Malignant Rhabdoid Tumor Medication

Updated: Oct 09, 2018
  • Author: James I Geller, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Medication

Medication Summary

The treatment for malignant rhabdoid tumor (MRT) remains investigational. No accepted standard therapy has been established for this disease. Enrollment of patients on clinical trials is strongly encouraged. The following regimen of ifosfamide-carboplatin-etoposide (ICE) alternating with vincristine-doxorubicin-cyclophosphamide (VDC) has been used to successfully treat MRT.

Due to excessive toxicity in affected infants and young children, chemotherapeutic doses in the most recent COG protocol AREN0321, which uses CyCE (rather than ICE) alternating with VDC, have been decreased. In general, infants and children undergoing intensive chemotherapy for MRT, with either VDC/CyCE (possibly adequate for patients with stage 1 and 2 non-CNS MRT) or VDC/ICE, must be carefully monitored for toxicity, and doses of chemotherapeutic agents must be adjusted as necessary.

Table 1. One Ifosfamide-Carboplatin-Etoposide regimen for MRT (Open Table in a new window)

Drug

Dosage

Route

Schedule

Carboplatin

Target dose to the AUC of 6 mg/mL/min by using the Calvert equation

IV

Day 1

Etoposide

3.3 mg/kg/dose or 100 mg/m2/dose

IV

Days 1, 2, and 3

Ifosfamide

65 mg/kg/dose or 2 g/m2/dose

IV

Days 1, 2, and 3

Mesna

16 mg/kg/dose or 500 mg/m2/dose

IV

Start immediately after and at 3 h, 6 h, and 9 h after ifosfamide

Filgrastim G-CSF

5 mcg/kg/dose

SC

Start 24 h after chemotherapy and continue until ANC recovers

Note.—AUC = area under the concentration-time curve; IV = intravenous; G-CSF = granulocyte colony-stimulating factor; SC = subcutaneous; ANC = absolute neutrophil count.

Table 2. One Vincristine-Doxorubicin-Cyclophosphamide Regimen for MRT (Open Table in a new window)

Drug

Dosage

Route

Schedule

Vincristine

0.05 mg/kg/dose or 1.5 mg/m2/dose; not to exceed 2 mg/dose

IV

Days 1, 8, and 15

Doxorubicin

1.2 mg/kg/dose or 37.5 mg/m2/dose

IV

Days 1 and 2

Cyclophosphamide

60 mg/kg/dose or 1.8 g/m2/dose

IV

Day 1

Mesna

15 mg/kg/dose or 450 mg/m2/dose

IV

Start immediately after and at 3, 6, and 9 h after cyclophosphamide

Filgrastim G-CSF

5 mcg/kg/dose

SC

Start 24 h after chemotherapy and continue until ANC recovers

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Antineoplastic agents

Class Summary

For children older than 12 months and more than 10 kg, chemotherapy drugs should be dosed according to the child's body surface area. The total number of cycles of ICE or VDC necessary to treat MRT is unknown. Some investigators have advocated for between 8-10 cycles of chemotherapy total. The most recent COG MRT protocol used 5 cycles each of VDC and CyCE (10 cycles total).

Ifosfamide (Ifex)

Inhibits DNA and protein synthesis and, therefore, cellular proliferation by causing DNA cross-linking and denaturation of double helix.

Carboplatin (Paraplatin)

Analog of cisplatin. Heavy-metal coordination complex that exerts cytotoxic effect by platinating DNA; mechanism analogous to alkylation, leading to interstrand and intrastrand DNA cross-linking and inhibited DNA replication. Binds to protein and other compounds containing SH group. Cytotoxicity can occur at any stage of cell cycle, but cell most vulnerable in G1 and S phases. Same efficacy as cisplatin but improved toxicity profile. Main advantages over cisplatin include decreased nephrotoxicity and ototoxicity not requiring extensive prehydration and reduced risk of nausea and vomiting, but more likely than cisplatin to induce myelotoxicity.

Etoposide (VePesid, Toposar, VP-16)

Glycosidic derivative of podophyllotoxin that exerts cytotoxic effect by stabilizing normally transient covalent intermediates formed between DNA substrate and topoisomerase II, leading to single- and double-strand DNA breaks. This arrests cell proliferation in late S or early G2 portion of cell cycle.

Vincristine (Oncovin, Vincasar PFS)

Inhibits cellular mitosis by inhibiting intracellular tubulin function, binding to microtubule and spindle proteins in S phase.

Doxorubicin (Adriamycin)

Cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius. Blocks DNA and RNA synthesis by inserting between adjacent base pairs and binding to sugar-phosphate backbone of DNA, inhibiting DNA polymerase. Binds to nucleic acids presumably by specific intercalation of anthracycline nucleus with DNA double helix.

Also powerful iron chelator. Iron-doxorubicin complex induces production of free radicals that can destroy DNA and cancer cells. Can also cause breakage of DNA strands by means of effects on topoisomerase II. Maximum toxicity occurs during S phase of cell cycle.

Multiphasic disappearance curve, with half-lives as long as 30 h. Does not cross blood-brain barrier but taken up rapidly by heart, lungs, liver, kidney, and spleen. Mutagenic and carcinogenic.

Cyclophosphamide (Cytoxan)

Chemically related to nitrogen mustards. Activated in liver to active metabolite 4-hydroxycyclophosphamide, which alkylates target sites in susceptible cells in all-or-none reaction. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

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Uroprotective antidote

Class Summary

Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide and cyclophosphamide. In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, which is the ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity.

Mesna (Mesnex)

Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity.

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