High-dose methotrexate in      osteosarcoma   Pros and Cons of outpatient         administration           Joseph Felician...
Objectives• To understand the pathophysiology and  epidemiology of osteosarcoma• To recognize the place of high dose  meth...
Case• PG is a 24 y/o male with localized osteosarcoma of the  right distal femur.   – Oncology History      • 7/2011- Note...
Case continued• Antiemetic regimen:                    • Pain regimen:  – Lorazepam 1 mg PO Q6H PRN              – Naproxe...
Osteosarcoma• Osteosarcoma is the most common malignant  bone tumor in children and adults  – Median age of diagnosis 20 y...
Osteosarcoma• Possible risk factors include  – Prior radiation therapy  – Prior chemotherapy with an alkylating agent  – G...
Therapeutic Interventions• Surgery and chemotherapy are the standard of care   – Wide excision of the tumor site with neoa...
Chemotherapy for Nonmetastatic Osteogenic    Sarcoma: The MSKCC Experience• Purpose  – To review the institution’s experie...
Methotrexate• Mechanism of action  – Inhibits denovo purine synthesis by inhibiting the enzyme    needed for the conversio...
http://curriculum.toxicology.wikispaces.net/Methotrexate
Methotrexate• Commonly used in oncology as well as autoimmune and  inflammatory conditions   – Usual IV dose (Osteosarcoma...
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...
Pharmacokinetics of methotrexate• Metabolism  – Undergoes extensive hepatic and intracellular    metabolism dependent on t...
Pharmacokinetics of methotrexate• Excretion   – Triphasic elimination       • Distribution half-life: ~45 minutes       • ...
Methotrexate Monitoring• High-dose methotrexate IV monitoring   – Desired MTX levels      •   Therapeutic level post infus...
Leucovorin to the rescueClinical          Laboratory                               Leucovorin Dosage andSituation         ...
Leucovorin to the rescue
High-dose MTX as outpatient?• Institutional Considerations  – Monitoring levels  – Adequate hydration  – Toxicity  – Patie...
High-dose methotrexate as                 outpatient?• Patient Considerations   – Education and responsibility       • Wil...
The MSKCC experience with outpatient administration  of high-dose methotrexate with leucovorin rescue• Purpose   – To eval...
The MSKCC experience with outpatient administration  of high-dose methotrexate with leucovorin rescue• Results   – 82% of ...
The MSKCC experience with outpatient administration  of high-dose methotrexate with leucovorin rescue• Considerations  – P...
Ambulatory high-dose methotrexate administration among  pediatric osteosarcoma patients in an urban, underserved          ...
Ambulatory high-dose methotrexate administration among  pediatric osteosarcoma patients in an urban, underserved          ...
High-dose methotrexate as                 outpatient?• HDMTX administered as outpatient is not only safe but very  feasibl...
Case• PG 24 y/o male  – 10/24/12     • Patient presented to the sarcoma clinic complaining of fever       (100.8), chills,...
Case• PG 24 y/o male  – Patient was subsequently discharged on 10/28/12,    after stool, urine and blood cultures were all...
Questions?
References1. Mahadeo, Kris M., Ruth Santizo, Lindsay Baker, Joan OHanlon, and Richard Gorlick. "Ambulatory High-dose      ...
High-dose Methotrexate in Osteosarcoma: Pro's and Con's of Outpatient Administration
Upcoming SlideShare
Loading in …5
×

High-dose Methotrexate in Osteosarcoma: Pro's and Con's of Outpatient Administration

3,212 views

Published on

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.

0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
3,212
On SlideShare
0
From Embeds
0
Number of Embeds
5
Actions
Shares
0
Downloads
54
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide

High-dose Methotrexate in Osteosarcoma: Pro's and Con's of Outpatient Administration

  1. 1. High-dose methotrexate in osteosarcoma Pros and Cons of outpatient administration Joseph Feliciano PharmD Candidate MCPHS
  2. 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. 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. 4. 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
  5. 5. 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
  6. 6. 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
  7. 7. 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
  8. 8. 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%
  9. 9. 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
  10. 10. http://curriculum.toxicology.wikispaces.net/Methotrexate
  11. 11. 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
  12. 12. Methotrexate• Common adverse events – Nausea/vomiting – Stomatisis/mucositis – Renal toxicity – Neutropenia
  13. 13. 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)
  14. 14. 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
  15. 15. 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
  16. 16. 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
  17. 17. Leucovorin to the rescueClinical Laboratory Leucovorin Dosage andSituation DurationNormal MTX Serum MTX level approximately 10 15 mg orally, IM, or IV everyelimination 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 administrationDelayed Early Serum MTX level at 50 µmol or more 150 mg IV every 3 hr untiland/or Evidence at 24 hr, or 5 µmol or more at 48 hr MTX level is less than 1of Acute Renal after administration; OR a 100% or micromolar; then 15 mg IVInjury greater increase in SCr at 24 hr after every 3 hr until MTX level is administration less than 0.05 µmol
  18. 18. Leucovorin to the rescue
  19. 19. High-dose MTX as outpatient?• Institutional Considerations – Monitoring levels – Adequate hydration – Toxicity – Patient/caretaker education – Resources • Are they being use efficiently and effectively?
  20. 20. 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?
  21. 21. 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)
  22. 22. 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
  23. 23. 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
  24. 24. 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
  25. 25. 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
  26. 26. 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
  27. 27. 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
  28. 28. 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
  29. 29. Questions?
  30. 30. References1. Mahadeo, Kris M., Ruth Santizo, Lindsay Baker, Joan OHanlon, 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.

×