| Cycle length: 24-hour continuous IV infusion every 21 days. |
| Drug | Dose and route | Administration | Given on days |
| Trabectedin | 1.5 mg/m2* | Dilute in 500 mL NS or D5W¶ and administer by continuous IV infusion over 24 hours.¶Δ | Day 1 |
| Pretreatment considerations: |
| Emesis risk | - MODERATE (>30% and <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 | - Premedicate with 20 mg of IV dexamethasone 30 minutes prior to each infusion of trabectedin.[1]
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| Vesicant/irritant properties | - Trabectedin is a vesicant; avoid extravasation. Administer through a central venous line.
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| Infection prophylaxis | - Primary prophylaxis with G-CSF is not justified (estimated risk of febrile neutropenia is approximately 5%[1]).
- 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.
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| Dose adjustment for baseline liver or renal dysfunction | - The recommended dose in patients with preexisting moderate hepatic impairment (bilirubin 1.5 to 3 times the ULN, and AST/ALT <8 times the ULN) is 0.9 mg/m2.[1] Do not administer trabectedin to patients with severe hepatic impairment (bilirubin levels above 3 to 10 times the ULN, and ANY ALT/AST above the ULN).
- 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.
- No dosing adjustments are needed in patients with mild (CrCl 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. There are no data on the dosing of the drug in patients with severe (CrCl 30 mL/min) or end-stage renal impairment.[1]
- Refer to UpToDate topic on "Chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency: Conventional cytotoxic agents".
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| Cardiac issues | - Cardiomyopathy including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction has been reported with trabectedin use.[1]
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| Monitoring parameters: |
- CBC with differential and platelets prior to each cycle.
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- Rhabdomyolysis has been reported with the use of trabectedin.[1] Assess CPK prior to each infusion.
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- LFTs (AST, ALT, total bilirubin, ALP) prior to each cycle. Assess LFTs five to seven days after administration of each dose of trabectedin to monitor for LFT elevation, which can impact dosing for a subsequent cycle of therapy.
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- Assess LVEF by echocardiogram or MUGA scan at baseline and every two to three months thereafter.
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- Monitor for capillary leak syndrome (hypotension, edema, hypoalbuminemia).
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| Suggested dose modifications for toxicity: |
| Hematologic | - Do not administer a new cycle of therapy unless platelets are ≥100,000/microL; ANC is ≥1500/microL; total bilirubin is ≤ULN; ALP, transaminases (AST, ALT), and CPK all are ≤2.5 times the ULN; and all other nonhematologic drug-related effects are grade 2 or lower.
- For nadir platelets <25,000/microL, delay next dose for up to three weeks and reduce dose of trabectedin by one dose level (1.5 mg/m2 to 1.2 mg/m2 or 1.2 mg/m2 to 1.0 mg/m2).
- For nadir ANC <1000/microL with fever/infection, or ANC <500/microL lasting more than five days, delay next dose for up to three weeks, and reduce next dose of trabectedin by one dose level.*
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| Hepatotoxicity | - If total bilirubin is >ULN at any time during the prior cycle, delay next dose for up to three weeks until it is ≤ULN, and reduce next dose by one dose level.*
- If AST or ALT is >5 times the ULN at any time during the prior cycle, delay next dose for up to three weeks until it is ≤2.5 times the ULN, and reduce next dose by one dose level.*
- If ALP is >2.5 times the ULN at any time during the prior cycle, delay next dose for up to three weeks and reduce next dose by one dose level.*
- Permanently discontinue trabectedin for severe liver dysfunction (bilirubin 2 times the ULN and AST/ALT 3 times the ULN and ALP <2 times the ULN) in the prior treatment cycle for patients with normal liver function at baseline, or exacerbation of liver dysfunction in patients with preexisting moderate hepatic impairment.
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| CPK | - If CPK is ≥5 times the ULN at any time during the prior cycle, delay next dose for up to three weeks, and reduce next dose by one dose level.*
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| Cardiotoxicity | - For LVEF less than lower limit of normal or clinical evidence of cardiomyopathy, delay next dose for up to three weeks. For absolute decrease in LVEF ≥10% from baseline and less than lower limit of normal or clinical evidence of cardiomyopathy, reduce next dose by one dose level.*
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| Other nonhematologic toxicity | - For any other grade 3 or 4 nonhematologic toxicity, delay next dose for up to three weeks and decrease next dose of trabectedin by one dose level.*
- Permanently discontinue trabectedin for persistent adverse reactions requiring a delay in dosing of more than three weeks, and for adverse reactions requiring dose reduction following trabectedin administered at 1 mg/m2 for patients with normal hepatic function, or at 0.3 mg/m2 for patients with preexisting moderate hepatic impairment.
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