Cycle length: 21 days.
Duration of therapy: 6 cycles (adjuvant or neoadjuvant). |
| Drug | Dose and route | Administration | Given on days |
| Doxorubicin | 25 mg/m2 per day IV* | Administer undiluted (2 mg/mL) as an IV push over three to five minutes into a free flowing IV infusion of normal saline (NS) or 5% dextrose in water (D5W). If needed, each day's dose of doxorubicin can be diluted in NS or D5W and given as a slow IV infusion administered over 15 to 60 minutes[3] or administered by continuous infusion over 72 hours.[4] | Days 1, 2, and 3 |
| Cisplatin | 100 mg/m2 IV¶ | Dilute in 250 mL NS and administer over 60 minutes (or at a rate of 1 mg per minute). Do not administer with aluminum needles or sets.[1,5] Alternative: Dilute in 2 L NS, D5W in one-half or one-third NS containing 37.5 g of mannitol and infuse over six to eight hours.[1] Do not administer with aluminum needles or sets. | Day 1 |
| Pretreatment considerations: |
| Hydration | - 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.
- Alternatively, hydration with 1 to 2 L of NS-based fluid infused over 4 to 12 hours prior to and immediately after each dose of cisplatin.[5]
- Refer to UpToDate topics on cisplatin nephrotoxicity.
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| Emesis risk | - HIGH (>90% frequency of emesis).
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Prophylaxis for infusion reactions | - Routine prophylaxis not indicated.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
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| Vesicant/irritant properties | - Doxorubicin is a vesicant; avoid extravasation. Administer infusional regimens through a central venous line. Monitor IV or catheter site continuously throughout drug administration. Cisplatin is an irritant but can cause significant tissue damage; avoid extravasation.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
|
| Infection prophylaxis | - Routine primary prophylaxis with G-CSF was not used in this trial.[1] However, the reported incidence of myelosuppression associated with infection (grade 3 or 4, according to National Cancer Institute Common Toxicity Criteria) was 19%. The decision to use G-CSF should be individualized, depending on other risk factors for prolonged neutropenia.
- 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.
|
| Dose adjustment for baseline liver or renal dysfunction | - The optimal approach to cisplatin therapy in patients with preexisting renal impairment is unknown. Patients with a serum creatinine >1.69 mg/dL (>150 micromol/L) were excluded from the original trial.[1] Many clinicians would decrease the initial dose of cisplatin for a creatinine clearance <50 mL/min.
- Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency, conventional cytotoxic agents.
- A lower starting dose for doxorubicin may be needed in patients with hepatic impairment.
- Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents and chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents.
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| Cardiac issues | - Doxorubicin is associated with cardiomyopathy, the incidence of which is related to cumulative dose (cumulative lifetime dose should not exceed 450 mg/m2). Assess baseline LVEF prior to administration. Doxorubicin is contraindicated for patients with recent myocardial infarction, severe myocardial dysfunction, severe arrhythmia, or previous therapy with high cumulative doses of doxorubicin or any other anthracyclines.[3]
- Refer to UpToDate topics on cardiotoxicity of anthracycline-like chemotherapy agents.
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| Monitoring parameters: |
- CBC with differential and platelet count every three weeks prior to each new treatment cycle.
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- Serum electrolytes and liver and renal function tests every three weeks prior to each new treatment cycle.
|
- Monitor cumulative doxorubicin dose. Reassess LVEF periodically during therapy as clinically indicated. There are no prospective data on the use of dexrazoxane in osteosarcoma therapy, particularly in children. Some clinicians would add dexrazoxane to reduce incidence of cardiotoxicity once cumulative doxorubicin dose reaches 225 to 300 mg/m2.
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- Audiometry at baseline; monitor for hearing loss prior to each dose of cisplatin; repeat audiometry as clinically indicated.
|
| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Reduce doses of doxorubicin and cisplatin by 15% for any intracycle grade 3 hematologic toxicity (as assessed by WHO criteria) and by 30% for any grade 4 toxicity.[1] For each new cycle, delay chemotherapy until the white blood cell count was >3000 cells/microL, absolute neutrophil count >1500 cells/microL, and platelet count >100,000/microL with repeat CBC with differential performed weekly. Discontinue chemotherapy if recovery was not apparent after three weeks.
|
| Mucosal toxicity | - Reduce doxorubicin dose by 20% for WHO grade 3 or 4 mucositis.[1]
|
| Neurotoxicity | - Neuropathy usually is seen with cumulative doses of cisplatin >400 mg/m2, although there is marked inter-individual variation. Patients with mild neuropathy can continue to receive full cisplatin doses. However, if the neuropathy interferes with function, risk of potentially disabling neurotoxicity must be weighed against benefit of continued treatment.
- Refer to UpToDate topics on overview of neurologic complications of conventional non-platinum cancer chemotherapy.
|
| Nephrotoxicity | - In the original study, doses were not adjusted for reversible renal toxicity; however, repeat courses of cisplatin were not given if the serum creatinine level remained above 1.7 mg/dL.[1] For grade ≥2 nephrotoxicity during treatment (creatinine >1.5 times normal value despite adequate hydration), creatinine clearance should be determined prior to next cycle, with dose reduction of cisplatin if <60 mL/min.
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| Cardiotoxicity | - Guidelines for managing doxorubicin dose in patients with symptomatic cardiac dysfunction or asymptomatic changes in LVEF during therapy are addressed in detail separately.
- Refer to UpToDate topics on cardiotoxicity of anthracycline-like chemotherapy agents.
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
