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Systemic Anti-Cancer Therapy Regimen Library

Home > LYM NHL NK/T-cell Extra Nodal - mSMILE [dexamethasone, metHOTREXATe, IFOSFamide, pegaspargase, etoposide] [nasal type]

LYM NHL NK/T-cell Extra Nodal - mSMILE [dexamethasone, metHOTREXATe, IFOSFamide, pegaspargase, etoposide] [nasal type]

Treatment Overview

Number of cycles: 2 to 6 cycles.

Frequency: Every 21 days; the frequency can be extended to once every 28 days at the discretion of the clinician.


High dose methotrexate

  • methotrexate levels MUST be measured once every 24 hours.
  • Intravenous alkalinized fluids MUST be commenced at least 6 hours before the start of methotrexate infusion and MUST continue until the methotrexate serum level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice). Additional oral alkalinization can be considered as Ural® 2 sachets orally the night before and 2 sachets the morning of high dose methotrexate infusion.
  • Before commencing the high dose methotrexate infusion, urinary pH MUST be 7.5 or above (pH 7.5 to 8.0).
  • Closely monitor renal function, electrolytes, fluid balance, and weight.
  • folinic acid MUST start 36 hours after start of methotrexate infusion and MUST continue to be administered until serum methotrexate level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice).

This regimen contains a medicine where one or more biosimilars may exist. Any biosimilars used have been reviewed by the regulator (Medsafe) and relevant specialists were consulted nationally. Where regulators, in consultation with relevant specialists, have agreed that there are no clinically significant differences in either safety or effectiveness between a biosimilar and originator product, these drugs may be used interchangeably.

Cycles 1 to 6 - 21 days

Cycle length:
21

folinic acid:

  • MUST start 36 hours after start of methotrexate infusion and MUST continue to be administered every 6 hours until serum methotrexate level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice).
  • Some centres can consider using an alternative dosing strategy for certain patients commencing 36 hours after the start of the methotrexate infusion as foliNIc acid 300 mg IV over 24 hours before switching to 30 mg IV q6h dosing.

filgrastim:

  • Give filgrastim 5 microgram/kg subcutaneously ONCE daily from day 6 until neutrophil recovery past nadir.
  • If for stem cell harvest, mobilise as per institutional practice.

pegaspargase:

  • Intramuscular (IM) injection is the preferred route of administration because of the lower incidence of hepatotoxicity, coagulopathy, and gastrointestinal and renal disorders, as compared with the intravenous route. Pegaspargase can be administered intravenously over 120 minutes.
  • Pegaspargase (and asparaginase products) should only be administered by centres with appropriate expertise.
  • Consideration can be given to reducing dose of pegaspargase to 500 - 1000 international units/m2 for certain patients.
  • There is limited data available for use of pegaspargase in patients 65 years and older. Strongly consider not using pegaspargase in patients 65 years and older.
  • Monitor patients for one hour after administration of pegaspargase in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g. adrenaline, oxygen, intravenous steroids, antihistamines).
  • See also Further information - pegaspargase.

Cycle details

Cycles 1 to 6 - 21 days

Medication Dose Route Days Max Duration
potassium chloride 20mmol/1000mL + sodium chloride 0.18% + glucose 4% 125 mL/m²/hour intravenous 1 to 4
sodium bicarbonate 50 mmol intravenous 1 to 4
acetazolamide * 250 mg Four times daily oral administration 1 to 4
metHOTREXATe * 2000 mg/m² intravenous 1 6 hours
foliNIc acid (as calcium folinate) * 30 mg flat dosing Every six hours intravenous 2, 3, 4 2 minutes
dexamethasone * 40 mg flat dosing oral administration 2, 3, 4
etoposide (as phosphate) 100 mg/m² Once daily intravenous 2, 3, 4 60 minutes
sodium chloride 0.9 % intravenous 3, 4 120 minutes
mesna 300 mg/m² intravenous 2, 3, 4 15 minutes
IFOSFamide * 1500 mg/m² Once daily intravenous 2, 3, 4 6 hours
mesna 900 mg/m² intravenous 2, 3, 4 6 hours
sodium chloride 0.9 % intravenous 3, 4 120 minutes
mesna * 300 mg/m² intravenous 2, 3, 4 15 minutes
mesna * 300 mg/m² intravenous 2, 3, 4 15 minutes
filgrastim 5 microgram/kg Once daily subcutaneous injection 6
paracetamol * 1000 mg flat dosing oral administration 8
loratadine * 10 mg oral administration 8
famotidine * 20 mg oral administration 8
pegaspargase * 1500 international unit/m² intramuscular injection 8

folinic acid:

  • MUST start 36 hours after start of methotrexate infusion and MUST continue to be administered every 6 hours until serum methotrexate level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice).
  • Some centres can consider using an alternative dosing strategy for certain patients commencing 36 hours after the start of the methotrexate infusion as foliNIc acid 300 mg IV over 24 hours before switching to 30 mg IV q6h dosing.

filgrastim:

  • Give filgrastim 5 microgram/kg subcutaneously ONCE daily from day 6 until neutrophil recovery past nadir.
  • If for stem cell harvest, mobilise as per institutional practice.

pegaspargase:

  • Intramuscular (IM) injection is the preferred route of administration because of the lower incidence of hepatotoxicity, coagulopathy, and gastrointestinal and renal disorders, as compared with the intravenous route. Pegaspargase can be administered intravenously over 120 minutes.
  • Pegaspargase (and asparaginase products) should only be administered by centres with appropriate expertise.
  • Consideration can be given to reducing dose of pegaspargase to 500 - 1000 international units/m2 for certain patients.
  • There is limited data available for use of pegaspargase in patients 65 years and older. Strongly consider not using pegaspargase in patients 65 years and older.
  • Monitor patients for one hour after administration of pegaspargase in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g. adrenaline, oxygen, intravenous steroids, antihistamines).
  • See also Further information - pegaspargase.

Full details

Cycles 1 to 6 - 21 days

Day: 1

Medication Dose Route Max duration Details
potassium chloride 20mmol/1000mL + sodium chloride 0.18% + glucose 4% 125 mL/m²/hour intravenous
Instructions:
  • To each 1000 mL bag admix 50 mmol sodium bicarbonate.
  • Or an alternative alkalinized intravenous infusion may be used as per institutional practice.
  • Commence at least 6 hours prior to methotrexate infusion and run continuously until serum methotrexate level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice).
sodium bicarbonate 50 mmol intravenous
Instructions:
  • Admix 50 mmol sodium bicarbonate to each 1000 mL bag of potassium chloride 20 mmol + sodium chloride 0.18% + glucose 4%.
  • Dose of sodium bicarbonate is approximately 6 mmol/m2/hour when admixed bag is infused at 125 mL/m2/hour.
acetazolamide * 250 mg Four times daily oral administration
Instructions:

When required.

  • Administer immediately if urinary pH drops below 7.5 during methotrexate infusion and until serum methotrexate level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice).
metHOTREXATe * 2000 mg/m² intravenous 6 hours

Day: 2

Medication Dose Route Max duration Details
potassium chloride 20mmol/1000mL + sodium chloride 0.18% + glucose 4% 125 mL/m²/hour intravenous
Instructions:
  • To each 1000 mL bag admix 50 mmol sodium bicarbonate.
  • Or an alternative alkalinized intravenous infusion may be used as per institutional practice.
  • Run continuously until serum methotrexate level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice).
sodium bicarbonate 50 mmol intravenous
Instructions:
  • Admix 50 mmol sodium bicarbonate to each 1000 mL bag of potassium chloride 20 mmol + sodium chloride 0.18% + glucose 4%.
  • Dose of sodium bicarbonate is approximately 6 mmol/m2/hour when admixed bag is infused at 125 mL/m2/hour.
acetazolamide * 250 mg Four times daily oral administration
Instructions:

When required.

  • Administer immediately if urinary pH drops below 7.5 during methotrexate infusion and until serum methotrexate level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice).
foliNIc acid (as calcium folinate) * 30 mg flat dosing Every six hours intravenous 2 minutes
Instructions:
  • Starting 36 hours after start of methotrexate infusion and continue to administer every 6 hours until serum methotrexate level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice).
  • If methotrexate elimination is impaired the dose of folinic acid will need to be increased. Consult prescribing information.
dexamethasone * 40 mg flat dosing oral administration
Instructions:

Take in the morning with food.
etoposide (as phosphate) 100 mg/m² Once daily intravenous 60 minutes
mesna 300 mg/m² intravenous 15 minutes
Instructions:

Immediately prior to ifosfamide infusion over 15 minutes, or as per institutional practice.
IFOSFamide * 1500 mg/m² Once daily intravenous 6 hours
Instructions:

Admixed with mesna 900 mg/m2.
mesna 900 mg/m² intravenous 6 hours
Instructions:

Admixed with ifosfamide.

Or give as per institutional practice.
mesna * 300 mg/m² intravenous 15 minutes
Instructions:

At 4 hours after the end of ifosfamide/mesna infusion, or as per institutional practice.
mesna * 300 mg/m² intravenous 15 minutes
Instructions:

At 8 hours after the end of ifosfamide/mesna infusion, or as per institutional practice.

Day: 3

Medication Dose Route Max duration Details
potassium chloride 20mmol/1000mL + sodium chloride 0.18% + glucose 4% 125 mL/m²/hour intravenous
Instructions:
  • To each 1000 mL bag admix 50 mmol sodium bicarbonate.
  • Or an alternative alkalinized intravenous infusion may be used as per institutional practice.
  • Run continuously until serum methotrexate level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice).
sodium bicarbonate 50 mmol intravenous
Instructions:
  • Admix 50 mmol sodium bicarbonate to each 1000 mL bag of potassium chloride 20 mmol + sodium chloride 0.18% + glucose 4%.
  • Dose of sodium bicarbonate is approximately 6 mmol/m2/hour when admixed bag is infused at 125 mL/m2/hour.
acetazolamide * 250 mg Four times daily oral administration
Instructions:

When required.

  • Administer immediately if urinary pH drops below 7.5 during methotrexate infusion and until serum methotrexate level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice).
foliNIc acid (as calcium folinate) * 30 mg flat dosing Every six hours intravenous 2 minutes
Instructions:
  • Administer every 6 hours until serum methotrexate level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice).
  • If methotrexate elimination is impaired the dose of folinic acid will need to be increased. Consult prescribing information.
dexamethasone * 40 mg flat dosing oral administration
Instructions:

Take in the morning with food.
etoposide (as phosphate) 100 mg/m² Once daily intravenous 60 minutes
sodium chloride 0.9 % intravenous 120 minutes
Quantity:1000 mL
Instructions:

Prior to ifosfamide infusion.

Omit if alkalinized fluids are still running.

  • Recommended daily hydration is 3000 ml per day as oral or IV fluid on day(s) of ifosfamide and for 24 hours after, or as per institutional practice.
mesna 300 mg/m² intravenous 15 minutes
Instructions:

Immediately prior to ifosfamide infusion over 15 minutes, or as per institutional practice.
IFOSFamide * 1500 mg/m² Once daily intravenous 6 hours
Instructions:

Admixed with mesna 900 mg/m2.
mesna 900 mg/m² intravenous 6 hours
Instructions:

Admixed with ifosfamide.

Or give as per institutional practice.
sodium chloride 0.9 % intravenous 120 minutes
Quantity:1000 mL
Instructions:

After ifosfamide infusion.

Omit if alkalized fluids still running.

  • Recommended daily hydration is 3000 ml per day as oral or IV fluid on day(s) of ifosfamide and for 24 hours after, or as per institutional practice.
mesna * 300 mg/m² intravenous 15 minutes
Instructions:

At 4 hours after the end of ifosfamide/mesna infusion, or as per institutional practice.
mesna * 300 mg/m² intravenous 15 minutes
Instructions:

At 8 hours after the end of ifosfamide/mesna infusion, or as per institutional practice.

Day: 4

Medication Dose Route Max duration Details
potassium chloride 20mmol/1000mL + sodium chloride 0.18% + glucose 4% 125 mL/m²/hour intravenous
Instructions:
  • To each 1000 mL bag admix 50 mmol sodium bicarbonate.
  • Or an alternative alkalinized intravenous infusion may be used as per institutional practice.
  • Run continuously until serum methotrexate level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice).
  • Administration may continue past Day 4 if methotrexate level is still elevated.
sodium bicarbonate 50 mmol intravenous
Instructions:
  • Admix 50 mmol sodium bicarbonate to each 1000 mL bag of potassium chloride 20 mmol + sodium chloride 0.18% + glucose 4%.
  • Dose of sodium bicarbonate is approximately 6 mmol/m2/hour when admixed bag is infused at 125 mL/m2/hour.
  • Administration may continue past Day 4 if methotrexate level is still elevated.
acetazolamide * 250 mg Four times daily oral administration
Instructions:

When required.

  • Administer immediately if urinary pH drops below 7.5 during methotrexate infusion and until serum methotrexate level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice).
  • Administration may continue past Day 4 if methotrexate level is still elevated.
foliNIc acid (as calcium folinate) * 30 mg flat dosing Every six hours intravenous 2 minutes
Instructions:
  • Administer every 6 hours until serum methotrexate level is less than 0.05 µmol/L – 0.1 µmol/L (level as per institutional practice).
  • If methotrexate elimination is impaired the dose of folinic acid will need to be increased. Consult prescribing information.
  • Administration may continue past Day 4 if methotrexate level is still elevated.
dexamethasone * 40 mg flat dosing oral administration
Instructions:

Take in the morning with food.
etoposide (as phosphate) 100 mg/m² Once daily intravenous 60 minutes
sodium chloride 0.9 % intravenous 120 minutes
Quantity:1000 mL
Instructions:

Prior to ifosfamide infusion.

Omit if alkalinized fluids are still running.

  • Recommended daily hydration is 3000 ml per day as oral or IV fluid on day(s) of ifosfamide and for 24 hours after, or as per institutional practice.
mesna 300 mg/m² intravenous 15 minutes
Instructions:

Immediately prior to ifosfamide infusion over 15 minutes, or as per institutional practice.
IFOSFamide * 1500 mg/m² Once daily intravenous 6 hours
Instructions:

Admixed with mesna 900 mg/m2.
mesna 900 mg/m² intravenous 6 hours
Instructions:

Admixed with ifosfamide.

Or give as per institutional practice.
sodium chloride 0.9 % intravenous 120 minutes
Quantity:1000 mL
Instructions:

After ifosfamide infusion.

Omit if alkalized fluids still running.

  • Recommended daily hydration is 3000 ml per day as oral or IV fluid on day(s) of ifosfamide and for 24 hours after, or as per institutional practice.
mesna * 300 mg/m² intravenous 15 minutes
Instructions:

At 4 hours after the end of ifosfamide/mesna infusion, or as per institutional practice.
mesna * 300 mg/m² intravenous 15 minutes
Instructions:

At 8 hours after the end of ifosfamide/mesna infusion, or as per institutional practice.

Day: 6

Medication Dose Route Max duration Details
filgrastim 5 microgram/kg Once daily subcutaneous injection
Instructions:

Give ONCE daily from Day 6 until neutrophil recovery past the nadir.

  • Round dose to nearest prefilled syringe dose of 300 micrograms or 480 micrograms.

Day: 8

Medication Dose Route Max duration Details
paracetamol * 1000 mg flat dosing oral administration
Instructions:

30 minutes prior to pegaspargase.
loratadine * 10 mg oral administration
Instructions:

30 minutes prior to pegaspargase.
famotidine * 20 mg oral administration
Instructions:

30 minutes prior to pegaspargase.
pegaspargase * 1500 international unit/m² intramuscular injection
Instructions:
  • Alternatively, pegaspargase can be administered intravenously over 120 minutes.
  • Consider reducing dose of pegaspargase to 500 - 1000 international units/m2 for certain patients.
  • Monitor patients for one hour after administration of pegaspargase in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g. adrenaline, oxygen, intravenous steroids, antihistamines).

Supportive Care Factors

Factor Value
Antiviral prophylaxis for herpes virus: Routine antiviral prophylaxis may be considered
Emetogenicity: Variable
Folinic acid rescue for high dose methotrexate: Mandatory
Gastroprotection: Gastroprotection may be considered
Growth factor support: Recommended for primary prophylaxis
Hydration: Routine hydration recommended
Hypersensitivity / Infusion related reaction risk: High - routine premedication recommended
Mesna uroprotection: Routine mesna uroprotection recommended
Pneumocystis jirovecii pneumonia (PJP) prophylaxis: Routine antibiotic prophylaxis recommended
Tumour lysis syndrome prophylaxis: Tumour lysis syndrome prophylaxis may be considered

Antiviral prophylaxis for hepatitis B virus: Guidance is limited to high-risk anti-cancer medicines. Clinicians will need to assess individual patient risk for other anti-cancer medicines.


Emetogenicity:

  • MEDIUM day 1, high dose methotrexate may be highly emetogenic in certain patients.
  • MEDIUM days 2 to 4.
  • MINIMAL day 8.

PJP prophylaxis If trimethoprim + sulfamethoxazole is used as prophylaxis, it is recommended to withhold at least 48 hours prior to high dose methotrexate administration and until serum methotrexate level is less than 0.05 µmol/L – 0.1µmol/L (as per institutional practice).

References

Kwong, Y. L., W. S. Kim, S. T. Lim, et al. 2012. "SMILE for natural killer/T-cell lymphoma: analysis of safety and efficacy from the Asia Lymphoma Study Group." Blood 120(15):2973-2980. , PMID: 22919026

Yamaguchi, M., Y. L. Kwong, W. S. Kim, et al. 2011. "Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study." J Clin Oncol 29(33):4410-4416., PMID: 21990393

Ghione P, Qi S, Imber BS, et al. Modified SMILE (mSMILE) and intensity-modulated radiotherapy (IMRT) for extranodal NK-T lymphoma nasal type in a single-center population. Leuk Lymphoma. 2020 Dec;61(14):3331-3341. doi: 10.1080/10428194.2020.1811864. Epub 2020 Aug 26., PMID: 32844695

Servier Laboratories (Aust.) Ltd Oncaspar®Australian Product Information 19 April 2022 https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2019-PI-01257-1&d=20220614172310101 (accessed 14 June 2022).

Tabernero J, Vyas M, Giuliani R, et al. Biosimilars: a position paper of the European Society for Medical Oncology, with particular reference to oncology prescribers. ESMO Open. 2017 Jan 16;1(6):e000142. doi: 10.1136/esmoopen-2016-000142., PMID: 28848668

Lyman GH, Balaban E, Diaz M, et al. American Society of Clinical Oncology Statement: Biosimilars in Oncology. J Clin Oncol. 2018 Apr 20;36(12):1260-1265. doi: 10.1200/JCO.2017.77.4893. Epub 2018 Feb 14., PMID: 29443651

* The medicines, doses, combinations, and schedule in this treatment regimen have been carefully reviewed against international best practice guidelines by specialists in medical oncology around New Zealand and this advice has been accepted for publication by Te Aho o Te Kahu (the Cancer Control Agency). Sometimes medicines that are used in routine clinical practice have not been through a formal review process by the NZ Medicines Regulator Medsafe and are therefore considered unapproved or off-label. These medicines are legally able to be prescribed through sections 25 and 29 of the Medicines Act and by obtaining informed consent from patients. All treatment regimens listed on this website have been through robust peer review and are considered an accepted standard of care, whether prescribed through sections 25 or 29 or carrying formal Medsafe Approval.

s29: This symbol indicates that some formulations of the associated medicine are legally only able to be prescribed under section 29 of the Medicines Act. You can see which formulations are section 29 by hovering over the s29 symbol. You can access full medication details from the New Zealand Formulary by clicking on the medication name. Each clinician retains full responsibility for ensuring they have complied with all relevant obligations and requirements of section 29 including obtaining informed patient consent prior to prescribing the applicable medicine.