High-dose methotrexate in osteosarcoma

Pros and Cons of outpatient administrationJoseph Feliciano

PharmD Candidate MCPHS

Objectives

• To understand the pathophysiology and epidemiology of osteosarcoma

• To recognize the place of high dose methotrexate in therapy

• To understand the pros and cons of high dose methrotrexate being administered on an outpatient basis

Case

• PG is a 24 y/o male with localized osteosarcoma of the right distal femur.– Oncology History

• 7/2011- Noted pain in right leg after running a 10K– No significant change in gait

• 8/2012- X-ray of right knee reveals lytic lesion in distal medial right femur condoyle. MRI reveals mass on the growth plate. No metastases.

• 9/12-9/13/12- Week 1 of doxorubicin (37.5 mg/m2 ) and cisplatin (60 mg/m2) days 1 and 2 with pegfilgrastim 6mg SQ

• 9/21-9/24/12 admitted and treated for febrile neutropenia• 10/03-10/6/212- First dose of HDMTX (12g/m2 ,20g max) inpatient• 10/10-10/14/12 Second dose of HDMTX inpatient• 10/16-10/17/12 C2D1 doxorubicin and cisplatin

Case continued

• Antiemetic regimen:– Lorazepam 1 mg PO Q6H PRN

N/V/A– Prochlorperazine 10 mg PO Q6H

PRN nausea– Dexamethasone 4 mg PO begin

on D3 of cycle, BID on D3, QD D4 and D5

– Olanzapine 5mg PO QHS PRN nausea

– Ondansetron 8mg Q8H PRN nausea

– Palonosetron 0.25mg IV 30 min. prior to doxorubicin and cisplatin

• Pain regimen:– Naproxen 500mg PO BID PPA– Oxycodone 5mg PO Q4H PPA

• Bowel Regimen:– Docusate sodium 100mg PO

BID– Polyethylene glycol-3350 1

capful mixed with water PO QD

– Senna 2 tabs PO QHS

Osteosarcoma

• Osteosarcoma is the most common malignant bone tumor in children and adults – Median age of diagnosis 20 years old

– High-grade intramedullary osteosarcoma comprises 80% of all bone cancer • Spindle cell tumor that produces osteoid cells• Most frequent sites are the metaphyseal areas of the

distal femur or proximal tibia– Most common site of metastases is the lungs

Osteosarcoma

• Possible risk factors include– Prior radiation therapy – Prior chemotherapy with an alkylating agent – Genetic predisposition or cancer syndrome

• Survival data– Localized tumor• 60-80% 5 year survival rate

– Metastatic tumor• 15-30% 5 year survival rate

Therapeutic Interventions

• Surgery and chemotherapy are the standard of care

– Wide excision of the tumor site with neoadjuvant and

adjuvant chemotherapy

• Most common (neo)adjuvant chemotherapy includes

doxorubicin, cisplatin, and high-dose methotrexate with

leucovorin rescue

– Other agents used include ifosfamide (poor responder post neo),

etoposide, and cyclophosphamide

Chemotherapy for Nonmetastatic Osteogenic Sarcoma: The MSKCC Experience

• Purpose– To review the institution’s experience with using chemotherapy

to treat ostesarcoma before and after surgery and its effect on 5 year disease free survival

• Methods– Retrospective analysis of 279 patients treated for nonmetastatic

osteosarcoma from 1975 to 1984, with doxorubicin, high-dose methotrexate, cisplatin, bleomycin, cyclophosphamide, and dactinomycin

• Results– Patients treated with doxorubicin, cisplatin and high-dose

methotrexate had a 5 year DFS of 76%

Methotrexate

• Mechanism of action

– Inhibits denovo purine synthesis by inhibiting the enzyme

needed for the conversion of dihydrofolate to

tetrahydrofolate (folinic acid)

• High-dose methotrexate acts by stopping the S phase of mitosis

while arresting cells during the G1 phase

• Results in a depletion of useful folate

– Therefore inhibiting the conversion or deoxyuridine to deoxythymidine

http://curriculum.toxicology.wikispaces.net/Methotrexate

Methotrexate

• Commonly used in oncology as well as autoimmune and inflammatory conditions– Usual IV dose (Osteosarcoma): 12g/m2 (Max 20g/dose) over 4 hours

• Reduce dose by half in patients with moderate renal failure (GFR= 10-50ml/min)

• Reduce dose by 25% if bilirubin is 3.1-5mg/dL or AST >180 IU

• Leucovorin Rescue– Synthetic form of folinic acid (THF) bypasses inhibition of DHFR caused

by methotrexate• Usual dose: 15mg ORALLY every 6 hours for 10 doses starting 24 hours after

start of MTX infusion– Adjusted based on serum MTX levels

Methotrexate

• Common adverse events

– Nausea/vomiting

– Stomatisis/mucositis

– Renal toxicity

– Neutropenia

Pharmacokinetics of methotrexate

• Absorption

– Intravenous bioavailability: 100%

• Oral: ~60% at doses less than 30mg/m2

• Distribution

– Acidic drug (Hydrophilic)

• Vd= 0.4-0.8L/kg

– 50% protein bound (Not highly protein bound)

Pharmacokinetics of methotrexate

• Metabolism

– Undergoes extensive hepatic and intracellular

metabolism dependent on the route of administration

• It is either converted to 7-hydroxymethotrexate via the

liver or to a polyglutamated form intracellularly

– Polyglutamate form inhibits dihydrofolate reductase and

thymidylate synthetase

– Usually via the oral route

Pharmacokinetics of methotrexate

• Excretion

– Triphasic elimination

• Distribution half-life: ~45 minutes

• Second half-life: ~3.5 hours

• Terminal half-life: ~10-12 hours

– Excretion is primarily via the kidneys in the urine

• Active tubular secretion of methotrexate occurs

• High urine concentrations may result crystallization

– Therefore urine alkalinization and aggressive hydration are necessary part of high-

dose methotrexate therapy

Methotrexate Monitoring

• High-dose methotrexate IV monitoring– Desired MTX levels

• Therapeutic level post infusion: >1000µmol/L• 24 hours post infusion start: <10µmol/L• 48 hours post infusion start: <1µmol/L• 72 hours post infusion start: <0.1µmol/L

• Supportive care– Hydration and urine alkalization

• D5W with 50mEq of sodium bicarbonate @ 3L/m2 /day

– CBC with differential– LFT’s– Serum creatinine, BUN

Leucovorin to the rescueClinical Situation

Laboratory Leucovorin Dosage and Duration

Normal MTX elimination

Serum MTX level approximately 10 µmol 24 hr after administration, 1 micromolar at 48 hr, and less than 0.2 micromolar at 72 hr

15 mg orally, IM, or IV every 6 hr for 60 hr (10 doses starting at 24 hr after start of MTX infusion)

Delayed Late MTX Elimination

Serum MTX level remaining above 0.2 µmol at 72 hr, and more than 0.05 micromolar at 96 hr after administration

Continue 15 mg orally, IM, or IV every 6 hr until MTX level is less than 0.05 µmol

Delayed Early and/or Evidence of Acute Renal Injury

Serum MTX level at 50 µmol or more at 24 hr, or 5 µmol or more at 48 hr after administration; OR a 100% or greater increase in SCr at 24 hr after administration

150 mg IV every 3 hr until MTX level is less than 1 micromolar; then 15 mg IV every 3 hr until MTX level is less than 0.05 µmol

Leucovorin to the rescue

High-dose MTX as outpatient?

• Institutional Considerations

– Monitoring levels

– Adequate hydration

– Toxicity

– Patient/caretaker education

– Resources

• Are they being use efficiently and effectively?

High-dose methotrexate as outpatient?

• Patient Considerations

– Education and responsibility

• Will they understand the directions?

– Access to emergency care

• Will they get medical attention when warranted?

– Ability to identify toxicities

• Serious versus common

– Traveling/inconvenience

• Are they willing to do it?

The MSKCC experience with outpatient administration of high-dose methotrexate with leucovorin rescue

• Purpose– To evaluate the safety and feasibility of high-dose methotrexate being

administered on an outpatient basis• Methods

– Methotrexate was administered at a dose 12g/m2 IV over 4 hours– Urine alkalinization was achieved with IV bolus sodium bicarbonate and

oral tablets as needed – Daily visits to the outpatient clinic follow– Leucovorin was given at a standard dose of 10mg every 6 hours and dose

is escalated according to an institutional algorithm.– Patients with a MTX level > 50 micromoles/L after 24 hours were admitted– Retrospective review of HDMTX courses administered between 1996 and

2002 (n=708)

The MSKCC experience with outpatient administration of high-dose methotrexate with leucovorin rescue

• Results

– 82% of all high-dose methotrexate administrations were

completed as outpatient

– 49% of patients receiving HDMTX were treated with

standard doses of leucovorin, most dose escalations did not

exceed 20-30 mg PO every 6 hours

– 84% of observed toxicities were grade 0-1 reversible

nephrotoxicity and transaminitis

The MSKCC experience with outpatient administration of high-dose methotrexate with leucovorin rescue

• Considerations– Patient instruction• Patients/caretakers were told to maintain urine output

at around 1,500-1800 mL/m2 with the first 24 hours of infusion• Home hydration was given through an ambulatory

home infusion pump to maintain urine output between 3,000-4000 mL/day• No one was administered HDMTX inpatient based soley

on socioeconomic factors

– Economic impact

Ambulatory high-dose methotrexate administration among pediatric osteosarcoma patients in an urban, underserved

setting is feasible, safe, and cost-effective

• Methods– Retrospective analysis of all ambulatory HDMTX among

patients with osteosarcoma between January 2005 and December 2008 at Montefiore Medical Center’s Children’s Hospital

– Demographics about the patients (n=12) were extracted from the EMR including sex, age, ethnicity and insurance.• All patients were enrolled in NYS Medicaid, an indicator of economic

disadvantage

– Cost estimate was performed to assess the economic impact of ambulatory HDMTX from the hospital perspective• Cost of an outpatient cycle was compared to the presumed cost of

room and board care associated with an avoided admission

Ambulatory high-dose methotrexate administration among pediatric osteosarcoma patients in an urban, underserved

setting is feasible, safe, and cost-effective

• Results

– 96 of 97 courses of HDMTX were successfully administered as

outpatient

• 1 hospital admission resulted from hydration pump malfunction. Patient

completed subsequent courses as outpatient

– 24% of courses were associated with grade 3 or 4 neutropenia

– Average cost per treatment cycle of HDMTX was $968 versus

$2,375 for an inpatient course

• Average cost per patient was $8,712 versus $21,375, respectively

High-dose methotrexate as outpatient?

• HDMTX administered as outpatient is not only safe but very

feasible

– This is a practice that has been done at some institutions with

great success

• 82% of courses administered were successfully administered as

outpatient

– Through daily clinic visits until MTX levels drop to <0.1 µmol/L,

safety and effectiveness of therapy can be ensured

– Cost and time saving for the institution is invaluable

Case

• PG 24 y/o male

– 10/24/12

• Patient presented to the sarcoma clinic complaining of

fever (100.8), chills, sore throat and was seen to have

thrush upon examination

• Patient was given ceftazidime 2g IV per DFCI febrile

neutropenia protocol

– Subsequently admitted to BWH for IV fluids and antibiotics

Case

• PG 24 y/o male

– Patient was subsequently discharged on 10/28/12, after

stool, urine and blood cultures were all negative and

further antibiotic coverage was not necessary

– Patient will return for final course of HDMTX in 1 week

prior to surgery in November

– Adjuvant chemotherapy may be administered with

antibiotic coverage and possible dose reduction

Questions?

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Administration among Pediatric Osteosarcoma Patients in an Urban, Underserved Setting Is Feasible, Safe, and Cost Effective." Pediatric Blood Cancer 55 (2010): 1296-299. Web.

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3. "Methotrexate." Micromedex. Reuters, n.d. Web. <http://www.thomsonhc.com.ezproxy.mcphs.edu/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/249BF8/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/24F017/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/evidencexpert.DoIntegratedSearch?SearchTerm=methotrexate>.

4. Meyers, Paul A., Glenn Heller, John Healy, Andrew Huvos, Joseph Lane, Ralph Marcove, Anne Applewhite, Vaia Vlamis, and Gerald Rosen. "Chemotherapy for Nonmetastatic Osteogenic Sarcoma: The Memorial Sloan-Kettering Experience." Journal of Clinical Oncology 10.1 (1992): 5-15. Print.

5. "Osteosarcoma." Detailed Guide. N.p., n.d. Web. 30 Oct. 2012. <http://www.cancer.org/cancer/osteosarcoma/detailedguide/index>.

6. Winkler, K., G. Beron, G. Delling, U. Heise, H. Kabisch, C. Purfurst, J. Berger, J. Ritter, J. Ritter, H. Jurgens, V. Gerein, N. Graf, W. Russe, E.R. Gruemayer, W. Ertelt, R. Kotz, P. Preusser, G. Prindull, W. Brandeis, and G. Landbeck. "Neoadjuvant Chemotherapy of Osteosarcoma: Randomized Cooperative Trial (coss-82) with Salvage Chemotherapy Based on Histological Tumor Response." Journal of Clinical Oncology 6.2 (1988): 329-37. Web.

7. Zelcer, Shayna, Michael Kellick, Leonard H. Wexler, Richard Gorlick, and Paul A. Meyers. "The Memorial Sloan Kettering Cancer Center Experience with Outpatient Administration of High Dose Methotrexate with Leucovorin Rescue." Pediatric Blood & Cancer 50.6 (2008): 1176-180. Print.