Description:

Thiotepa is a cell cycle-phase nonspecific antineoplastic agent used in the treatment of breast, ovarian, and bladder carcinomas. It commonly is used as a bladder irrigation to treat papillary bladder cancer, and, in very high doses, as part of a preparative regimen prior to an autologous bone marrow transplant and peripheral stem cell transplantation. Thiotepa has been used as an intrathecal agent to treat carcinomatous meningitis�, however the reformulated preparation of thiotepa is now hypotonic and undiluted intrathecal use with this formulation has not been studied (dilution with normal saline may still be feasible). Thiotepa is a member of the alkylating-agent class of antineoplastic drugs, which includes busulfan, cyclophosphamide, ifosfamide, mechlorethamine, chlorambucil, and melphalan. Thiotepa was introduced in the 1950's, but during the 1980's renewed interest produced improved pharmacokinetic and pharmacologic data, reflecting technical and clinical advances. This resulted in the release of a new lyophilized thiotepa powder with a longer shelf life, in 1995. Thiotepa was originally approved by the FDA in 1959. Mechanism of Action: Thiotepa is a polyfunctional alkylating agent and exerts its chemotherapeutic effects by alkylating DNA, causing interstrand crosslinking, inhibiting protein synthesis, and causing cell death. Thiotepa, the main metabolite N,N�,N��,-triethylenephosphoramide (TEPA), and possibly other minor metabolites, may all contribute to the cytotoxicity. The lipophilic nature of thiotepa allows it to diffuse into cells. Alkylation of DNA is thought to be caused by aziridine, produced intracellularly by hydrolysis from thiotepa which has three aziridine groups. However, loss of one aziridine group may allow the remaining moiety, N, N�-diethylenethiophosphoramide to form interstrand cross-links since a related cytotoxic metabolite of ifosfamide is known to form cross-links. Which moiety is actually responsible for the cross-linking has not been determined. Over a period of time it has been established that thiotepa and TEPA release substantial amounts of aziridine. There are differences in cytotoxicity between thiotepa and TEPA, probably reflecting their different interactions with DNA. Thiotepa's cytotoxic effects appear to be catalyzed by cytochrome P450 enzymes. The same enzymes may not affect TEPA. If thiotepa is used in the bladder it is more active in acidic conditions and less active as pH increases. TEPA is not thought to reduce interstrand cross-linking, but does produce alkali-resistant DNA lesions. TEPA hydrolyzes more rapidly to arizidine than does thiotepa, and DNA lesions may be caused by the arizidine. Other metabolites of thiotepa remain unidentified, but experimental evidence suggest that these may make a contribution to overall cytoxicity. Action may be intracellular or at the cell surface. Also, combination therapy with cisplatin may inhibit DNA repair. Finally, thiotepa exhibits pseudocholinesterase activity which may be clinically significant at therapeutic doses (see Drug Interactions). Pharmacokinetics: Thiotepa is administered by IV injection, or by intravesical or intracavitary instillation. Thiotepa is unstable in acid conditions and absorption is poor and variable following oral administration. Other routes of administration produce rapid absorption. Immediate peak plasma concentrations of thiotepa are observed after rapid IV administration, TEPA becoming detectable within minutes. TEPA concentrations increase gradually, exceeding those of the parent drug within hours. After IM administration, absorption is complete within 1 hour; plasma concentrations of thiotepa are about the same as those seen after a rapid IV dose. Systemic absorption from intravesical administration is variable, ranging from 10�100% after 1�2 hours retention. Plasma concentrations of thiotepa and TEPA are detectable within 15 minutes of intravesical administration. Thiotepa concentrations peak immediately after IV administration and decline rapidly, whereas TEPA concentrations exceed those of thiotepa and remain more or less constant for 6 hours. After intraperitoneal administration, lipophilicity and low molecular weight allow rapid diffusion across the peritoneum and systemic absorption. TEPA concentrations are low in the peritoneum and probably result from intraperitoneal diffusion after systemic formation. Distribution of thiotepa after IV administration is rapid and extensive. Thiotepa becomes detectable in most tissues (heart, lung, liver, kidney, skin and skeletal muscle), although liver concentrations are about 10% those of other tissues, probably bacause of hepatic metabolism. Thiotepa distributes into the CSF, with equivalent concentrations in plasma, lumbar, and ventricular CSF. There is better distribution of thiotepa in CSF following IV use than with intrathecal administration. Within 3�5 hours of parent drug IV administration, TEPA concentrations in the CSF approximate those of plasma. Thiotepa does not preferentially concentrate in neoplastic tissue. Distribution of thiotepa or its metabolites into breast milk has not been ascertained. Distribution at the cellular level is by passive diffusion. Protein binding, mainly to albumin, is variable depending on the given dose. TEPA is more extensively bound than thiotepa. Metabolism of thiotepa is by oxidative desulfuration to TEPA, thought to take place in the liver via the cytochrome P450 PB-4, IIC1, IIC6 enzyme system. Observed DNA interactions suggest other as yet unidentified metabolites. As thiotepa is oxidized to TEPA, TEPA appears to suicidally inactivate P450 PB-4, and may affect other microsomal enzymes. Other reactive metabolites may be formed by the S9 fraction of liver enzymes from thiotepa, but not from TEPA. Hydrolysis of thiotepa and TEPA releases aziridine, some of which is hydrolyzed to ethanolamine. Elimination is mainly a result of metabolic processes; urinary elimination accounts for little of the parent drug or its metabolites. Thiotepa has an initial plasma half-life of 6�12 minutes and an elimination half-life of 1.2�2.9 hours. Plasma elimination half-life of TEPA is 10�21 hours. It would appear that metabolic saturation or TEPA occurs, although it is not certain that clearance of thiotepa is dose-dependent. Data is limited regarding elimination in hepatically or renally impaired patients, but hepatic impairment may decrease clearance. The urinary clearance of thiotepa and TEPA is complete within 6�8 hours and 8�12 hours, respectively. Alkylating activity, however, remains and suggests unidentified metabolites.

Indications...Dosage For the treatment of breast cancer or ovarian cancer: Intravenous dosage: Adults: 0.2 mg/kg IV once daily for 4 days, repeated every 2�4 weeks; or 0.3�0.4 mg/kg IV once every 1�4 weeks; or 15�35 mg/m2 IV once every 3�4 weeks. For the treatment of bladder cancer such as superficial papillary bladder tumors: Intravesical dosage: Adults: 60 mg of a 1 mg/ml solution instilled into the bladder once weekly for 4 weeks. The solution should be retained in the bladder for 2 hours. If the patient cannot retain 60 ml for this period, the dose may be given in a volume of 30 ml. If necessary the course may be repeated. For the treatment of carcinomatous meningitis�: Intrathecal dosage�: Adults: 10�15 mg intrathecally given 3�4 times weekly until the cerebrospinal fluid is clear of disease. The reconstituted solution should be diluted in normal saline prior to instillation into the cerebrospinal fluid to create a solution nearly isotonic or nearly isotonic. The final volume to be instilled is usually proportional to the amount of cerebrospinal fluid removed. For the treatment of Hodgkin's disease: Intravenous dosage: Adults: As a single agent, thiotepa may be given in a dose of 0.3 to 0.4 mg/kg IV every 1 to 4 weeks. For the treatment of non-Hodgkin's lymphoma (NHL): Intravenous dosage: Adults: Doses of 20� 40 mg/m2 IV every 3�4 weeks in combination with other agents or 0.3 to 0.4 mg/kg IV every 1 to 4 weeks as a single agent. Thiotepa 20 mg/m2 IV once every 21 days with mitoxantrone, prednisone, and vincristine has been used in patients over age 65.[1319] In older patients with central nervous system lymphoma, thiotepa has been given in a dose of 40 mg/m2 IV every 4 weeks along with procarbazine, and vincristine, and IV and intrathecal methotrexate.[1347] For bone marrow ablation� therapy, in combination with other cytotoxic agents, prior to autologus or allogeneic bone marrow transplantation: Intravenous dosage: Adults: Regimens have included thiotepa 180 to 1125 mg/m2 IV. CNS toxicity may begin at a doses of 900 mg/m2 IV. Children: Regimens have included thiotepa 300 mg/m2 IV over 3 hours every 24 hours for 3 doses. Maximum tolerated dose over 3 days ranges from 900�1125 mg/m2. CNS toxicity may begin at a doses of 900 mg/m2. For the treatment of malignant pleural effusion, pericardial effusion, or peritoneal effusion: Intracavitary dosage: Adults: 0.6�0.8 mg/kg instilled via the drainage tube at intervals at least one week apart. For the treatment of soft-tissue sarcoma�: Intravenous dosage: Children: Regimens have included thiotepa 25�65 mg/m2 IV as a single dose every 3�4 weeks in combination with other chemotherapy agents. Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. �non-FDA-approved indication

Administration CAUTION: Observe and exercise usual cautions for handling, preparing, and administering solutions of cytotoxic drugs. Parenteral Administration �Thiotepa is administered intravenously as a bolus injection or infusion or intravesically, intrapertioneally, or intracavitary. Reconstitution: �Thioplex� (lyophilized thiotepa): Add 1.5 ml of sterile water for injection to 15 mg of thiotepa to make a solution containing 10 mg/ml of thiotepa. This solution is hypotonic. �Filter reconstituted solution through a 0.22-micron filter. Solutions that are not clear after filtering should be discarded. �Reconstituted solutions are stable for 8 hours under refrigeration. �To make an isotonic solution, reconstitute as above and dilute with NS to make an injection solution containing 1 mg/ml of thiotepa. Use immediately after dilution. Intravenous injection: �Use the reconstituted solution (10 mg/ml). No further dilution is necessary. �Inject appropriate dose of the reconstituted injection solution (10 mg/ml) into the tubing of a free flowing IV solution. Administer over 1�3 minutes. Intracavitary instillation: �Use the isotonic reconstituted solution (1 mg/ml). No further dilution is necessary. �Instill via the tube used to drain the effusion. Intravesical instillation: �Patients should be dehydrated for 8�12 hours prior to treatment. �Mix 60 mg of thiotepa in 30�60 ml of NS. Use 30 ml for patients unable to hold 60 ml. �Instill solution into the bladder via catheter. Reposition the patient every 15 minutes for maximum tumor contact. The solution should be retained for 2 hours.

Contraindications Thiotepa is contraindicated in patients with severe bone marrow suppression. Thiotepa should be used cautiously in patients with who have had previous myelosuppressive therapy such as chemotherapy or radiation therapy. Since these adverse effects can be fatal, the patient must be warned to immediately report any signs such as fever, sore throat, or abnormal bleeding. Patients with preexisting marrow suppression, including neutropenia and/or thrombocytopenia, should be allowed to recover their counts prior to thiotepa administration. Hematological status (hematocrit, hemoglobin concentration, leukocyte and platelet counts) should be monitored closely during thiotepa therapy (weekly) and for at least 3 weeks after discontinuance of therapy. Thiotepa dosages should be reduced or discontinued if leukocyte counts fall below 3000/mm3 or if platelet counts fall below 150,000/mm3. Patients with an active infection should be treated prior to receiving thiotepa. Patients with a history of varicella zoster, other herpes infections (e.g., herpes simplex), or other viral infections are at risk for reactivation of the infection when treated with chemotherapy. Myelosuppressive effects of thiotepa can increase the risk of infection or bleeding; therefore, dental work should be delayed until blood counts have returned to normal. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks. Intramuscular injections should not be administered to patients with platelet count < 50,000/mm3 who are receiving thiotepa. IM injections may cause bleeding, bruising, or hematomas due to thiotepa-induced thrombocytopenia. Tumor lysis syndrome may occur due to treatment with thiotepa; appropriate measures (e.g., aggressive hydration and allopurinol) must be taken to prevent hyperuricemia in patients with large chemosensitive tumors. The resulting hyperuricemia could aggravate gout or urate nephrolithiasis. Preexisting hepatic disease, renal impairment, or renal failure can cause acccumulation of the drug worsening thiotepa's toxicity. Dosing may need to be reduced in either clinical situation. Thiotepa is a FDA pregnancy category D drug. Many teratogenic effects have been tributed to thiotepa. Administration to pregnant women is contraindicated unless the potential benefit of therapy outweighs the teratogenic risk to the fetus. If therapy is essential in patients of childbearing potential, they should be advised to use effective methods of contraception. Although it is unknown whether thiotepa and its metabolites are excreted into breast milk, its use during breast-feeding is generally not recommended due to its carcinogenic and mutagenic effects. Safe and effective use of thiotepa in children has not been established. Use care to avoid accidental exposure to thiotepa during preparation, handling, and administration. The use of protective gowns, gloves and goggles is recommended. Following skin or ocular exposure, skin and eyes should be thoroughly rinsed. Vaccination during chemotherapy or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

Interactions Thiotepa can decrease pseudocholinesterase activity. At least one patient who had received thiotepa experienced prolonged apnea after the administration of succinylcholine prior to surgery. Succinylcholine should be administered cautiously to patients receiving thiotepa. Also, thiotepa may prolong muscular paralysis and respiratory depression in patients receiving mivacurium as this particular non-depolarizing neuromuscular blocker is also metabolized by cholinesterase. Concurrent use of thiotepa with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects. The immune response of the immunocompromised patient to vaccines is decreased and higher doses or more frequent boosters may be required. Despite these dose increases, the immune response may still be suboptimal. Live virus vaccines are contraindicated during therapy with antineoplastic agents due to the potentiation of virus replication, adverse reactions to the virus, and the immunocompromised status of the patient. Those undergoing antineoplastic therapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Estimates for postponing vaccination vary from 3 months to 1 year following discontinuation of treatment depending of the type of antineoplastic agent used and the disease state of the patient. Due to the thrombocytopenic effects of thiotepa, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. Large doses of salicylates (>= 6 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Because antineoplastic agents exert their toxic effects against rapidly growing cells, such as hematopoietic progenitor cells, sargramostim, GM-CSF, and filgrastim, G-CSF, are contraindicated for use in patients within 24 hours of treatment with antineoplastic agents. Due to sudden lysis of chemosensitive tumor cells by thiotepa, serum uric acid levels may increase rapidly. This may compromise the efficacy of the uricosuric agents probenecid and sulfinpyrazone. Dosage adjustments of antigout agents may be necessary to control hyperuricemia. To prevent uric acid nephropathy in thiotepa-induced hyperuricemia, allopurinol is preferred over uricosuric agents. Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; no significant change was seen with digoxin capsules, and the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. Digoxin capsules (Lanoxicaps�) may be utilized to avoid this interaction in patients receiving antineoplastic agents and digoxin tablets. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.

Adverse Reactions Hematologic toxicity is the major adverse effect associated with thiotepa therapy and is usually dose-related and cumulative. Manifestations of hematologic toxicity include thrombocytopenia, leukopenia, neutropenia, anemia, and sometimes pancytopenia, which can be fatal. Thrombocytopenia can be prolonged. Hematological status (hematocrit, hemoglobin concentration, leukocyte and platelet counts) should be monitored closely during thiopeta therapy (weekly) and for at least 3 weeks after discontinuance of therapy. Thiotepa dosages should be reduced or discontinued if leukocyte counts fall below 3000/mm3 or if platelet counts fall below 150,000/mm3. Bone marrow function should be allowed to recover fully between treatments. Severe hematological toxicity may be treated with supportive therapy, antibiotics for infections, and blood transfusions. Thiotepa-induced cellular destruction releases large amounts of uric acid, resulting in hyperuricemia. Uric acid nephropathy, acute renal failure, and nephrolithiasis also can occur. These problems are more severe when a large tumor mass is treated. Aggressive alkalinization of the urine and use of allopurinol can prevent urate nephropathy. Febrile reaction and discharge from a subcutaneous lesion may result from breakdown of a tumor mass. Hypersensitivity reactions, manifested as bronchospasm or urticaria, have been noted with thiotepa therapy. Laryngeal edema, wheezing, and anaphylactic shock may occur. Intravesical thiotepa therapy may cause local toxicity. Irritative symptoms such as dysuria, urinary urgency and related bladder symptoms are common. Urinary retention may occur. Rare occurrences of chemical or hemorrhagic cystitis may follow intravesical, but not intravenous thiotepa therapy. Adverse intravesical effects rarely lead to discontinuation of therapy. Injection site reaction, specifically pain or contact dermatitis, has been reported with intravenous thiotepa administration. Instillation of thiotepa may also be associated with pain. Thiotepa can cause dermatitis and alopecia. There have been reports of skin depigmentation following topical administration. Instances of skin hyperpigmentation have been reported following high IV doses of thiotepa. In some cases this was thought to be a result of local skin concentration, possibly due to occlusive materials. Pigmentation became evident within 1�4 days, darkened over a week, then faded over the next month. Gastrointestinal effects are infrequent with recommended doses of thiotepa. They include abdominal pain, anorexia, and nausea/vomiting. At doses >= 700�800 mg/m2 esophagitis, stomatitis, and enterocolitis may occur. Adverse effects of thiotepa on the CNS are dose limiting. At recommended doses dizziness, headache, and blurred vision may occur. There have been reports of amenorrhea with thiotepa therapy. Fatigue and weakness are generalized reactions. Secondary malignancy, specificallyacute nonlymphocytic leukemia, has been observed after intravenous thiotepa use.

Thiotepa Thioplex�

1319. Lichtman SM. Lymphoma in the older patient. Sem Oncol 1995;22:25�8.

1347. Freilich RJ, Delattre JY, Monjour A, et al. Chemotherapy without radiation therapy as initial treatment for primary CNS lymphoma in older patients. Neurology 1996;46:435�9.