Cisplatin, doxorubicin, and methotrexate for non-metastatic high-grade osteosarcoma in young adults and children^[1]

Preoperative: Weeks 1 and 6.

Dilute in 1000 mL NS^¶ and administer as a continuous IV infusion over 24 hours daily.

Preoperative: Weeks 1 and 6.

Preoperative: Week 4, 5, 9, and 10.

Preoperative: Week 4, 5, 9, and 10.

• Cisplatin: NS-based IV fluid to establish a urine flow of at least 100 mL/hour for at least two hours prior to and two hours after cisplatin administration. Alternative: Pretreatment hydration with 1 to 2 L of NS-based fluid infused for 8 to 12 hours prior to each dose of cisplatin.^¶[2]
• Refer to UpToDate topics on cisplatin nephrotoxicity.
• Methotrexate: Adequate IV fluid (approximately 125 to 150 mL/hour) with electrolytes and bicarbonate must be given to maintain adequate urine output and alkalinization for methotrexate clearance. A urine pH >7 must be achieved before starting the methotrexate infusion and maintained until the methotrexate serum level is <0.1 microM.
• Refer to UpToDate topics on therapeutic use and toxicity of high-dose methotrexate.

• Cisplatin plus doxorubicin: HIGH (>90% risk of emesis).
• Methotrexate: LOW (10 to 30% risk of emesis).
• Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.

• There is no standard premedication regimen for cisplatin, doxorubicin, or methotrexate.
• Refer to UpToDate topics on infusion reactions to systemic chemotherapy.

• Cisplatin is an irritant but can cause significant tissue damage with a large-volume, concentrated extravasation; avoid extravasation. Doxorubicin is a vesicant; avoid extravasation. Administer infusions of doxorubicin through a central venous line.
• Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.

• The AOST 0331/EURAMOS-1 protocol recommended secondary prophylaxis with G-CSF after doxorubicin/cisplatin cycles if prior doxorubicin/cisplatin cycles were complicated by fever and neutropenia with noncatheter-related sepsis or prolonged hospitalization (>7 days). However, many centers give G-CSF with each cycle of doxorubicin/cisplatin. If given, begin growth factor support at least 24 hours after completion of chemotherapy; if given daily, continue until WBC count ≥5000/mm³ after the nadir, and discontinue at least two days prior to next course of chemotherapy.
• Refer to UpToDate topics on use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation.

• A lower starting dose of cisplatin and methotrexate may be needed for patients with renal impairment, although the optimal approach to cisplatin therapy in patients with preexisting renal impairment is unknown. Many clinicians would decrease the initial dose of cisplatin for a creatinine clearance <50 mL/min. A lower starting dose of doxorubicin and methotrexate may be needed for patients with liver impairment. Methotrexate should not be administered in the setting of severe liver impairment (total bilirubin >4 × ULN).^[3]
• In the AOST0331 protocol:
  • For total bilirubin ≥1.25 mg/dL and <2.1 mg/dL, doxorubicin doses were reduced by 25%;
  • For total bilirubin ≥2.1 mg/dL and <3.06 mg/dL, doxorubicin doses were reduced by 50%;
  • For total bilirubin ≥3.06 mg/dL and <5 mg/dL, doxorubicin doses were reduced by 75%; and
  • For total bilirubin ≥5 mg/dL, doxorubicin was omitted.^[1]
• For patients with third-space fluid collections (eg, ascites, pleural effusion), await resolution or perform drainage before initiating methotrexate.
• Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents; chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency, conventional cytotoxic agents; and therapeutic use and toxicity of high-dose methotrexate.

• Doxorubicin is associated with dose-dependent cardiomyopathy; the incidence is related to cumulative dose. The risk of developing congestive heart failure increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m². Cardiac toxicity may occur at lower cumulative doses whether or not cardiac risk factors are present. Assess baseline LVEF prior to initiating therapy. Doxorubicin is contraindicated for patients with recent myocardial infarction, severe myocardial dysfunction, severe arrhythmias, or prior treatment with maximum cumulative doses of anthracyclines.^[2]

• CBC with differential prior to treatment.

• Assess electrolytes and liver and renal function prior to treatment and daily during treatment.

• Baseline audiometry, monitor for hearing loss prior to each dose of cisplatin; repeat audiometry as clinically indicated.

• Assess change in neurologic function prior to each treatment.

• Assess patient for third-space fluid collection prior to treatment.

• Monitor for diarrhea, stomatitis, and cutaneous toxicity.

• Monitor for clinically significant nausea and vomiting.

• Monitor serum methotrexate concentration daily starting 24 hours after the start of the methotrexate infusion and continue until serum methotrexate level is <0.1 microM. If toxic concentrations of methotrexate with reduced clearance occur in the setting of renal insufficiency, consider emergent use of glucarpidase.
• Refer to UpToDate topics on therapeutic use and toxicity of high-dose methotrexate.

• Monitor daily fluid balance (intake and output), weight, CBC with differential, platelets, blood pressure, LFTs (AST, ALT, total bilirubin), and serum creatinine daily during and after methotrexate therapy until the methotrexate serum level is <0.1 microM.

• For cycles of cisplatin plus doxorubicin, hold treatment until ANC is ≥750/microL and platelet count is ≥75,000/microL. If ANC and platelets recovery is ≤7 days, no dose adjustment is required. If recovery is delayed >7 days or if there is febrile neutropenia with prolonged hospitalization, decrease the cisplatin dose by 25%.^[1]
• For high-dose methotrexate, if the ANC is <250/microL or platelets are <50,000/microL, hold methotrexate until adequate hematologic recovery occurs.^[1]

• For any hearing loss with a threshold >30 dB at ≤2 kHz, discontinue cisplatin.^[1]
• Refer to UpToDate topics on overview of neurologic complications of platinum-based chemotherapy.

• For LVEF <50% or shortening fraction <28%, repeat MUGA or echocardiogram in one week. If the MUGA or echocardiogram is within normal limits, then proceed with chemotherapy. If LVEF does not normalize after one week, omit all further doxorubicin.^[1] There are no prospective data on the use of the cardioprotective agent dexrazoxane in osteosarcoma therapy, particularly in children. Dexrazoxane may be used if a 10% decrease in LVEF or similar decrease within the normal range of shortening fraction (as determined by echocardiogram) occurs. Some clinicians add dexrazoxane once cumulative doxorubicin dose reaches 225 to 300 mg/m². If cardioprotection is used, doxorubicin should be administered daily over 15 minutes immediately following dexrazoxane.

• For elevated LFTs that are not methotrexate induced, delay methotrexate treatment for one week and administer methotrexate if ALT is <10 times normal.
• For elevated LFTs that are probably methotrexate induced (ie, up to three weeks after methotrexate), it is expected that patients receiving high-dose methotrexate will develop hypertransaminasemia and occasionally hyperbilirubinemia. These elevations can last up to two weeks following the methotrexate infusion and should not be considered a toxicity requiring dose reduction or discontinuation of the drug. However, for total bilirubin >1.5 times normal for longer than three weeks, discontinue methotrexate.^[1]
• Refer to UpToDate topics on therapeutic use and toxicity of high-dose methotrexate.

• For grade 4 mucositis or typhlitis or repeated grade 3 mucositis, hold cisplatin and doxorubicin until toxicity has resolved and then decrease subsequent doxorubicin total dose to 60 mg/m² per cycle.^[1]
• For grade 3 or 4 mucositis or diarrhea after methotrexate, consider leucovorin rescue dose adjustment.^◊[1] Also, maximize measures for methotrexate elimination.
• Refer to UpToDate topics on therapeutic use and toxicity of high-dose methotrexate.
• If grade 3 or 4 mucositis or diarrhea after methotrexate in week 4 (cycle 1) and it persists for longer than one week, omit week 5 methotrexate and proceed to week 6 of preoperative chemotherapy (or surgery).^[1]

• Hold cisplatin if serum creatinine is greater than twice baseline or if GFR is <70 mL/min/1.73 m². If renal function does not improve, omit cisplatin and administer doxorubicin alone. Cisplatin can be restarted in future courses if GFR improves to ≥70 mL/min/1.73 m².
• Hold methotrexate treatment if GFR is <70 mL/min/1.73 m² until GFR is ≥70 mL/min/1.73 m². If renal function does not improve within one week, then omit methotrexate and proceed to the next possible cycle. If renal function subsequently improves, resume methotrexate.^[1]