly (ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models CLINICAL CANCER RESEARCH Albert, J. M., Cao, C., Kim, K. W., Willey, C. D., Geng, L., Xiao, D., Wang, H., Sandler, A., Johnson, D. H., Colevas, A. D., Low, J., Rothenberg, M. L., Lu, B. 2007; 13 (10): 3033-3042

    Abstract

    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.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.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.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.

    View details for DOI 10.1158/1078-0432.CCR-06-2872

    View details for Web of Science ID 000246572600029

    View details for PubMedID 17505006

  • Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma JOURNAL OF CLINICAL ONCOLOGY Nabors, L. B., Mikkelsen, T., Rosenfeld, S. S., Hochberg, F., Akella, N. S., Fisher, J. D., Cloud, G. A., Zhang, Y., Carson, K., Wittemer, S. M., Colevas, A. D., Grossman, S. A. 2007; 25 (13): 1651-1657

    Abstract

    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 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.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.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.

    View details for DOI 10.1200/JCO.2006.06.6514

    View details for Web of Science ID 000246299500006

    View details for PubMedID 17470857

  • A phase II study of ixabepilone (BMS-247550) in metastatic renal-cell carcinoma CANCER BIOLOGY & THERAPY Posadas, E. M., Undevia, S., Manchen, E., Wade, J. L., Colevas, A. D., Karrison, T., Vokes, E. E., Stadler, W. M. 2007; 6 (4): 490-493

    Abstract

    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.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.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.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.

    View details for Web of Science ID 000248102700009

    View details for PubMedID 17457044

  • Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia BLOOD Byrd, J. C., Lin, T. S., Dalton, J. T., Wu, D., Phelps, M. A., Fischer, B., Moran, M., Blum, K. A., Rovin, B., Brooker-McEldowney, M., Broering, S., Schaaf, L. J., Johnson, A. J., Lucas, D. M., Heerema, N. A., Lozanski, G., Young, D. C., Suarez, J., Colevas, A. D., Grever, M. R. 2007; 109 (2): 399-404

    Abstract

    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.

    View details for DOI 10.1182/blood-2006-05-020735

    View details for Web of Science ID 000243416600008

    View details for PubMedID 17003373

  • Phase I study of continuous weekly dosing of dimethylamino benzoylphenylurea (BPU) in patients with solid tumours EUROPEAN JOURNAL OF CANCER Messersmith, W. A., Rudek, M. A., Baker, S. D., Zhao, M., Collins, C., Colevas, A. D., Donehower, R. C., Carducci, M. A., Wolff, A. C. 2007; 43 (1): 78-86

    Abstract

    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.

    View details for DOI 10.1016/j.ejca.2006.09.006

    View details for Web of Science ID 000244311000019

    View details for PubMedID 17084620

  • Adverse event reporting in publications compared with sponsor database for cancer clinical trials JOURNAL OF CLINICAL ONCOLOGY Scharf, O., Colevas, A. D. 2006; 24 (24): 3933-3938

    Abstract

    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.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.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.Lack of consistency in and reporting of AEs are associated with NCI database and trial publication AE data discrepancy.

    View details for DOI 10.1200/JCO.2005.05.3959

    View details for Web of Science ID 000240052300020

    View details for PubMedID 16921045

  • Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck JOURNAL OF CLINICAL ONCOLOGY Colevas, A. D. 2006; 24 (17): 2644-2652

    Abstract

    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.

    View details for DOI 10.1200/JCO.2005.05.3348

    View details for Web of Science ID 000238379900008

    View details for PubMedID 16763278

  • Phase II evaluations of cilengitide in asymptomatic patients with androgen-independent prostate cancer: Scientific rationale and study design CLINICAL GENITOURINARY CANCER Beekman, K. W., Colevas, A. D., Cooney, K., DiPaola, R., Dunn, R. L., Gross, M., Keller, E. T., Pienta, K. J., Ryan, C. J., Smith, D., Hussain, M. 2006; 4 (4): 299-302

    Abstract

    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.

    View details for Web of Science ID 000242526800012

    View details for PubMedID 16729916

  • In vitro and in vivo clinical pharmacology of dimethyl benzoylphenylurea, a novel oral tubulin-interactive agent CLINICAL CANCER RESEARCH Rudek, M. A., Zhao, M., Smith, N. F., Robey, R. W., He, P., Hallur, G., Khan, S., Hidalgo, M., Jimeno, A., Colevas, A. D., Messersmith, W. A., Wolff, A. C., Baker, S. D. 2005; 11 (23): 8503-8511

    Abstract

    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.

    View details for DOI 10.1158/1078-0432.CCR-05-1037

    View details for Web of Science ID 000233701300038

    View details for PubMedID 16322314

  • Phase I and pharmacokinetic study of flavopiridol followed by 1-beta-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias CLINICAL CANCER RESEARCH Karp, J. E., Passaniti, A., Gojo, I., Kaufmann, S., Bible, K., Garimella, T. S., Greer, J., Briel, J., Smith, B. D., Gore, S. D., Tidwell, M. L., Ross, D. D., Wright, J. J., Colevas, A. D., Bauer, K. S. 2005; 11 (23): 8403-8412

    Abstract

    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.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.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%).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.

    View details for DOI 10.1158/1078-0432.CCR-05-1201

    View details for Web of Science ID 000233701300026

    View details for PubMedID 16322302

  • Ixabepilone (epothilone B analogue BMS-247550) is active in chemotherapy-naive patients with hormone-refractory prostate cancer: A southwest oncology group trial S0111 JOURNAL OF CLINICAL ONCOLOGY Hussain, M., Tangen, C. M., Lara, P. N., Vaishampayan, U. N., Petrylak, D. P., Colevas, A. D., Sakr, W. A., Crawford, E. D. 2005; 23 (34): 8724-8729

    Abstract

    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).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.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).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.

    View details for DOI 10.1200/JCO.2005.02.4448

    View details for Web of Science ID 000233690200026

    View details for PubMedID 16314632

  • 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 CANCER Amrein, P. C., Clark, J. R., Supko, J. G., Fabian, R. L., Wang, C. C., Colevas, A. D., Posner, M. R., Deschler, D. G., Rocco, J. W., Finkelstein, D. M., McIntyre, J. F. 2005; 104 (7): 1418-1427

    Abstract

    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.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.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.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.

    View details for DOI 10.1002/cncr.21312

    View details for Web of Science ID 000232001200011

    View details for PubMedID 16116597

  • 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 JOURNAL OF CLINICAL ONCOLOGY Galsky, M. D., Small, E. J., Oh, W. K., Chen, I., Smith, D. C., Colevas, A. D., Martone, L., Curley, T., Delacruz, A., Scher, H. I., Kelly, W. K. 2005; 23 (7): 1439-1446

    Abstract

    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 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.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.Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

    View details for DOI 10.1200/JCO.2005.09.042

    View details for Web of Science ID 000227367900015

    View details for PubMedID 15735119

  • Current clinical trials of cilengitide, an alpha(v) antagonist in clinical development as an anticancer agent ONCOLOGY-NEW YORK Colevas, A. D., Scharf, O., Schoenfeldt, M. 2004; 18 (14): 1778-?
  • Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma INVESTIGATIONAL NEW DRUGS Burdette-Radoux, S., Tozer, R. G., Lohmann, R. C., Quirt, I., Ernst, D. S., Walsh, W., Wainman, N., Colevas, A. D., Eisenhauer, E. A. 2004; 22 (3): 315-322

    Abstract

    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 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.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.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.

    View details for Web of Science ID 000221132400012

    View details for PubMedID 15122079

  • HER2 expression in salivary gland carcinomas: Dependence on histological subtype CLINICAL CANCER RESEARCH Glisson, B., Colevas, A. D., Haddad, R., Krane, J., El-Naggar, A., Kies, M., Costello, R., Summey, C., Arquette, M., Langer, C., Amrein, P. C., Posner, M. 2004; 10 (3): 944-946

    Abstract

    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.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.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%).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.

    View details for Web of Science ID 000188982700017

    View details for PubMedID 14871971

  • Herceptin in patients with advanced or metastatic salivary gland carcinomas. A phase II study ORAL ONCOLOGY Haddad, R., Colevas, A. D., Krane, J. F., Cooper, D., Glisson, B., Amrein, P. C., Weeks, L., Costello, R., Posner, M. 2003; 39 (7): 724-727

    Abstract

    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.

    View details for DOI 10.1016/S1368-8375(03)00097-6

    View details for Web of Science ID 000185296300012

    View details for PubMedID 12907212

  • CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment SEMINARS IN RADIATION ONCOLOGY Trotti, A., Colevas, A. D., SETSER, A., Rusch, V., Jaques, D., Budach, V., Langer, C., Murphy, B., Cumberlin, R., Coleman, C. N., Rubin, P. 2003; 13 (3): 176-181

    Abstract

    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.

    View details for DOI 10.1016/S01053-4296(03)00031-6

    View details for Web of Science ID 000184670300002

    View details for PubMedID 12903007

  • Development of investigational radiation modifiers JOURNAL OF THE NATIONAL CANCER INSTITUTE Colevas, A. D., Brown, J. M., Hahn, S., Mitchell, J., Camphausen, K., Coleman, C. N. 2003; 95 (9): 646-651

    View details for Web of Science ID 000182672800007

    View details for PubMedID 12734315

  • 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 CANCER Haddad, R., Colevas, A. D., Tishler, R., Busse, P., Goguen, L., Sullivan, C., Norris, C. M., Lake-Willcutt, B., Case, M. A., Costello, R., Posner, M. 2003; 97 (2): 412-418

    Abstract

    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.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.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.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.

    View details for DOI 10.1002/cncr.11063

    View details for Web of Science ID 000180401600009

    View details for PubMedID 12518365

  • Organ preservation-induction chemotherapy. Cancer treatment and research Colevas, A. D. 2003; 114: 213-234

    View details for PubMedID 12619543

  • Timed sequential therapy of acute leukemia with flavopiridol: In vitro model for a phase I clinical trial CLINICAL CANCER RESEARCH Karp, J. E., Ross, D. D., Yang, W. D., Tidwell, M. L., Wei, Y. T., Greer, J., Mann, D. L., Nakanishi, T., Wright, J. J., Colevas, A. D. 2003; 9 (1): 307-315

    Abstract

    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).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.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).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.

    View details for Web of Science ID 000180430600039

    View details for PubMedID 12538483

  • 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 CANCER Tishler, R. B., Norris, C. M., Colevas, A. D., Lamb, C. C., Karp, D., Busse, P. M., Nixon, A., Frankenthaler, R., Lake-Willcutt, B., Costello, R., Case, M., Posner, M. R. 2002; 95 (7): 1472-1481

    Abstract

    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.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.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.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.

    View details for DOI 10.1002/cncr.10873

    View details for Web of Science ID 000178128600010

    View details for PubMedID 12237916

  • Phase I/II trial of outpatient docetaxel, cisplatin, 5-fluorouracil, leucovorin (opTPFL) as induction for squamous cell carcinoma of the head and neck (SCCHN) AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Colevas, A. D., Norris, C. M., Tishler, R. B., Lamb, C. C., Fried, M. P., Goguen, L. A., Gopal, H. V., Costello, R., Read, R., Adak, S., Posner, M. R. 2002; 25 (2): 153-159

    Abstract

    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.

    View details for Web of Science ID 000174906300010

    View details for PubMedID 11943893

  • Hypothyroidism incidence after multimodality treatment for stage III and IV squamous cell carcinomas of the head and neck INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Colevas, A. D., Read, R., Thornhill, J., Adak, S., Tishler, R., Busse, P., Li, Y., Posner, M. 2001; 51 (3): 599-604

    Abstract

    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.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.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.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.

    View details for Web of Science ID 000171892800004

    View details for PubMedID 11597798

  • Clinical trials referral resource: Current clinical trials of epothilone B analog (BMS-247550) ONCOLOGY-NEW YORK Colevas, A. D., West, P. J., Cheson, B. D. 2001; 15 (9): 1168-?

    View details for Web of Science ID 000174070500015

    View details for PubMedID 11589064

  • 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 JOURNAL OF CLINICAL ONCOLOGY Posner, M. R., Glisson, B., Frenette, G., al-Sarraf, M., Colevas, A. D., Norris, C. M., Seroskie, J. D., Shin, D. M., Olivares, R., Garay, C. A. 2001; 19 (4): 1096-1104

    Abstract

    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.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.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%).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.

    View details for Web of Science ID 000167219400023

    View details for PubMedID 11181674

  • NCCN Practice Guidelines for head and neck cancers ONCOLOGY-NEW YORK Forastiere, A. A., Pfister, D. G., Ang, K., Brockstein, B., Colevas, A. D., Ellenhorn, J., Goepfert, H., Hicks, W. L., Hong, W. K., Kies, M. S., Lydiatt, W., McCaffrey, T., Mittal, B. B., Ridge, J. A., Schuller, D. E., Shah, J. P., Spencer, S., Trotti, A., Urba, S., Weymuller, E. A., Wheeler, R. H., Wolf, G. T. 2000; 14 (11A): 163-194

    View details for Web of Science ID 000166713700017

    View details for PubMedID 11195409

  • The role of induction chemotherapy in the curative treatment of squamous cell cancer of the head and neck SEMINARS IN ONCOLOGY Posner, M. R., Colevas, A. D., Tishler, R. B. 2000; 27 (4): 13-24

    Abstract

    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.

    View details for Web of Science ID 000089136200003

    View details for PubMedID 10952434

  • A phase II trial of palliative docetaxel plus 5-fluorouracil for squamous-cell cancer of the head and neck ANNALS OF ONCOLOGY Colevas, A. D., Adak, S., Amrein, P. C., Barton, J. J., Costello, R., Posner, M. R. 2000; 11 (5): 535-539

    Abstract

    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 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.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.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.

    View details for Web of Science ID 000087581500012

    View details for PubMedID 10907945

  • Phase II trial of docetaxel, cisplatin, fluorouracil, and leucovorin as induction for squamous cell carcinoma of the head and neck JOURNAL OF CLINICAL ONCOLOGY Colevas, A. D., Norris, C. M., Tishler, R. B., Fried, M. P., Gomolin, H. I., Amrein, P., Nixon, A., Lamb, C., Costello, R., Barton, J., Read, R., Adak, S., Posner, M. R. 1999; 17 (11): 3503-3511

    Abstract

    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).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.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.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.

    View details for Web of Science ID 000083473700020

    View details for PubMedID 10550148

  • Re: "Sialadenosis: a presenting sign in Bulemia" (Head and Neck 20: 758-762, 1998) Head & neck Colevas, A. D. 1999; 21 (6): 582-?

    View details for PubMedID 10449677

  • Intramucosal spread of malignant melanoma of the oral cavity OTOLARYNGOLOGY-HEAD AND NECK SURGERY Bhattacharyya, N., Norris, C. M., Colevas, A. D., Chasse, T. A. 1998; 119 (6): 711-711

    View details for Web of Science ID 000077409400033

    View details for PubMedID 9852557

  • Docetaxel in head and neck cancer - A review AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Colevas, A. D., Posner, M. R. 1998; 21 (5): 482-486

    Abstract

    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.

    View details for Web of Science ID 000076339300013

    View details for PubMedID 9781605

  • Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: A phase I/II trial JOURNAL OF CLINICAL ONCOLOGY Colevas, A. D., Busse, P. M., Norris, C. M., Fried, M., Tishler, R. B., Poulin, M., Fabian, R. L., Fitzgerald, T. J., Dreyfuss, A., Peters, E. S., Adak, S., Costello, R., Barton, J. J., Posner, M. R. 1998; 16 (4): 1331-1339

    Abstract

    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).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.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.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.

    View details for Web of Science ID 000072875700015

    View details for PubMedID 9552034

  • The Prognostic Value of Thymidylate Synthase and p53 Expression in Patients Treated with Induction Chemotherapy for Squamous Cell Carcinoma of the Head and Neck. The oncologist Posner, M. R., Johnston, P. G., Tishler, R. B., Andersen, J., Fiorentino, M., Busse, P. M., Cavacini, L. A., Colevas, A. D., Clark, J., Norris, C. M. 1998; 3 (6): 424-431

    Abstract

    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.

    View details for PubMedID 10388134

  • Future directions in the treatment of squamous cell carcinoma of the head and neck: the role of UFT. Oncology (Williston Park, N.Y.) Colevas, A. D. 1997; 11 (9): 86-89

    Abstract

    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.

    View details for PubMedID 9348576

Conference Proceedings


  • Effect of stimulation of natural killer cells with an anti-CD137 mAb on the efficacy of trastuzumab, cetuximab, and rituximab Kohrt, H. E., Houot, R., Weiskopf, K., Goldstein, M., Lund, P., Scheeren, F., Czerwinski, D., Colevas, A. D., Weng, W., Clarke, M. F., Carlson, R. W., Sunwoo, J., Tedder, T., Chen, L., Levy, R. AMER SOC CLINICAL ONCOLOGY. 2012
  • Intensity-Modulated Radiotherapy for Tumors of the Nasal Cavity and Paranasal Sinuses: Clinical Outcomes and Patterns of Failure Wiegner, E. A., Daly, M. E., Murphy, J. D., Abelson, J., Chapman, C. H., Chung, M., Yu, Y., Colevas, A. D., Kaplan, M. J., Fischbein, N., Quynh-Thu Le, Q. T., Chang, D. T. ELSEVIER SCIENCE INC. 2012: 243-251

    Abstract

    To report outcomes in patients treated with intensity-modulated radiotherapy (IMRT) for tumors of the paranasal sinuses and nasal cavity (PNS/NC).Between June 2000 and December 2009, 52 patients with tumors of the PNS/NC underwent postoperative or definitive radiation with IMRT. Twenty-eight (54%) patients had squamous cell carcinoma (SCC). Twenty-nine patients (56%) received chemotherapy. The median follow-up was 26.6 months (range, 2.9-118.4) for all patients and 30.9 months for living patients.Eighteen patients (35%) developed local-regional failure (LRF) at median time of 7.2 months. Thirteen local failures (25%) were observed, 12 in-field and 1 marginal. Six regional failures were observed, two in-field and four out-of-field. No patients treated with elective nodal radiation had nodal regional failure. Two-year local-regional control (LRC), in-field LRC, freedom from distant metastasis (FFDM), and overall survival (OS) were 64%, 74%, 71%, and 66% among all patients, respectively, and 43%, 61%, 61%, and 53% among patients with SCC, respectively. On multivariate analysis, SCC and >1 subsite involved had worse LRC (p = 0.0004 and p = 0.046, respectively) and OS (p = 0.003 and p = 0.046, respectively). Cribriform plate invasion (p = 0.005) and residual disease (p = 0.047) also had worse LRC. Acute toxicities included Grade ?3 mucositis in 19 patients (37%), and Grade 3 dermatitis in 8 patients (15%). Six patients had Grade ?3 late toxicity including one optic toxicity.IMRT for patients with PNS/NC tumors has good outcomes compared with historical series and is well tolerated. Patients with SCC have worse LRC and OS. LRF is the predominant pattern of failure.

    View details for DOI 10.1016/j.ijrobp.2011.05.044

    View details for Web of Science ID 000302993900057

    View details for PubMedID 22019239

  • Excellent early local control with tumor volume adapted dosing of stereotactic body radiation therapy for pulmonary tumors Chang, C. N., Zhou, L. Y., MacFarlane, G., Tran, P., Rao, A., Chapman, C., Le, Q., Wakelee, H., Colevas, A. D., Whyte, R., Hristov, D., Dieterich, S., Maxim, P., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S938-S939
  • Does Pre-treatment Metabolic Tumor Growth Rate (MTGR) Predict Progression in Lung Cancer? Eastham, D. V., Chapman, C. H., Rao, A. K., Narasimhan, B., Quon, A., Vasanawala, M. S., Wakelee, H., Le, Q., Colevas, A. D., Loo, B. W. ELSEVIER SCIENCE INC. 2009: S446-S446
  • A Phase II study of combined oral uracil and ftorafur with leucovorin for patients with squamous cell carcinoma of the head and neck Colevas, A. D., Amrein, P. C., Gomolin, H., Barton, J. J., Read, R. R., Adak, S., Benner, S., Costello, R., Posner, M. R. JOHN WILEY & SONS INC. 2001: 326-331

    Abstract

    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).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.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%).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.

    View details for Web of Science ID 000169943900016

    View details for PubMedID 11466686

  • An initial experience using concurrent paclitaxel and radiation in the treatment of head and neck malignancies Tishler, R. B., Busse, P. M., Norris, C. M., Rossi, R., Poulin, M., Thornhill, L., Costello, R., Peters, E. S., Colevas, A. D., Posner, M. R. ELSEVIER SCIENCE INC. 1999: 1001-1008

    Abstract

    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.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.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.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.

    View details for Web of Science ID 000079279100010

    View details for PubMedID 10192347

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