Regimen: High-Dose Methotrexate, Cisplatin, and Doxorubicin
Meyers PA et al. J Clin Oncol 2005;23:2004–2011
The regimen consists of 10 weeks of induction chemotherapy followed by limb-sparing surgery or amputation, which is followed by adjuvant maintenance chemotherapy beginning in week 12 and continuing until week 31
Note: Adjuvant maintenance chemotherapy should begin at week 12 provided wound healing is adequate
Hydration before and after cisplatin: ≥1000 mL 0.45% sodium chloride injection (0.45% NS); administer intravenously over a minimum of 2–4 hours
Cisplatin 120 mg/m2; administer intravenously in 150–1000 mL 0.9% sodium chloride injection (0.9% NS) over 4 hours, for 4 cycles, during weeks 0 and 5 in the induction phase and weeks 12 and 17 in the maintenance phase (total dosage/cycle = 120 mg/m2)
Note: Encourage patients to increase oral intake of nonalcoholic fluids, and monitor serum electrolytes and replace as needed (potassium, magnesium, sodium)
Doxorubicin 25 mg/m2 per day; administer intravenously in 50–1000 mL 0.9% NS or 5% dextrose injection (D5W) over 24 hours for 3 consecutive days, on days 1–3, for 6 cycles, during weeks 0 and 5 in the induction phase, and weeks 12, 17, 22, and 27 in the maintenance phase (total dosage/cycle = 75 mg/m2)
Hydration: 1500–3000 mL/m2 per day; administer intravenously. Use a solution containing a total amount of sodium not >0.9% NS (ie, ≤154 mEq sodium/1000 mL) by intravenous infusion during methotrexate administration and for at least 24 hours afterward
Fluid administration may commence 2–12 hours before starting methotrexate, depending on a patient's fluid status
Urine output should be at least 100 mL/hour before starting methotrexate infusion
Maintain hydration at a rate that maintains urine output ≥100 mL/hour until the serum methotrexate concentration is <0.1 μmol/L
Urine pH should be increased within the range ≥7.0 to ≤8.0 to enhance methotrexate solubility and ensure elimination
Sodium bicarbonate 50–150 mEq/1000 mL is added to the parenteral solution to maintain urine pH ≥7.0 to ≤8.0
Methotrexate 12,000 mg/m2 (maximum dose = 20,000 mg); administer intravenously in 500–2000 mL 0.9% NS or D5W (or saline and dextrose combinations) over 4 hours for 12 cycles during weeks 3, 4, 8, and 9 in the induction phase, and weeks 15, 16, 20, 21, 25, 26, 30, and 31 in the maintenance phase (total dosage/cycle = 12,000 mg/m2; maximum dose/cycle = 20,000 mg)
Note: For logistical practicality and efficiency, parenteral admixtures containing methotrexate may include a portion, or all of the fluid and sodium bicarbonate needed to meet hydration and urinary alkalinization requirements during methotrexate administration
Leucovorin 10 mg (a fixed dose); administer intravenously in 25–250 mL 0.9% NS or D5W over 15 minutes every 6 hours, starting 24 hours after methotrexate administration began and continuing until the serum methotrexate concentration is <0.1 μmol/L (ie, <1 × 10-7 mol/L, or <100 nmol/L)
Note: Leucovorin may be administered orally after completing 1 day of parenteral administration if patients are compliant, are not vomiting, and have no other potentially mitigating complications
Leucovorin 10 mg (fixed dose); administer orally every 6 hours until the serum methotrexate concentration is <0.1 μmol/L (ie, <1 × 10−7 mol/L, or <100 nmol/L)
Leucovorin rescue for delayed methotrexate excretion:
Hydration, urinary alkalinization, and a more intensive leucovorin regimen are required if methotrexate excretion is delayed (eg, worsening renal function, effusions present)
If 24 hours after the completion of methotrexate administration a patient's serum creatinine is increased by ≥50% above the baseline value, or if serum methotrexate concentration is ≥5 μmol/L (≥5 × 10−6 mol/L), increase the leucovorin dosage and schedule to 100 mg/m2 per dose intravenously (not orally) every 3 hours until serum methotrexate level is <0.1 μmol/L (<1 × 10−7 mol/L, <100 nmol/L); then resume leucovorin 10 mg/dose orally or intravenously every 6 hours until serum methotrexate concentration is <0.05μmol/L (<5 × 10−8 mol/L, or <50 nmol/L), or until undetectable (if the lower limit of assay sensitivity is ≥0.05 μmol/L [≥5 × 10−8 mol/L, or ≥50 nmol/L])
Supportive Care
Antiemetic prophylaxis
Emetogenic potential during cycles with cisplatin + doxorubicin is HIGH. Potential for delayed symptoms
Emetogenic potential with doxorubicin alone is MODERATE
Emetogenic potential with methotrexate is MODERATE
See Chapter 39 for antiemetic recommendations
Hematopoietic growth factor (CSF) prophylaxis
Primary prophylaxis is indicated with 1 of the following:
Filgrastim (G-CSF) 5 mcg/kg per day by subcutaneous injection, or
Sargramostim (GM-CSF) 250 mcg/m2 per day by subcutaneous injection
See Chapter 43 for more information
Antimicrobial prophylaxis
Risk of fever and neutropenia is HIGH
Antimicrobial primary prophylaxis is recommended:
Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)
See Chapter 47 for more information
Oral care
Prophylaxis and treatment for mucositis/stomatitis
General advice:
Encourage patients to maintain intake of non-alcoholic fluids
Evaluate patients for oral pain and provide analgesic medications
Consider histamine (H2-subtype) receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain
Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea
Patients with intact oral mucosa:
Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultra-soft toothbrush with fluoride toothpaste
Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth
Patients may use saline or commercial bland, non-alcoholic rinses
If mucositis or stomatitis is present:
Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute
Rinse mouth several times a day to remove debris
Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse
Do not use mouthwashes that contain alcohols
Foam-tipped swabs (eg, Toothettes®) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque
Advise patients who develop mucositis to:
Choose foods that are easy to chew and swallow
Take small bites of food, chew slowly, and sip liquids with meals
Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs
For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids
Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks
Patient Population Studied
A prospective randomized intergroup phase III study of newly diagnosed patients with histologically confirmed high-grade, intramedullary osteosarcoma who were 30 years of age or younger. There were 677 patients enrolled without clinically detectable metastases; 340 received this regimen, including 168 who also received liposomal muramyl tripeptide