An evaluation of available literature regarding the use of high-dose methotrexate in osteosarcoma, and whether it can be safe, effective, and possibly cost effective when administered as an outpatient chemotherapy rather than inpatient.
High-dose Methotrexate in Osteosarcoma: Pro's and Con's of Outpatient Administration
1. High-dose methotrexate in
osteosarcoma
Pros and Cons of outpatient
administration
Joseph Feliciano
PharmD Candidate
MCPHS
2. 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
3. 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
4.
5. Case continued
• Antiemetic regimen: • Pain regimen:
– Lorazepam 1 mg PO Q6H PRN – Naproxen 500mg PO BID PPA
N/V/A
– Oxycodone 5mg PO Q4H PPA
– Prochlorperazine 10 mg PO Q6H
PRN nausea • Bowel Regimen:
– Dexamethasone 4 mg PO begin
– Docusate sodium 100mg PO
on D3 of cycle, BID on D3, QD D4
and D5 BID
– Olanzapine 5mg PO QHS PRN – Polyethylene glycol-3350 1
nausea capful mixed with water PO
– Ondansetron 8mg Q8H PRN QD
nausea – Senna 2 tabs PO QHS
– Palonosetron 0.25mg IV 30 min.
prior to doxorubicin and cisplatin
6. 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
7. 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
8. 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
9. 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%
10. 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
12. 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
14. 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)
15. 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
16. 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
17. 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
18. Leucovorin to the rescue
Clinical Laboratory Leucovorin Dosage and
Situation Duration
Normal MTX Serum MTX level approximately 10 15 mg orally, IM, or IV every
elimination µmol 24 hr after administration, 1 6 hr for 60 hr (10 doses
micromolar at 48 hr, and less than starting at 24 hr after start
0.2 micromolar at 72 hr of MTX infusion)
Delayed Late Serum MTX level remaining above Continue 15 mg orally, IM,
MTX Elimination 0.2 µmol at 72 hr, and more than or IV every 6 hr until MTX
0.05 micromolar at 96 hr after level is less than 0.05 µmol
administration
Delayed Early Serum MTX level at 50 µmol or more 150 mg IV every 3 hr until
and/or Evidence at 24 hr, or 5 µmol or more at 48 hr MTX level is less than 1
of Acute Renal after administration; OR a 100% or micromolar; then 15 mg IV
Injury greater increase in SCr at 24 hr after every 3 hr until MTX level is
administration less than 0.05 µmol
20. High-dose MTX as outpatient?
• Institutional Considerations
– Monitoring levels
– Adequate hydration
– Toxicity
– Patient/caretaker education
– Resources
• Are they being use efficiently and effectively?
21. 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?
22. 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)
23. 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
24. 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
25. 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
26. 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
27. 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
28. 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
29. 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
31. References
1. Mahadeo, Kris M., Ruth Santizo, Lindsay Baker, Joan O'Hanlon, and Richard Gorlick. "Ambulatory High-dose
Methotrexate Administration among Pediatric Osteosarcoma Patients in an Urban, Underserved Setting Is
Feasible, Safe, and Cost Effective." Pediatric Blood Cancer 55 (2010): 1296-299. Web.
2. "Methotrexate." Clinical Pharmacology. Elsevier, n.d. Web. <http://www.clinicalpharmacology-
ip.com.ezproxy.mcphs.edu/Forms/drugoptions.aspx?cpnum=385&n=Methotrexate>.
3. "Methotrexate." Micromedex. Reuters, n.d. Web.
<http://www.thomsonhc.com.ezproxy.mcphs.edu/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencex
pert/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.
