DOCSLIB.ORG

Phase I Clinical and Pharmacological Study of O6-Benzylguanine Followed by Carmustine in Patients with Advanced Cancer1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Phase I Clinical and Pharmacological Study of O6-Benzylguanine Followed by Carmustine in Patients with Advanced Cancer1 Vol. 6, 3025–3031, August 2000 Clinical Cancer Research 3025 Phase I Clinical and Pharmacological Study of O6-Benzylguanine Followed by Carmustine in Patients with Advanced Cancer1 Richard L. Schilsky,2 M. Eileen Dolan,3 dose-limiting toxicity of BG combined with carmustine and Donna Bertucci, Reginald B. Ewesuedo, was cumulative in some patients. The neutrophil nadir oc- Nicholas J. Vogelzang, Sridhar Mani, curred at a median of day 27, with complete recovery in most patients by day 43. Nonhematological toxicity included Lynette R. Wilson, and Mark J. Ratain fatigue, anorexia, increased bilirubin, and transaminase el- Department of Medicine, Section of Hematology-Oncology, Cancer evation. Recommended doses for Phase II testing are 120 Research Center and Committee on Clinical Pharmacology, mg/m2 BG given with carmustine at 40 mg/m2. BG rapidly University of Chicago, Chicago, Illinois 60637 disappeared from plasma and was converted to a major metabolite, O6-benzyl-8-oxoguanine, which has a 2.4-fold ABSTRACT higher maximal concentration and 20-fold higher area un- O6-benzylguanine (BG) is a potent inactivator of the der the concentration versus time curve than BG. AGT DNA repair protein O6-alkylguanine-DNA alkyltransferase activity in peripheral blood mononuclear cells was rapidly (AGT) that enhances sensitivity to nitrosoureas in tumor cell and completely suppressed at all of the BG doses. The rate lines and tumor-bearing animals. The major objectives of of AGT regeneration was more rapid for patients treated this study were to define the optimal modulatory dose and with the lowest dose of BG but was similar for BG doses 2 associated toxicities of benzylguanine administered alone ranging from 20–120 mg/m . In conclusion, coadministra- and in combination with carmustine; to define the maxi- tion of BG and carmustine is feasible in cancer patients, but mally tolerated dose and associated toxicities of carmustine the maximal dose of carmustine that can be safely adminis- administered with benzylguanine and to describe the phar- tered with BG is approximately one-third of the standard macokinetics of BG in humans and its effects on AGT clinical dose. Bone marrow suppression, which may be cu- depletion and recovery in peripheral blood mononuclear mulative, is the dose-limiting toxicity of the combination. cells. Patients with histologically confirmed advanced solid Prolonged AGT suppression is likely attributable primarily 6 tumors or lymphoma that had failed to respond to standard to the effect of O -benzyl-8-oxoguanine. therapy or for which no standard therapy was available were eligible to participate in this study. Patients initially INTRODUCTION received BG as a 1-h i.v. infusion without carmustine. After The DNA repair protein AGT4 (1) plays an important role a 14-day washout (i.e., without therapy) period, patients in the protection of cells from the cytotoxic effects of alkylni- received BG as a 1-h i.v. infusion followed, 1 h later, by a trosoureas and methylating agents. AGT removes adducts from 15-min i.v. infusion of carmustine. Cycles of chemotherapy the O6 position of guanine in DNA through covalent binding of were repeated every 6 weeks. Cohorts of patients received the alkyl group to a cysteine residue on the protein within the BG doses ranging from 10 to 120 mg/m2 and carmustine active site (1). During this process, irreversible inactivation of doses ranging from 13 to 50 mg/m2. Plasma and urine the protein occurs and the synthesis of new protein molecules is samples were collected and analyzed for BG, and O6-benzyl- required to regenerate AGT activity. 8-oxoguanine concentrations and AGT activity was deter- There is an inverse relationship between the level of AGT mined in peripheral blood mononuclear cells. and the sensitivity of tumor cells grown in culture and as There was no toxicity attributable to BG alone at any xenografts to the cytotoxic effects of alkylnitrosoureas (1). dose tested. Bone marrow suppression was the primary and Increased AGT activity has been found in many human solid tumors including colon cancer (2), malignant melanoma (3), lung cancer, gliomas (4, 5), and others (6), and may account for the relative ineffectiveness of nitrosourea therapy in these dis- Received 12/6/99; accepted 2/15/00. eases. Inactivation of AGT leads to an enhancement of the The costs of publication of this article were defrayed in part by the cytotoxic effects of chloroethylnitrosoureas (e.g., carmustine) payment of page charges. This article must therefore be hereby marked and methylating agents (e.g., dacarbazine, temozolomide) in advertisement in accordance with 18 U.S.C. Section 1734 solely to both cell culture and animal tumor xenograft models (7–9). indicate this fact. 1 Supported by USPHS Grants CA14599 (to R. L. S.), CA67098 (to M. E. D.), and CA69852 (to M. J. R.) from the National Cancer Insti- tute, NIH, Bethesda, MD, and by Grant MO1 RR00055 to The General Clinical Research Center, University of Chicago. 4 The abbreviations used are: AGT, O6-alkylguanine-DNA alkyltrans- 2 To whom requests for reprints should be addressed: Division of the ferase; BCNU, bischloronitrosourea, carmustine; BG, O6-benzylgua- Biological Sciences, University of Chicago, 5841 South Maryland nine; MTD, maximally tolerated dose; PBMC, peripheral blood mono- Avenue, MC1000, Chicago, IL 60637. Phone: (773) 834-3914; Fax: nuclear cell; BG max, maximal dose of BG; DLT, dose-limiting (773) 834-3915; E-mail: [email protected]. toxicity; DLCO, carbon monoxide diffusion capacity; AUC, area under 3 Author has disclosed a financial interest in Procept, a company that has the concentration versus time curve; 8-oxo-BG, O6-benzyl-8-oxogua- licensed O6-benzylguanine. nine. 3026 Phase I Trial of Benzylguanine plus Carmustine Therefore, various strategies have been attempted to deplete creatinine level less than 1.7 mg/dl or measured creatinine cells of AGT and thereby increase the sensitivity of tumor cells clearance of at least 60 ml/min. Patients must have been off of to carmustine and related agents. all previous anticancer therapy for at least 4 weeks (6 weeks if Agents that methylate DNA, such as streptozotocin and the previous therapy included mitomycin C or a nitrosourea) and dacarbazine, deplete AGT activity incompletely and produce must have recovered from the toxic effects of any prior therapy. significant clinical toxicity (10). BG, a low-molecular-weight Patients were excluded from the study if they had a significant AGT substrate, binds readily to the same cysteine residue on cardiac, pulmonary, neurological, endocrine, gastrointestinal, AGT that is used for alkyl group transfer and inactivates the rheumatological, dermatological, or allergic disorder that would protein stoichiometrically, requiring micromolar concentrations make administration of the therapy hazardous or would obscure and only minutes of exposure to completely inactivate AGT (11, the interpretation of adverse effects. Pregnant and lactating 12). Once AGT is inactivated, cells become vulnerable to killing women were also excluded, and all of the patients with repro- by nitrosoureas because lesions that are present at the O6 posi- ductive potential were required to use an effective contraceptive tion of guanine cannot be repaired until new AGT synthesis method during treatment and for 2 months after completion of occurs (13–16). There is a strong correlation between the degree treatment if they were sexually active. All of the patients gave of sensitization that can be achieved and the level of AGT written informed consent according to institutional and federal activity in cells, with little or no BG-induced enhancement of guidelines. BCNU cytotoxicity occurring in cells that express low levels of Study Design. The initial goal of the study was to define AGT and the greatest enhancement observed in cells with high the dose of BG that produced maximal AGT suppression in AGT activity (13). BCNU preceded by BG treatment results in human PBMCs without excessive toxicity and to define the time significantly greater growth inhibition of human brain and colon course of this inhibition. Once this dose of BG was defined, tumor xenografts in nude mice compared with that observed in cohorts of patients were to be treated at a fixed dose of BG and animals treated with BCNU alone (8, 17). at increasing doses of BCNU to determine the MTD of BCNU Preclinical toxicology studies in mice and dogs revealed given with BG. Thus, patients who were enrolled in the study BG alone to be nontoxic. When combined with BCNU, bone initially received BG as a 1-h i.v. infusion without BCNU. After marrow toxicity was dose-limiting, and the MTD of BCNU was a 14-day washout period, patients received the assigned dose of 2- to 3-fold lower in mice and 6-fold lower in dogs than in the BG as a 1-h i.v. infusion followed, 1 h later, by a 15-min i.v. absence of BG (18, 19). infusion of BCNU. Cycles of chemotherapy were repeated every On the basis of the strong preclinical evidence that BG 6 weeks as long as the patient’s tumor was stable or responding administration could potentially reverse resistance to alkylnitro- to treatment and the patient did not experience DLT. 2 soureas, we conducted a Phase I study of the combination of BG The starting dose of BG was 10 mg/m . Escalation of the and BCNU in patients with advanced cancer. The major objec- BG dose occurred in increments of 100% until maximal AGT tives of the study were to define the optimal modulatory dose suppression was observed in PBMCs 6 h after dosing or until the and associated acute and cumulative toxicities of BG adminis- appearance of grade 1–2 toxicity attributable to BG. Dose es- tered alone and in combination with BCNU; to define the MTD calation of BG was to continue until AGT suppression of at least and associated acute and cumulative toxicities of BCNU admin- 90% was observed in at least two of three patients in two istered with BG; to determine the time course of AGT depletion successive dose cohorts (BG max).
Load more

Recommended publications
  • Australian Public Assessment Report for Aminolevulinic Acid Hcl
    Australian Public Assessment Report for Aminolevulinic acid HCl Proprietary Product Name: Gliolan Sponsor: Specialised Therapeutics Australia Pty Ltd March 2014 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) · The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health, and is responsible for regulating medicines and medical devices. · The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary. · The work of the TGA is based on applying scientific and clinical expertise to decision- making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. · The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. · To report a problem with a medicine or medical device, please see the information on the TGA website < http://www.tga.gov.au>. About AusPARs · An Australian Public Assessment Record (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. · AusPARs are prepared and published by the TGA. · An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations, and extensions of indications. · An AusPAR is a static document, in that it will provide information that relates to a submission at a particular point in time. · A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA.
    [Show full text]
  • NOV 1 72010 1.0 Submitter
    510(k) SUMMARY NOV 1 72010 1.0 Submitter Name Shen Wei (USA) Inc. Street Address 33278 Central Ave., Suite 102 Union City, CA. 94587 Phone No. (510)429-8692 Fax No. (510)487-5347 Date of Summary Prepared: 08/12/10 Prepared by: Albert Li 2.0 Name of the device: Glove Proprietary or Trade Name: Blue and Red with Pearlescent® Pigment, Powder Free Nitrile Examination Gloves with Aloe Vera, Tested for use with Chemotherapy Drugs Common Name: Exam gloves Classification Name: Patient examination glove, Specialty Chemotherapy'(per 21 CFR 880.6250 product code LZC) Classification Information: Class I Nitrile patient examination glove 8OLZC, powder-free and meeting all the requirements of ASTM D 631 9-O0a-05 and is tested with chemotherapy drugs according to ASTM D 6978-05. 3.0 Identification of the Legally Marketed Device: Blue and Red with Pearlescent® Pigment, Powder Free Nitrile Examination Gloves with Aloe Vera Regulatory Class I Nitrile patient examination Product code: 8OLZA 5 10(k): K092411 4.0 Description of the Device: Blue and Red with Pearlescent® Pigment, Powder Free Nitrite Examination Gloves with Aloe Vera, Tested for use with Chemotherapy Drugs meets all the requirements of ASTM D 6978-05, ASTM D63 19-00a(2005) and FDA 21 CFT 880.6250. 5.0 Intended Use of Device: Product: Red with Pearlescent® Pigment, Powder Free Nitrile Examination Gloves with Aloe Vera, Tested for use with Chemotherapy Drugs A disposable device intended for medical purpose that is worn on the examiner's hand to prevent contamination between patient and examiner. This device is single use only.
    [Show full text]
  • Primary Central Nervous System Lymphoma: Consolidation Strategies
    12 Review Article Page 1 of 12 Primary central nervous system lymphoma: consolidation strategies Carole Soussain1,2, Andrés J. M. Ferreri3 1Division of Hematology, Institut Curie, Site Saint-Cloud, Saint-Cloud, France; 2INSERM U932, Institut Curie, PSL Research University, Paris, France; 3Lymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milano, Italy Contributions: (I) Conception and design: All authors; (II) Administrative support: None; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Carole Soussain. Institut Curie, 35 rue Dailly, 92210 Saint-Cloud, France. Email: [email protected]. Abstract: To eliminate residual malignant cells and prevent relapse, consolidation treatment remains an essential part of the first-line treatment of patients with primary central nervous system lymphoma. Conventional whole-brain radiotherapy (WBRT) delivering 36–40 Gy was the first and most used consolidation strategy for decades. It is being abandoned because of the overt risk of neurotoxicity while other consolidation strategies have emerged. Reduced-dose WBRT is effective for reducing the risk of relapse in patients with complete response (CR) after induction chemotherapy compared to patients who did not receive consolidation treatment, with an apparent reduced risk of neurotoxicity, which needs to be confirmed in patients over 60 years of age. Preliminary results showed the feasibility of stereotaxic radiotherapy as an alternative to WBRT. Nonmyeloablative chemotherapy, consisting of high doses of etoposide and cytarabine, has shown encouraging therapeutic results in a phase II study, with a high risk of hematologic and infectious toxicity.
    [Show full text]
  • Wear the Battle Gear That Protects Against 52 Chemotherapy Drugs!
    YOU’RE FIGHTING CANCER. Wear the Battle Gear That Protects Against 52 Chemotherapy Drugs! PURPLE NITRILE-XTRA* Gloves and HALYARD* Procedure Gowns for Chemotherapy Use have been tested It’s 52 vs. You. for resistance to 52 chemotherapy drugs.† Arsenic Trioxide (1 mg/ml) Cyclophosphamide (20 mg/ml) Fludarabine (25 mg/ml) Mitomycin (0.5 mg/ml) Temsirolimus (25 mg/ml) Azacitidine (Vidaza) (25 mg/ml) Cytarabine HCl (100 mg/ml) Fluorouracil (50 mg/ml) Mitoxantrone (2 mg/ml) Trastuzumab (21 mg/ml) Bendamustine (5 mg/ml) Cytovene (10 mg/ml) Fulvestrant (50 mg/ml) Oxaliplatin (2 mg/ml) ThioTEPA (10 mg/ml) Bleomycin Sulfate (15 mg/ml) Dacarbazine (10 mg/ml) Gemcitabine (38 mg/ml) Paclitaxel (6 mg/ml) Topotecan HCl (1 mg/ml) Bortezomib (Velcade) (1 mg/ml) Daunorubicin HCl (5 mg/ml) Idarubicin (1 mg/ml) Paraplatin (10 mg/ml) Triclosan (1 mg/ml) Busulfan (6 mg/ml) Decitabine (5 mg/ml) Ifosfamide (50 mg/ml) Pemetrexed (25 mg/ml) Trisenox (0.1 mg/ml) Carboplatin (10 mg/ml) Docetaxel (10 mg/ml) Irinotecan (20 mg/ml) Pertuzumab (30 mg/ml) Vincrinstine Sulfate (1 mg/ml) Carfilzomib (2 mg/ml) Doxorubicin HCl (2 mg/ml) Mechlorethamine HCl (1 mg/ml) Raltitrexed (0.5 mg/ml) Vinblastine (1 mg/ml) Carmustine (3.3 mg/ml)† Ellence (2 mg/ml) Melphalan (5 mg/ml) Retrovir (10 mg/ml) Vinorelbine (10 mg/ml) Cetuximab (Erbitux) (2 mg/ml) Eribulin Mesylate (0.5 mg/ml) Methotrexate (25 mg/ml) Rituximab (10 mg/ml) Zoledronic Acid (0.8 mg/ml) Cisplatin (1 mg/ml) Etoposide (20 mg/ml) † Testing measured no breakthrough at the Standard Breakthrough Rate of 0.1ug/cm2/minute, up to 240 minutes for gloves and 480 minutes for gowns, except for carmustine.
    [Show full text]
  • The Effects of the Nanosphere Carrier for the Combined Carmustine-Busulfan Trastuzumab in Human Breast Cancer Tissue Culture
    Sahib et al (2019): Nanosphere carrier in human breast cancer November 2019 Vol. 22 (7) The effects of the nanosphere carrier for the combined carmustine-busulfan trastuzumab in human breast cancer tissue culture Zena Hasan Sahib 1 , Sarmad Nory Gany Al-Dujaili 1 , Hussein Abdulkadhim 1 , Rana A. Ghaleb 2 1 Department of Pharmacology and Therapeutics, College of Medicine, University of Kufa 2 Department of Anatomy and Histology, College of medicine, University of Babylon Corresponding author email: [email protected] Abstract Cancer of the breast is from the highest cancer type’s incidence. Cancer in general represents a high therapeutic challenge. Considerable adverse effects and cytotoxicity of highly potent drugs for healthy tissue require the development of novel drug delivery systems to improve pharmacokinetics and result in selective distribution of the loaded agent. Targeted therapy is a novel maneuver to achieve proper selectivity index. And as the main goal of nanocarriers is to target specific sites and improve the circulation time of the drug which is entrapped, encapsulate or conjugate in the carrier system so we chose nanoliposome as a drug carrier. Liposomes improved a potent drug targeting successfully in the last decade, but nanoliposomes offer more surface area and they have more solubility, improve controlled release, enhance bioavailability, and permit precision targeting of the material that is encapsulated to a greater extent. The Aims and objectives of the study is the formulation of HER2 Ab directed nanosphere carrier for a combined Carmustine-busulfan and trastuzumab (LCBT), then Assessing antineoplastic efficacy of (LCBT) in lung carcinoma cell line. A dose-dependent cellular growth inhibition on all three cell lines (P-value < 0.001) was seen.
    [Show full text]
  • A Guide to Safe Handling of Chemotherapy Drugs
    Dynamic Permeation Device A Guide to Safe Handling of Chemotherapy Drugs In order to ensure your maximum protection when In partnership with the Université Catholique de handling cytostatics, Ansell has invested in a totally Louvain, Brussels, Belgium, we have developed new permeation assessment protocol. a unique dynamic permeation device. After dynamic permeation simulation, aliquots of the collecting Because gloves are made to be used under dynamic medium are analysed by LC-MS/MS1 or HPLC-DAD2. physical conditions (stretching, tension, rubbing etc.) some of our products have been tested for cytostatic permeation under the same constraints. Dynamic permeation device. The Molecules Tested are the Following LOD LOQ Analytical (Detection (Quantification Mol. Cytostatic Brand Name Company Method Concentration Limit) Limit) Weight Log P 1 Carmustine Nutrimon BICNU Almirall-Prodesfarma HPLC-DAD 3.0mg/ml 59.02ng/ml 196.73ng/ml 214.0 1.50 2 Cisplatin Platinol Bristol-Myers Squibb HPLC-DAD 1.0mg/ml 49.70ng/ml 165.67ng/ml 300.1 -2,20 3 Cyclophosph- Endoxan AstaMedica LCMS/MS 20.0mg/ml 1.95ng/ml 31.60ng/ml 261.1 0.60 amide 4 Cytarabine Cytosar Pharmacia & UpJohn LCMS/MS 100.0mg/ml 0.97ng/ml 4.93ng/ml 243.2 -2.50 5 Docetaxel Taxotere Aventis Pharma LCMS/MS 10.0mg/ml 3.11ng/ml 17.32ng/ml 807.8 NA 6 Doxorubicin Adriblastina Pharmacia LCMS/MS 2.0mg/ml 35.26ng/ml 55.10ng/ml 543.5 1.30 7 Etoposide Vepesid Bristol-Myers Squibb HPLC-DAD 20.0mg/ml 63.06ng/ml 210.19ng/ml 588.5 0.60 8 5-Fluorouracil Fluoroblastine Pharmacia & UpJohn HPLC-DAD 50.0mg/ml 37.47ng/ml 124.92ng/ml 130.1 -1.00 9 Ifosfamide Holoxan AstaMedica LCMS/MS 100.0mg/ml 4.11ng/ml 45.11ng/ml 261.1 NA 10 Irinotecan Campto Aventis Pharma LCMS/MS 20.0mg/ml 16.32ng/ml 30.73ng/ml 586.6 NA 11 Methotrexate Ledertrexate Wyeth Lederle LCMS/MS 25.0mg/ml 1.41ng/ml 12.85ng/ml 454.4 -1.80 The results contained in this brochure are based on laboratory tests, and reflect the best judgement of Ansell at the time of preparation.
    [Show full text]
  • CYTOTOXIC and NON-CYTOTOXIC HAZARDOUS MEDICATIONS
    CYTOTOXIC and NON-CYTOTOXIC HAZARDOUS MEDICATIONS1 CYTOTOXIC HAZARDOUS MEDICATIONS NON-CYTOTOXIC HAZARDOUS MEDICATIONS Altretamine IDArubicin Acitretin Iloprost Amsacrine Ifosfamide Aldesleukin Imatinib 3 Arsenic Irinotecan Alitretinoin Interferons Asparaginase Lenalidomide Anastrazole 3 ISOtretinoin azaCITIDine Lomustine Ambrisentan Leflunomide 3 azaTHIOprine 3 Mechlorethamine Bacillus Calmette Guerin 2 Letrozole 3 Bleomycin Melphalan (bladder instillation only) Leuprolide Bortezomib Mercaptopurine Bexarotene Megestrol 3 Busulfan 3 Methotrexate Bicalutamide 3 Methacholine Capecitabine 3 MitoMYcin Bosentan MethylTESTOSTERone CARBOplatin MitoXANtrone Buserelin Mifepristone Carmustine Nelarabine Cetrorelix Misoprostol Chlorambucil Oxaliplatin Choriogonadotropin alfa Mitotane CISplatin PACLitaxel Cidofovir Mycophenolate mofetil Cladribine Pegasparaginase ClomiPHENE Nafarelin Clofarabine PEMEtrexed Colchicine 3 Nilutamide 3 Cyclophosphamide Pentostatin cycloSPORINE Oxandrolone 3 Cytarabine Procarbazine3 Cyproterone Pentamidine (Aerosol only) Dacarbazine Raltitrexed Dienestrol Podofilox DACTINomycin SORAfenib Dinoprostone 3 Podophyllum resin DAUNOrubicin Streptozocin Dutasteride Raloxifene 3 Dexrazoxane SUNItinib Erlotinib 3 Ribavirin DOCEtaxel Temozolomide Everolimus Sirolimus DOXOrubicin Temsirolimus Exemestane 3 Tacrolimus Epirubicin Teniposide Finasteride 3 Tamoxifen 3 Estramustine Thalidomide Fluoxymesterone 3 Testosterone Etoposide Thioguanine Flutamide 3 Tretinoin Floxuridine Thiotepa Foscarnet Trifluridine Flucytosine Topotecan Fulvestrant
    [Show full text]
  • Current FDA-Approved Therapies for High-Grade Malignant Gliomas
    biomedicines Review Current FDA-Approved Therapies for High-Grade Malignant Gliomas Jacob P. Fisher 1,* and David C. Adamson 2,3 1 Division of Biochemistry, Southern Virginia University, Buena Vista, VA 24416, USA 2 Department of Neurosurgery, School of Medicine, Emory University, Atlanta, GA 30322, USA; [email protected] 3 Atlanta VA Healthcare System, Decatur, GA 30033, USA * Correspondence: Jacob.fi[email protected] Abstract: The standard of care (SOC) for high-grade gliomas (HGG) is maximally safe surgical resection, followed by concurrent radiation therapy (RT) and temozolomide (TMZ) for 6 weeks, then adjuvant TMZ for 6 months. Before this SOC was established, glioblastoma (GBM) patients typically lived for less than one year after diagnosis, and no adjuvant chemotherapy had demonstrated significant survival benefits compared with radiation alone. In 2005, the Stupp et al. randomized controlled trial (RCT) on newly diagnosed GBM patients concluded that RT plus TMZ compared to RT alone significantly improved overall survival (OS) (14.6 vs. 12.1 months) and progression-free survival (PFS) at 6 months (PFS6) (53.9% vs. 36.4%). Outside of TMZ, there are four drugs and one device FDA-approved for the treatment of HGGs: lomustine, intravenous carmustine, carmustine wafer implants, bevacizumab (BVZ), and tumor treatment fields (TTFields). These treatments are now mainly used to treat recurrent HGGs and symptoms. TTFields is the only treatment that has been shown to improve OS (20.5 vs. 15.6 months) and PFS6 (56% vs. 37%) in comparison to the current SOC. TTFields is the newest addition to this list of FDA-approved treatments, but has not been universally accepted yet as part of SOC.
    [Show full text]
  • The Role of Rituximab in the Treatment of Primary Central Nervous System Lymphoma
    cancers Review The Role of Rituximab in the Treatment of Primary Central Nervous System Lymphoma Ruben Van Dijck 1 , Jeanette K. Doorduijn 1 and Jacoline E.C. Bromberg 2,* 1 Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; [email protected] (R.V.D.); [email protected] (J.K.D.) 2 Department of Neuro-Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands * Correspondence: [email protected] Simple Summary: Primary central nervous system lymphoma (PCNSL) is a rare form of cancer and the treatment of newly diagnosed patients is challenging. Many chemotherapy regimens are being used, and methotrexate is an important component in most. The role of the immunotherapy rituximab is not as clear. This review focuses on the available evidence for the use of this monoclonal antibody in the treatment of patients with PCNSL. Abstract: Primary central nervous system lymphoma (PCNSL) is a type of non-Hodgkin lymphoma limited to the central nervous system. It has a poor prognosis. Consensus has been reached on the treatment of newly diagnosed patients with high-dose methotrexate-based chemotherapy, but whether the addition of the monoclonal anti-CD20 antibody rituximab improves survival, as it does in systemic B-cell non-Hodgkin lymphoma, remains disputed. In this review, we reflect on the available evidence of the use of rituximab in PCNSL. Whether rituximab has any beneficial effect Citation: Van Dijck, R.; Doorduijn, remains uncertain. J.K.; Bromberg, J.E.C. The Role of Rituximab in the Treatment of Keywords: primary central nervous system lymphoma (PCNSL); non-Hodgkin lymphoma; ritux- Primary Central Nervous System imab; high-dose methotrexate Lymphoma.
    [Show full text]
  • Gleostine (Lomustine) Capsules
    GleostineTM (lomustine) Capsules WARNINGS Gleostine (lomustine) should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Bone marrow suppression, notably thrombocytopenia and leukopenia, which may contribute to bleeding and overwhelming infections in an already compromised patient, is the most common and severe of the toxic effects of Gleostine (see WARNINGS and ADVERSE REACTIONS). Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose (see ADVERSE REACTIONS). At the recommended dosage, courses of Gleostine should not be given more frequently than every 6 weeks. The bone marrow toxicity of Gleostine is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose (see dosage adjustment table under DOSAGE AND ADMINISTRATION). DESCRIPTION TM Gleostine (lomustine) (CCNU) is one of the nitrosoureas used in the treatment of certain neoplastic diseases. It is 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea. It is a yellow powder with the empirical formula of C9H16ClN3O2 and a molecular weight of 233.71. Gleostine is soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). Gleostine is relatively insoluble in water (<0.05 mg per mL). It is relatively un-ionized at a physiological pH. Inactive ingredients in Gleostine Capsules are magnesium stearate and mannitol. 1 Reference ID: 3509888 The structural formula is: Gleostine is available in 10 mg, 40 mg, and 100 mg capsules for oral administration. CLINICAL PHARMACOLOGY Although it is generally agreed that lomustine alkylates DNA and RNA, it is not cross resistant with other alkylators.
    [Show full text]
  • Cancer Drug Costs for a Month of Treatment at Initial Food
    Cancer drug costs for a month of treatment at initial Food and Drug Administration approval Year of FDA Monthly Cost Monthly cost (2013 Generic name Brand name(s) approval (actual $'s) $'s) Vinblastine Velban 1965 $78 $575 Thioguanine, 6-TG Thioguanine Tabloid 1966 $17 $122 Hydroxyurea Hydrea 1967 $14 $97 Cytarabine Cytosar-U, Tarabine PFS 1969 $13 $82 Procarbazine Matulane 1969 $2 $13 Testolactone Teslac 1969 $179 $1,136 Mitotane Lysodren 1970 $134 $801 Plicamycin Mithracin 1970 $50 $299 Mitomycin C Mutamycin 1974 $5 $22 Dacarbazine DTIC-Dome 1975 $29 $125 Lomustine CeeNU 1976 $10 $41 Carmustine BiCNU, BCNU 1977 $33 $127 Tamoxifen citrate Nolvadex 1977 $44 $167 Cisplatin Platinol 1978 $125 $445 Estramustine Emcyt 1981 $420 $1,074 Streptozocin Zanosar 1982 $61 $147 Etoposide, VP-16 Vepesid 1983 $181 $422 Interferon alfa 2a Roferon A 1986 $742 $1,573 Daunorubicin, Daunomycin Cerubidine 1987 $533 $1,090 Doxorubicin Adriamycin 1987 $521 $1,066 Mitoxantrone Novantrone 1987 $477 $976 Ifosfamide IFEX 1988 $1,667 $3,274 Flutamide Eulexin 1989 $213 $399 Altretamine Hexalen 1990 $341 $606 Idarubicin Idamycin 1990 $227 $404 Levamisole Ergamisol 1990 $105 $187 Carboplatin Paraplatin 1991 $860 $1,467 Fludarabine phosphate Fludara 1991 $662 $1,129 Pamidronate Aredia 1991 $507 $865 Pentostatin Nipent 1991 $1,767 $3,015 Aldesleukin Proleukin 1992 $13,503 $22,364 Melphalan Alkeran 1992 $35 $58 Cladribine Leustatin, 2-CdA 1993 $764 $1,229 Asparaginase Elspar 1994 $694 $1,088 Paclitaxel Taxol 1994 $2,614 $4,099 Pegaspargase Oncaspar 1994 $3,006 $4,713
    [Show full text]
  • NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2010
    NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2010 DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention National Institute for Occupational Safety and Health NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2010 DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention National Institute for Occupational Safety and Health This document is in the public domain and may be freely copied or reprinted. DISCLAIMER Mention of any company or product does not constitute endorsement by the National Institute for Occupational Safety and Health (NIOSH). In addition, citations to Web sites external to NIOSH do not constitute NIOSH endorsement of the sponsoring organizations or their programs or products. Furthermore, NIOSH is not responsible for the content of these Web sites. ORDERING INFORMATION To receive documents or other information about occupational safety and health topics, contact NIOSH at Telephone: 1–800–CDC–INFO (1–800–232–4636) TTY:1–888–232–6348 E-mail: [email protected] or visit the NIOSH Web site at www.cdc.gov/niosh For a monthly update on news at NIOSH, subscribe to NIOSH eNews by visiting www.cdc.gov/niosh/eNews. DHHS (NIOSH) Publication Number 2010−167 September 2010 Preamble: The National Institute for Occupational Safety and Health (NIOSH) Alert: Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings was published in September 2004 (http://www.cdc.gov/niosh/docs/2004-165/). In Appendix A of the Alert, NIOSH identified a sample list of major hazardous drugs. The list was compiled from infor- mation provided by four institutions that have generated lists of hazardous drugs for their respec- tive facilities and by the Pharmaceutical Research and Manufacturers of America (PhRMA) from the American Hospital Formulary Service Drug Information (AHFS DI) monographs [ASHP/ AHFS DI 2003].
    [Show full text]