Toxicological Emergencies in the Oncology Patient: Antidotal Therapies

1. Toxicological Emergencies in the Oncology Patient: Antidotal Therapies 2008 ACMT Pre-Meeting Symposium Rama B. Rao, MD NYCPCC NYPH-Weill-Cornell Medical Center

2. Methotrexate and Carboxypeptidase G2GLUCARPIDASE

3. FOLATE METABOLISM Dihydrofolatereductase (DHFR) Tetrahydrofolate (THF) Folate N5,N10-Methylene-THF N10-Formyl-THF N5-Methyl-THF Homo- cysteine dUMP IMP(purines de novo synthesis) S-Adenosylmethionine (Methylation of proteins, lipids, RNA and DNA) dTMP (DNA synthesis)

4. Methotrexate Dihydrofolatereductase (DHFR) Tetrahydrofolate (THF) Folate N5,N10-Methylene-THF N10-Formyl-THF N5-Methyl-THF Homo- cysteine dUMP IMP(purines de novo synthesis) S-Adenosylmethionine (Methylation of proteins, lipids, RNA and DNA) dTMP (DNA synthesis)

5. Methotrexate • Neoplasms • Fetal cells • Disorders of • Immune system • Rheumatology • Dermatology

6. 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 Not for publication.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.

7. Systemic Methotrexate Toxicity • Mucositis, stomatitis • Dermatitis • GI distress • Hematologic/Immuno-suppression • Organ dysfunction • Hepatitis • Pulmonary • Renal Scheinfeld N. Derm Online Journal 2006;12(7):15. Not for publication. For educational use only.

8. 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.

9. Identifying Systemic Methotrexate Toxicity • Known overdose • Therapeutic monitoring plasma levels: • Therapeutic < 1 M/L at 48 hours • Toxicity > 1 M/L at 48 hours > 10 M/L at 24 hours • Clinical findings: Manifest over a few days Wang 2006, Howland 2006

10. Leucovorin Bypass inhibited pathways Infectious vigilance1 Hydration GCSF Decrease MTX Concentrations Supportive NaHCO3 Invasive therapy 1. Moisa 2006

11. Leucovorin 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 Bypass inhibited pathways Infectious vigilance Hydration GCSF Decrease MTX Concentrations Supportive NaHCO3 Invasive therapy

12. Mechanism of methotrexate Methotrexate Dihydrofolatereductase (DHFR) Tetrahydrofolate (THF) Folate N5,N10-Methylene-THF N10-Formyl-THF N5-Methyl-THF Homo- cysteine dUMP IMP(purines de novo synthesis) S-Adenosylmethionine (Methylation of proteins, lipids, RNA and DNA) dTMP (DNA synthesis)

13. Leucovorin Bypass inhibited pathways Infectious vigilance Hydration GCSF Decrease MTX Concentrations Supportive NaHCO3 Enhances solubility

14. Leucovorin Bypass inhibited pathways Infectious vigilance Hydration GCSF Decrease MTX Concentrations Supportive NaHCO3 Invasive therapy HD/HP

15. Leucovorin Bypass inhibited pathways Infectious vigilance Hydration GCSF Decrease MTX Concentrations Supportive NaHCO3 Invasive therapy GLUCARPIDASE

16. 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

17. Methotrexate GLUCARPIDASE OH DAMPA Glutamate

18. 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

19. 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

20. 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 > 10M/L at 24 hours Package insert. Widemann 2004.

21. Intrathecal Methotrexate Toxicity

22. 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

23. Leucovorin IV Bypass inhibited pathways Infectious vigilance Hydration GCSF Decrease MTX Concentrations Supportive IV NaHCO3 Invasive therapy CSF drainage/ irrigation/perfusion

24. 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.

25. Leucovorin IV Bypass inhibited pathways Infectious vigilance Hydration GCSF Decrease MTX Concentrations Supportive IV NaHCO3 Invasive therapy CSF drainage/ irrigation/perfusion IT GLUCARPIDASE

26. 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

27. 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

28. 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

29. 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

30. 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

31. DEXRAZOXANE

32. Extravasations of Chemotherapy 1. 3. 2. • NEIS 2. Schulmeister 3. Sauerland • Not for publication. For educational use only.

33. Chemotherapy Extravasations • Incidence • 0.1- 6% • Unknown for intrathoracic • Retrospective study at a major cancer center • <0.01% Sauerland 2006, Khan 2002, Langenstein 2002

34. 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 Mouridsen2007

35. 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

36. Chemotherapy Classification • Irritants • Vesicants

37. 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

38. Irritant Oxaliplatin Kretzschmar A. Clin Onc 2003;21(21):4068-4069 Not for publication. For educational use only. Wood LS Am J Nursing 1993

39. Vesicants • Non DNA-binding • DNA binding Goolsby 2006, Schrijvers 2003, Wang 2006

40. Non-DNA Binding Vesicants Class Example Vinca alkaloids Vincristine, vinblastine Taxane Paclitaxel Non-classical alkylator Amsacrine Goolsby 2006, Schrijvers 2003, Wang 2006

41. Non-DNA Binding Vesicants Doxcetaxel El Saghir NS. Anticancer Drugs 2004;15:401-404. Not for publication. For educational use only.

42. Non-DNA Binding Vesicants Vinblastine Viale PH. Sem Onc Nuring 2006;22(3):144-151. Not for publication. For educational use only.

43. DNA Binding Vesicants Class Examples Alkylating agents Mechlorethamine Antitumor antibiotics Dactinomycin Anthracyclines Doxorubicin, daunorubicin

44. Doxorubicin effects on human hepatoma cells. Eom YW. Oncogene 2005;24:2765 Not for publication. Educational use only.

45. 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 Re-release Schulmeister 2007, Sauerland 2006, Eom 2005

46. DNA Binding Vesicants Sauerland C. Onc Nursing Forum 2006 Not for publication. For educational use only.

47. Doxorubicin Extravasation Courtesy of Lisa Schulmeister Not for publication. For educational use only.

48. Liposomal Doxorubicin Courtesy of Lisa Schulmeister Not for Publication. For educational use only.

49. Oncology Nursing Society • Strongly urges training of providers administering anti-neoplastic agents • Major cancer centers have similar, if not identical guidelines

50. Risk Factors for Extravasation • Untrained personnel • 33/38 extravasations during administration by housestaff, faculty physicians or substitute nurses Linder 1985