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Toxicological Emergencies in the Oncology Patient: Antidotal Therapies 2008 ACMT Pre-Meeting Symposium Rama B. Rao, MD NYCPCC NYPH-Weill-Cornell Medical Center Methotrexate and Carboxypeptidase G2 GLUCARPIDASE FOLATE METABOLISM Dihydrofolate reductase (DHFR) Tetrahydrofolate (THF) Folate N5,N10-Methylene-THF N10-Formyl-THF Homocysteine dUMP dTMP (DNA synthesis) N5-Methyl-THF IMP (purines de novo synthesis) S-Adenosylmethionine (Methylation of proteins, lipids, RNA and DNA) Methotrexate Dihydrofolate reductase (DHFR) Tetrahydrofolate (THF) Folate N5,N10-Methylene-THF N10-Formyl-THF Homocysteine dUMP dTMP (DNA synthesis) N5-Methyl-THF IMP (purines de novo synthesis) S-Adenosylmethionine (Methylation of proteins, lipids, RNA and DNA) Methotrexate • Neoplasms • Fetal cells • Disorders of – Immune system – Rheumatology – Dermatology Methotrexate Toxicity Scheinfeld N. Three cases of toxic skin eruptions associated with methotrexate…Derm Online Journal 2006;12(7):15. Not for publication. For educational use only. Systemic Methotrexate Toxicity • • • • Mucositis, stomatitis Dermatitis GI distress Hematologic/Immunosuppression • Organ dysfunction – Hepatitis – Pulmonary – Renal Scheinfeld N. Derm Online Journal 2006;12(7):15. Not for publication. For educational use only. Risk Factors: MTX Toxicity • Renal Impairment – Medication interactions – Failure • Overdose • Idiosyncratic: – Wide differences in concentrations with administration of 1 gm/m2 IV Smith S, et al. J Med Tox 2008;4(2):132-140; Evans WE, et al. Clinical pharmacodynamics of high dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect. New Engl J Med 1986;314(8):471-477. Identifying Systemic Methotrexate Toxicity • Known overdose • Therapeutic monitoring plasma levels: – Therapeutic – Toxicity < 1 M/L at 48 hours > 1 M/L at 48 hours > 10 M/L at 24 hours • Clinical findings: Manifest over a few days Wang 2006, Howland 2006 Leucovorin Bypass inhibited pathways Infectious vigilance1 Hydration GCSF 1. Moisa 2006 Supportive Decrease MTX Concentrations NaHCO3 Invasive therapy Leucovorin Bypass inhibited pathways Infectious vigilance Hydration GCSF Supportive Dose to ≥ MTX plasma concentration 100 mg/m2 IV Q 6 hours NEVER INTRATHECALLY Continue treatment in severely ill patients until there is evidence of recovery Decrease MTX Concentrations NaHCO3 Invasive therapy Mechanism of methotrexate Methotrexate Dihydrofolate reductase (DHFR) Tetrahydrofolate (THF) Folate N5,N10-Methylene-THF N10-Formyl-THF Homocysteine dUMP dTMP (DNA synthesis) N5-Methyl-THF IMP (purines de novo synthesis) S-Adenosylmethionine (Methylation of proteins, lipids, RNA and DNA) Leucovorin Bypass inhibited pathways Infectious vigilance Hydration GCSF Supportive Decrease MTX Concentrations NaHCO3 Enhances solubility Leucovorin Bypass inhibited pathways Infectious vigilance Hydration GCSF Supportive Decrease MTX Concentrations NaHCO3 Invasive therapy HD/HP Leucovorin Bypass inhibited pathways Infectious vigilance Hydration GCSF Supportive Decrease MTX Concentrations NaHCO3 Invasive therapy GLUCARPIDASE Glucarpidase (CPDG2) • FDA approved as single use Investigational New Drug for compassionate therapy • Dosing for systemic methotrexate toxicity – 50 u/kg IV over 5 minutes • 70 patients reduction of methotrexate concentrations by 98% at 15 minutes • Adverse events in 329 patients: – Flushing, hypersensitivity, pruritis – HTN, dysrhythmias? Package Insert Glucarpidase, O’Marcaigh 1996. Schwartz S et al.Oncologist 2007; 12:1299-1308; Snyder 2007 Methotrexate GLUCARPIDASE OH DAMPA Glutamate Glucarpidase Limitations • DAMPA – Low solubility in urine • Continue alkalinization of urine – Affects methotrexate assays • Use HPLC post treatment to follow MTX • Cleaves leucovorin – Allow 2-4 hour interval between medications – Current investigation – Continue therapy for 48 hours after glucarpidase • Availability: HD/HP while awaiting Schwartz S et al.Oncologist 2007; 12:1299-1308 Glucarpidase Limitations • DAMPA – Low solubility in urine • Continue alkalinization of urine – Affects methotrexate assays • Use HPLC post treatment to follow MTX • Cleaves leucovorin – Allow 2-4 hour interval between medications – Current investigation – Continue therapy for 48 hours after glucarpidase • Availability: HD/HP while awaiting Schwartz S et al.Oncologist 2007; 12:1299-1308 IV Glucarpidase Indications • • • • Advanced signs of clinical toxicity Persistently elevated MTX concentrations Clcr ≤ 60 mL/min/m2 Patient with a combination of: – Renal failure – On leucovorin – Plasma MTX concentration > 10M/L at 24 hours Package insert. Widemann 2004. Intrathecal Methotrexate Toxicity CSF Methotrexate Toxicity • Within 60 minutes to a few hours – Headache – Vomiting – Altered mentation – Seizure – Apnea – CV instability – Death Ettinger 1985;Jakobson 1992,Finkelstein 2004 Leucovorin IV Bypass inhibited pathways Infectious vigilance Hydration GCSF Supportive Decrease MTX Concentrations IV NaHCO3 Invasive therapy CSF drainage/ irrigation/perfusion CSF Drainage • Remove up to 94% of MTX if drainage occurs within first 15 minutes • Diminishes to 30-40% if performed at 2 hours Riva 1999, O’Marcaigh 1996, Jakobson 1992, Widemann 2004. Leucovorin IV Bypass inhibited pathways Infectious vigilance Hydration GCSF Supportive Decrease MTX Concentrations IV NaHCO3 Invasive therapy CSF drainage/ irrigation/perfusion IT GLUCARPIDASE Intrathecal Glucarpidase • Non-human primate model of intrathecal MTX overdose – 400 fold decrease in CSF concentrations within 5 minutes of administration • No primate deaths Adamson 1991 Intrathecal Glucarpidase • Human data – 7 patients 155 mg – 600 mg MTX – Included 4 children ages 5-9 – All received: • Drainage (some with perfusion) • Intravenous Leucovorin • Intrathecal Glucarpidase within 5 hours Widemann 2004 Indications? • May depend on intrathecal MTX dosage and symtoms: – Less than 100 mg: many adults will respond well to drainage and IV leucovorin alone – Between 100 mg and 500 mg MTX have variable outcomes – One survivor of 1200 mg IT MTX without glucarpidase Consider IT Glucarpidase • Severe CNS symptoms • Consider when dosage of MTX is > 100 mg • Ideal patient is yet to be defined • Dosing: 2 vials IT (1000 units/vial) standard for adults or children after initial drainage IV/IT Glucarpidase • Adjunctive therapy in methotrexate overdose • May obviate the need for: – HD/HP in systemic toxicity – Ventricular-lumbar perfusion in IT toxicity • Prevention is key DEXRAZOXANE Extravasations of Chemotherapy 1. 3. 2. 1. NEIS 2. Schulmeister 3. Sauerland Not for publication. For educational use only. Chemotherapy Extravasations • Incidence – 0.1- 6% – Unknown for intrathoracic • Retrospective study at a major cancer center – <0.01% Sauerland 2006, Khan 2002, Langenstein 2002 Chemotherapy Extravasations • Recent prospective study, 36 centers in 5 countries in Europe – Time period and total number of administrations not reported – 80 potential extravasation cases Mouridsen 2007 Natural History • • • • • • • • Fullness, induration Resistance to flushing the line Pain Redness Blistering Discoloration Necrosis Full thickness skin loss Kretschmar 2006, Stein 1997, Mayo 1998, Loth 1991, Eom 2005, Linder 1985 Chemotherapy Classification • Irritants • Vesicants Irritants Class Examples Alkylating agents Carmustine, ifosfamide Platinum analogs Carboplatin, cisplatin Topoisomerase II inhibitors Etoposide ? Liposomal anthracyclines Goolsby 2006, Schrijvers 2003, Wang 2006, NEIS discussion forum Irritant Oxaliplatin Kretzschmar A. Clin Onc 2003;21(21):4068-4069 Not for publication. For educational use only. Wood LS Am J Nursing 1993 Vesicants • Non DNA-binding • DNA binding Goolsby 2006, Schrijvers 2003, Wang 2006 Non-DNA Binding Vesicants Class Example Vinca alkaloids Vincristine, vinblastine Taxane Paclitaxel Non-classical alkylator Amsacrine Goolsby 2006, Schrijvers 2003, Wang 2006 Non-DNA Binding Vesicants Doxcetaxel El Saghir NS. Anticancer Drugs 2004;15:401-404. Not for publication. For educational use only. Non-DNA Binding Vesicants Vinblastine Viale PH. Sem Onc Nuring 2006;22(3):144-151. Not for publication. For educational use only. DNA Binding Vesicants Class Alkylating agents Examples Mechlorethamine Antitumor antibiotics Dactinomycin Anthracyclines Doxorubicin, daunorubicin Doxorubicin effects on human hepatoma cells. Eom YW. Oncogene 2005;24:2765 Not for publication. Educational use only. Mechanism DNA Binding Vesicants • Enter nucleus • Bind nucleic acids – Inhibit topoisomerase II – Precipitate multiple DNA strand breaks – Free radical formation through • Semiquinones • Iron • Apoptosis/mitotic catastrophe Schulmeister 2007, Sauerland 2006, Eom 2005 Re-release DNA Binding Vesicants Sauerland C. Onc Nursing Forum 2006 Not for publication. For educational use only. Doxorubicin Extravasation Courtesy of Lisa Schulmeister Not for publication. For educational use only. Liposomal Doxorubicin Courtesy of Lisa Schulmeister Not for Publication. For educational use only. Oncology Nursing Society • Strongly urges training of providers administering anti-neoplastic agents • Major cancer centers have similar, if not identical guidelines Risk Factors for Extravasation • Untrained personnel – 33/38 extravasations during administration by housestaff, faculty physicians or substitute nurses Linder 1985 DNA Binding Vesicants D’Andrea Scand J Plast Recon Surg 2004. Not for publication. For educational use only. DNA Binding Vesicants D’Andrea Scand J Plast Recon Surg 2004. Not for publication. For educational use only. Training • Selection/assessment of access site – Order and placement of peripheral attempts • Checklists: – Tourniquet removal – Patient education – Assessment • Central lines, infusion pumps, bolus dosing • Response to patient complaints • Assumption of extravasation when in doubt Schulmeister 2006, Sauerland 2006 Training • Selection/assessment of access site – Order and placement of peripheral attempts • Checklists: – Tourniquet removal – Patient education – Assessment • Central lines, infusion pumps, bolus dosing • Response to patient complaints • Assumption of extravasation when in doubt Schulmeister 2006, Sauerland 2006 DNA Binding Vesicants Doxorubicin extravasation. Rudolph R. J Clin Onc 1987. Not for publication. For educational use only. Less Preventable Risk Factors • Sudden movement from vomiting • Use of agents that cause sedation • Patient co-morbidities or prior sequelae from chemotherapy • Proximal scarring or thrombosis Schulmeister 2006, Sauerland 2006, Mayo 1998 Central Line Risk Factors • Catheter migration or fracture • Multiple attempts • Perforation of vessel Mayo 1998, Bozkurt 2003, Anderson 1996, Krasna 1991, Kassner 2000, Durhsen 1997, Crues 2002, Lokich 1999, Leong 1996 Intrathoracic Extravasations • Mediastinitis • Effusions – Pleural – Pericardial • Phrenic nerve palsy • Protracted cough • Fatality Mayo 1998, Bozkurt 2003, Anderson 1996, Krasna 1991, Kassner 2000, Durhsen 1997, Crues 2002, Lokich 1999, Leong 1996; Schulmeister L. A complication of vascular access device insertion. J Intravenous Nursing 1998;21:197-202. Chest Wall Extravasation • Extrusion from venotomy site • Inadequate placement of line in relation to SVC • Fibrin sheath formation Mayo 1998, Bozkurt 2003, Anderson 1996, Krasna 1991, Kassner 2000, Durhsen 1997, Crues 2002, Lokich 1999, Leong 1996 Fibrin Sheath Formation Mayo DJ. Supp Care Cancer 1998. Not for publication. For educational use only. Doxorubicin extravasation with neuropathy at 2 months. Disa JJ et al. 1998 Not for publication. For educational use only. Extremity Extravavasations: Clinical Consequences • • • • • Prolonged morbidity Multiple surgeries Septicemia Poor mobility Delay of chemotherapy • Compartment syndrome • • • • • • Contractures Scarring Lymphedema Recall reactions Chronic pain Quality of life issues Kumar 2001, Linder 1985, Sauerland 2006, Anderson 1996, Bozkurt 2003, Durhsen 1997, Quintanar Verdugues 2008 Consequence or Coincidence? • A patient survives early diagnosis of adenocarcinoma of stomach • Tumor formation on the dorsum of her hand which was diagnosed as squamous cell carcinoma Lauvin 1995 Consequence or Coincidence? • The site of extravasation of doxorubicin ten years prior • Lymph node metastases • Patient died within 16 months of diagnosis 1Lauvin 1995 Extravasation Differential Diagnosis • Flare reaction – Local irritation – Streaking – Phlebitis • Recall reaction Wood 1993, Cox 1984, Wickham 2006, Valencak 2007, Saini 2006, Susser 1999, Shapiro 1994, Schulmeister 2006 Recall Reaction • Proper intravenous administration causes irritation, swelling and even blistering at a remote site of previous: – Radiation – Extravasation of the same agent • Can occur weeks to years after initial injury Wood 1993, Cox 1984, Wickham 2006, Valencak 2007, Saini 2006, Susser 1999, Shapiro 1994, Schulmeister 2006, Du Bois 1996 Saini A. Recall inflammatory skin reaction after use of pegylated liposomal doxorubicin in site of previous drug extravasation. Lancet Oncol 2006;7:186-187. Not for publication. For educational use only. Management Extravasations Initial Management • Leave access in place and attempt to withdraw any extravasant • Debate regarding flushing the area with saline – Recommended for intrathoracic extravasations • Remove line Conundrum: Anthracyclines • Most of the event is subcutaneous • Injury is delayed • Outcome can be severe with up to 33% tissue necrosis Kretschmar 2006, Stein 1997, Mayo 1998, Loth 1991, Eom 2005, Linder 1985 Options for Anthracycline Extravastions • Wait and watch – Persistent pain after 2 weeks – OR for resection of necrotic tissue – Disadvantage: • Waiting for necrosis • May require prolonged hospitalization or revisitations • Some re-opening and debridement thereafter not uncommon – Advantage: • Some will recover without requiring resection Option: Anthracycline Extravasation • Aggressive Surgery – Assume the evolution of necrosis will occur – Perform wide excision early to avoid progression • Advantage: prevent the pain and debilitation of necrosed tissue • Disadvantage: Invasive, not always necessary Identifying Injured Tissue • Anthracyclines bind to nucleic acids • Can be identified by fluorescence microscopy of biopsy specimens1 • Negative specimens did not develop necrosis2 Dahlstrom1 1990; Andersson2 AP et al. 1993. Intermediate Therapy • Fluoresence microscopy of biopsy specimens • Resection of positive specimens • Disadvantage: Still invasive Mouridsen 2007, Andersson 1993, Schulmeister 2007, Scott Ely, MD Personal communication. Dexrazoxane Vd = 22 - 36 L/m2 Distribution in total body water. 42% elimination in urine No protein binding Dexrazoxane • FDA Approved September 2007 for extravasations of anthracyclines • Previously approved by FDA for use of limiting cardiotoxicity from anthracyclines in patients with >300 mg/m2 cumulative dose Schucter 2002, Schulmeister 2008 DEXRAZOXANE Schulmeister 2008, Langer 2000 Dexrazoxane Metabolism Dexrazoxane Hasinoff BB. 2008;17(2):21-233 Fe binding metabolite Mechanism Anthracycline Injury • Enter nucleus • Bind nucleic acids – Inhibit topoisomerase II – Precipitate multiple DNA strand breaks – Free radical formation through • Semiquinones • Iron • Apoptosis/mitotic catastrophe Schulmeister 2007, Sauerland 2006, Eom 2005 Re-release Animal Model: Dexrazoxane • Mice receive SC administration of an anthracycline (AC) or H2O2 or saline • Followed by systemic dexrazoxane • Reduction of tissue lesions of AC • No reduction of H2O2 lesions Langer 2000 Dexrazoxane in Humans • Sporadic case reports – Epirubicin – Doxorubicin – No surgeries – Some delay to therapy Bos AM, et al., Acta Oncologica 2001. Not for publication. For educational use only. POST USE DEZRAZOXANE Langer 2000 (letter), Bos 2001, Jensen 2003 Frost 2006, El Saghir 2004, Uges 2006 Dexrazoxane: Prospective Study • Prospective multi-center, multi-country • Well defined criteria for enrollment • Sequential observation, single arm, open label • Administration of dexrazoxane not delayed • Outcome measures: decrease in surgeries Mouridsen 2007 Dexrazoxane Study Results • 80 patients identified • 53 of 54 were assessable • Reduction in surgery at one arm of study by 100% • Only one patient required surgery Mouridsen 2007 Dexrazoxane Study: Adverse Events • • • • Pain at infusion site Nausea, vomiting up to 18.8% in one wing Wound infections Transient elevations in LFTs Mouridsen 2007 Dexrazoxane Study Limits • Relation to makers of dexrazoxane • Design might by default reduce surgeries in some places where immediate surgical evaluation was standard. (single armed investigation) • Design might enhance vigilance and limit extent of injury Mouridsen 2007 Strengths • Well defined criteria for injury – Study Size – Diagnosis • Clinically relevant, biopsy proven exposures – 4 patients had intrathoracic extravasations Mouridsen 2007 Dexrazoxane for Extravasation • Administered < 6 hours of extravasation – 1000 mg/m2 IV first dose over 2 hours not to exceed 2000 mg – 1000 mg/m2 IV at 24 hours over 1-2 hours, max 2000 mg – 500 mg/m2 IV at 48 hours over 1-2 hours, max 1000 mg • Adjust in creatinine clearance administering 50% of the above doses for CLCR < 40 mL/min – Urinary excretion 42% Hasinoff 2008, Package Insert Dexrazoxane Dexrazoxane • Three makers in USA – Generic – Patent holders for prevention of cardiotoxicity – Patent holders for extravasation • Dosing is higher for extravasations than for prevention of cardiotoxicity American Society of Health Systems Pharmacists 25 August 2008 Dexrazoxane • Three makers in USA – Generic Unknown Cost. Available September 2008 – Patent holders for prevention of cardiotoxicity $513.08 for 500 mL of reconstituted solution Available November 2008 – Patent holders for extravasation $14,750 • Dosing is higher for extravasations than for prevention of cardiotoxicity American Society of Health Systems Pharmacists 25 August 2008 Dexrazoxane • Adverse events – Nausea, vomiting, LFT abnormalities, myelosuppression, phlebitis • Contraindications – Pregnant/nursing/children? • No concomitant use of topical DMSO – Based on animal model • No data on buffering Hasinoff 2008; Hooke MC. J Ped Onc Nursing 2005;22:261-264 Lipshultz SE, et al. The effect of dexrazoxane on myocardial injury. New Engl J Med 2004;351:145-152. Jensen JN. Dexrazoxane – a promising antidote in the treatment of accidental extravasation of anthracyclines. Scand J Plastic and Recon Sur Hand Surg 2003;37:3:174-175. Not for publication. For educational use only. Outstanding Questions • Role in liposomal extravasations • If/When to administer to children and at what dosing • Need for biopsy? • Role in intrathoracic extravasations Hooke MC. J Ped Onc Nursing 2005;22:261-264., Lipshultz SE, et al. The effect of dexrazoxane on myocardial injury. New Engl J Med 2004;351:145-152 Summary • Prevention is key • Fluorescence microscopy should be the gold standard for identifying at-risk tissue • Further evaluations of the safety and utility of dexrazoxane are indicated • The current data is promising Bos AM, et al., Acta Oncologica 2001. Not for publication. For educational use only. POST USE DEZRAZOXANE Disclosure/Information • I have no financial conflicts of interest to report. • Syllabus Material on extravasation • “Grab and go” section of clinically relevant articles – Summary sheet on carboxypeptidase G2 • Recent relevant publications • How to access medication J Med Tox 2008;4(2):132-140 Acknowledgements • Major Urban Cancer Centers in NYC • Lisa Schulmeister, RN • Scott Ely, MD, MPH • Faculty, NYC Poison Control Center • ACMT