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

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

N5,N10-Methylene-THF N5-Methyl-THFN10-Formyl-THF

dTMP(DNA synthesis)

S-Adenosylmethionine(Methylation of proteins,

lipids, RNA and DNA)

IMP(purines

de novo synthesis)

dUMPHomo-

cysteine

Dihydrofolatereductase (DHFR)

Folate Tetrahydrofolate (THF)

FOLATE METABOLISM


dTMP(DNA synthesis)



IMP(purines

de novo synthesis)

dUMPHomo-

cysteine

Methotrexate



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Not for publication.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/Immuno-

suppression• Organ dysfunction

– Hepatitis– Pulmonary – Renal

Scheinfeld N. Derm Online Journal 2006;12(7):15.


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 < 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 daysWang 2006, Howland 2006

Decrease MTX

Concentrations

Bypass inhibitedpathways

Leucovorin

NaHCO3

Invasive therapy

Infectiousvigilance1

HydrationGCSF

Supportive

1. Moisa 2006

Decrease MTX

Concentrations


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

NaHCO3

Invasive therapy

InfectiousvigilanceHydrationGCSF

Supportive

Mechanism of methotrexate


dTMP(DNA synthesis)



IMP(purines

de novo synthesis)

dUMPHomo-

cysteine

Methotrexate



Decrease MTX

Concentrations


Leucovorin

NaHCO3

Enhances solubility


Supportive

Decrease MTX

Concentrations


Leucovorin

NaHCO3

Invasive therapy HD/HP


Supportive

Decrease MTX

Concentrations


Leucovorin

NaHCO3

Invasive therapy


Supportive

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

Glutamate

Methotrexate

OH

DAMPA

GLUCARPIDASE

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

Decrease MTX

Concentrations


Leucovorin IV

IV NaHCO3

Invasive therapy CSF drainage/ irrigation/perfusion


Supportive

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.

Decrease MTX

Concentrations


Leucovorin IV

IV NaHCO3

Invasive therapy CSF drainage/ irrigation/perfusionIT GLUCARPIDASE


Supportive

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. NEIS 2. Schulmeister 3. Sauerland


1.

2.

3.

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 ExamplesAlkylating agents Carmustine, ifosfamide

Platinum analogs Carboplatin, cisplatin

Topoisomerase II inhibitors Etoposide

? Liposomal anthracyclines

Goolsby 2006, Schrijvers 2003, Wang 2006, NEIS discussion forum

OxaliplatinKretzschmar A. Clin Onc 2003;21(21):4068-4069


Irritant

Wood LS Am J Nursing 1993

Vesicants

• Non DNA-binding

• DNA binding

Goolsby 2006, Schrijvers 2003, Wang 2006

Non-DNA Binding Vesicants

Class ExampleVinca alkaloids Vincristine, vinblastine

Taxane Paclitaxel

Non-classical

alkylator Amsacrine

Goolsby 2006, Schrijvers 2003, Wang 2006

DoxcetaxelEl Saghir NS. Anticancer Drugs

2004;15:401-404.Not for publication. For educational use only.


VinblastineViale PH. Sem Onc Nuring 2006;22(3):144-151.



DNA Binding Vesicants

Class Examples

Alkylating agents Mechlorethamine

Antitumor antibiotics Dactinomycin

Anthracyclines Doxorubicin, daunorubicin

Eom YW. Oncogene 2005;24:2765Not for publication. Educational use only.

Doxorubicin effects on human hepatoma cells.

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


Sauerland C. Onc Nursing Forum 2006Not for publication. For educational use only.

Doxorubicin Extravasation

Courtesy of Lisa SchulmeisterNot for publication. For educational use only.

Liposomal Doxorubicin

Courtesy of Lisa SchulmeisterNot 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


D’Andrea Scand J Plast Recon Surg 2004.Not for publication. For educational use only.


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

doubtSchulmeister 2006, Sauerland 2006


Doxorubicin extravasation.Rudolph R. J Clin Onc 1987.


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


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

• The site of extravasation of doxorubicin ten years prior

• Lymph node metastases

• Patient died within 16 months of diagnosis

Consequence or Coincidence?

1Lauvin 1995

ExtravasationDifferential 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 Fe bindingmetabolite

Hasinoff BB. 2008;17(2):21-233

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 Re-release

Schulmeister 2007, Sauerland 2006, Eom 2005

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

Langer 2000 (letter), Bos 2001, Jensen 2003 Frost 2006, El Saghir 2004, Uges 2006

Bos AM, et al., Acta Oncologica 2001.Not for publication. For educational use only.

POST USE DEZRAZOXANE

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 extravasationsHooke 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.

• SyllabusMaterial 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

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

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